EP1383533A2 - Proteine und diese kodierende nukleinsäuren - Google Patents

Proteine und diese kodierende nukleinsäuren

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Publication number
EP1383533A2
EP1383533A2 EP02723842A EP02723842A EP1383533A2 EP 1383533 A2 EP1383533 A2 EP 1383533A2 EP 02723842 A EP02723842 A EP 02723842A EP 02723842 A EP02723842 A EP 02723842A EP 1383533 A2 EP1383533 A2 EP 1383533A2
Authority
EP
European Patent Office
Prior art keywords
polypeptide
amino acid
protein
nucleic acid
seq
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02723842A
Other languages
English (en)
French (fr)
Other versions
EP1383533A4 (de
Inventor
Carol E. A. Pena
Xiaojia Guo
Richard A. Shimkets
Muralidhara Padigaru
Ramesh Kekuda
Kimberly A. Spytek
Fuad Mehraban
James N. Topper
Uriel M. Malyankar
Scott Wasserman
R. Shlomit Edinger
Glennda Smithson
Erik Gunther
Laszlo Komuves
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Millennium Pharmaceuticals Inc
CuraGen Corp
Original Assignee
Millennium Pharmaceuticals Inc
CuraGen Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Millennium Pharmaceuticals Inc, CuraGen Corp filed Critical Millennium Pharmaceuticals Inc
Publication of EP1383533A2 publication Critical patent/EP1383533A2/de
Publication of EP1383533A4 publication Critical patent/EP1383533A4/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals

Definitions

  • the invention relates to polynucleotides and the polypeptides encoded by such polynucleotides, as well as vectors, host cells, antibodies and recombinant methods for producing the polypeptides and polynucleotides, and methods for using the same.
  • the invention generally relates to nucleic acids and polypeptides encoded therefrom. More specifically, the invention relates to nucleic acids encoding cytoplasmic, nuclear, membrane bound, and secreted polypeptides, as well as vectors, host cells, antibodies, and recombinant methods for producing these nucleic acids and polypeptides.
  • Heart disease is the primary cause of death in most western societies. Death from heart disease is often induced by platelet-dependent ischemic syndromes which are initiated by atherosclerosis and arteriosclerosis and include, but are not limited to, acute myocardial infarction, clironic unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis and/or thrombosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and chronic cardiovascular devices (e.g., in-dwelling catheters or shunts "extracorporeal circulating devices").
  • platelet-dependent ischemic syndromes which are initiated by atherosclerosis and arteriosclerosis and include, but are not limited to, acute myocardial infarction, clironic unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsi
  • Thrombospondin-l-like proteins associate with the extracellular matrix and inhibits angiogenesis in vivo.
  • Thrombospondin-like proteins block capillary-like tube formation and endothelial cell proliferation.
  • the antiangiogenic activity is mediated by a region that contains 3 type 1 (properdin or thrombospondin) repeats.
  • Selectin-like proteins such as P-selectin, also called GMP-140, CD62, or selectin P, is a 140-kD adhesion molecule, expressed at the surface of activated cells, that mediates the interaction of activated endothelial cells or platelets with leukocytes.
  • the protein In endothelial cells, the protein is localized to the membranes of Weibel-Palade bodies, the intracellular storage granules for von Willebrand factor.
  • Many disease states are characterized by uncontrolled cell proliferation. These diseases involve a variety of cell types and include disorders such as cancer, psoriasis, pulmonary fibrosis, glomeralonepl ritis, atherosclerosis and restenosis following angioplasty.
  • Vital cellular functions such as cell proliferation and signal transduction are regulated in part by the balance between the activities of protein-tyrosine kinases (PTK) and protein-tyrosine phosphatases (PTPase). Oncogenesis can result from an imbalance.
  • PTK protein-tyrosine kinases
  • PPPase protein-tyrosine phosphatases
  • the invention is based in part upon the discovery of nucleic acid sequences encoding novel polypeptides.
  • novel nucleic acids and polypeptides are referred to herein as NONX, or ⁇ ON1, ⁇ ON2, ⁇ ON3, ⁇ ON4, ⁇ ON5, ⁇ ON6, ⁇ ON7, ⁇ ON8, ⁇ ON9, ⁇ ONlOa, ⁇ ONlOb, ⁇ ON11, ⁇ ON12, ⁇ ON13, ⁇ ON14, ⁇ ON15, and ⁇ ON16 nucleic acids and polypeptides.
  • nucleic acids and polypeptides as well as variants, derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as " ⁇ ONX” nucleic acid or polypeptide sequences.
  • the invention provides an isolated ⁇ ONX nucleic acid molecule encoding a ⁇ ONX polypeptide that includes a nucleic acid sequence that has identity to the nucleic acids disclosed in SEQ ID ⁇ OS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, and 33.
  • the NOVX nucleic acid molecule will hybridize under stringent conditions to a nucleic acid sequence complementary to a nucleic acid molecule that includes a protein-coding sequence of a NONX nucleic acid sequence.
  • the invention also includes an isolated nucleic acid that encodes a ⁇ ONX polypeptide, or a fragment, homolog, analog or derivative thereof.
  • the nucleic acid can encode a polypeptide at least 80% identical to a polypeptide comprising the amino acid sequences of SEQ ID ⁇ OS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, and 34.
  • the nucleic acid can be, for example, a genomic DNA fragment or a cDNA molecule that includes the nucleic acid sequence of any of SEQ ID NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, and 33.
  • an oligonucleotide e.g., an oligonucleotide which includes at least 6 contiguous nucleotides of a NONX nucleic acid (e.g., SEQ ID ⁇ OS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, and 33) or a complement of said oligonucleotide.
  • a NONX nucleic acid e.g., SEQ ID ⁇ OS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, and 33
  • NONX polypeptides SEQ ID ⁇ OS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, and 34.
  • the NONX polypeptides include an amino acid sequence that is substantially identical to the amino acid sequence of a human ⁇ ONX polypeptide.
  • the invention also features antibodies that immunoselectively bind to ⁇ ONX polypeptides, or fragments, homologs, analogs or derivatives thereof.
  • the invention includes pharmaceutical compositions that include therapeutically- or prophylactically-effective amounts of a therapeutic and a pharmaceutically- acceptable carrier.
  • the therapeutic can be, e.g., a ⁇ ONX nucleic acid, a ⁇ ONX polypeptide, or an antibody specific for a ⁇ OVX polypeptide.
  • the invention includes, in one or more containers, a therapeutically- or prophylactically-effective amount of this pharmaceutical composition.
  • the invention includes a method of producing a polypeptide by culturing a cell that includes a ⁇ ONX nucleic acid, under conditions allowing for expression of the ⁇ ONX polypeptide encoded by the D ⁇ A. If desired, the ⁇ ONX polypeptide can then be recovered.
  • the invention includes a method of detecting the presence of a
  • ⁇ ONX polypeptide in a sample in a sample.
  • a sample is contacted with a compound that selectively binds to the polypeptide under conditions allowing for formation of a complex between the polypeptide and the compound.
  • the complex is detected, if present, thereby identifying the ⁇ ONX polypeptide within the sample.
  • the invention also includes methods to identify specific cell or tissue types based on their expression of a ⁇ ONX.
  • Also included in the invention is a method of detecting the presence of a ⁇ ONX nucleic acid molecule in a sample by contacting the sample with a ⁇ ONX nucleic acid probe or primer, and detecting whether the nucleic acid probe or primer bound to a ⁇ ONX nucleic acid molecule in the sample.
  • the invention provides a method for modulating the activity of a ⁇ ONX polypeptide by contacting a cell sample that includes the ⁇ ONX polypeptide with a compound that binds to the ⁇ ONX polypeptide in an amount sufficient to modulate the activity of said polypeptide.
  • the compound can be, e.g., a small molecule, such as a nucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, lipid or other organic (carbon containing) or inorganic molecule, as further described herein.
  • a therapeutic in the manufacture of a medicament for treating or preventing disorders or syndromes including, e.g., those described for the individual NONX nucleotides and polypeptides herein, and/or other pathologies and disorders of the like.
  • the therapeutic can be, e.g., a ⁇ ONX nucleic acid, a ⁇ ONX polypeptide, or a ⁇ ONX- specific antibody, or biologically-active derivatives or fragments thereof.
  • the compositions of the present invention will have efficacy for treatment of patients suffering from the diseases and disorders disclosed below and/or other pathologies and disorders of the like.
  • the polypeptides can be used as immunogens to produce antibodies specific for the invention, and as vaccines. They can also be used to screen for potential agonist and antagonist compounds.
  • a cD ⁇ A encoding ⁇ ONX may be useful in gene therapy, and ⁇ ONX may be useful when administered to a subject in need thereof.
  • the compositions of the present invention will have efficacy for treatment of patients suffering from the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the invention further includes a method for screening for a modulator of disorders or syndromes including, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the method includes contacting a test compound with a ⁇ ONX polypeptide and determining if the test compound binds to said ⁇ ONX polypeptide. Binding of the test compound to the ⁇ ONX polypeptide indicates the test compound is a modulator of activity, or of latency or predisposition to the aforementioned disorders or syndromes.
  • Also within the scope of the invention is a method for screening for a modulator of activity, or of latency or predisposition to an disorders or syndromes including, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders of the like by administering a test compound to a test animal at increased risk for the aforementioned disorders or syndromes.
  • the test animal expresses a recombinant polypeptide encoded by a ⁇ ONX nucleic acid. Expression or activity of ⁇ ONX polypeptide is then measured in the test animal, as is expression or activity of the protein in a control animal which recombinantly- expresses ⁇ ONX polypeptide and is not at increased risk for the disorder or syndrome.
  • the expression of NOVX polypeptide in both the test animal and the control animal is compared. A change in the activity of NONX polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of latency of the disorder or syndrome.
  • the mvention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a ⁇ ONX polypeptide, a ⁇ ONX nucleic acid, or both, in a subject (e.g., a human subject).
  • the method includes measuring the amount of the NONX polypeptide in a test sample from the subject and comparing the amount of the polypeptide in the test sample to the amount of the ⁇ ONX polypeptide present in a control sample.
  • An alteration in the level of the ⁇ ONX polypeptide in the test sample as compared to the control sample indicates the presence of or predisposition to a disease in the subject.
  • the predisposition includes, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the expression levels of the new polypeptides of the invention can be used in a method to screen for various cancers as well as to determine the stage of cancers.
  • the invention includes a method of treating or preventing a pathological condition associated with a disorder in a mammal by administering to the subject a ⁇ ONX polypeptide, a ⁇ ONX nucleic acid, or a ⁇ ONX-specific antibody to a subject (e.g., a human subject), in an amount sufficient to alleviate or prevent the pathological condition.
  • the disorder includes, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the invention can be used in a method to identity the cellular receptors and downstream effectors of the invention by any one of a number of techniques commonly employed in the art.
  • the present invention provides novel nucleotides and polypeptides encoded thereby.
  • nucleic acid sequences and their polypeptides.
  • the sequences are collectively referred to as “NONX nucleic acids” or “ ⁇ ONX polynucleotides” and the corresponding encoded polypeptides are referred to as “ ⁇ ONX polypeptides” or “NONX proteins.” Unless indicated otherwise, " ⁇ ONX” is meant to refer to any of the novel sequences disclosed herein. Table A provides a summary of the ⁇ ONX nucleic acids and their encoded polypeptides.
  • NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts.
  • the various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NONX polypeptides belong.
  • the ⁇ ONX genes and their corresponding encoded proteins are useful for preventing, treating or ameliorating medical conditions, e.g., by protein or gene therapy.
  • Pathological conditions can be diagnosed by determining the amount of the new protein in a sample or by determining the presence of mutations in the new genes. Specific uses are described for each of the sixteen genes, based on the tissues in which they are most highly expressed. Uses include developing products for the diagnosis or treatment of a variety of diseases and disorders.
  • the ⁇ ONX nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance ⁇ ONX activity or function.
  • the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cell growth, cell metabolism, cell differentiation, cell proliferation, and/or cell signaling.
  • NONX or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of ⁇ ONX.
  • disorders include, but are not limited to, cancers such as adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus; neurological disorders such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyr
  • the ⁇ ONX nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed. These also include potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), (v) an agent promoting tissue regeneration in vitro and in vivo, and (vi) a biological defense weapon. Additional utilities for the ⁇ ONX nucleic acids and polypeptides according to the invention are disclosed herein.
  • ⁇ OV1 A ⁇ OV1 polypeptide has been identified as aPaladin-like protein (also referred to as CG93221-01).
  • the disclosed novel ⁇ OV1 nucleic acid (SEQ ID ⁇ O:l) of2600 nucleotides is shown in Table 1A.
  • the novel NOV1 nucleic acid sequences maps to the chromosome 10.
  • An ORF begins with an ATG initiation codon at nucleotides 15-17 and ends with a TAG codon at nucleotides 2583-2585.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 1A, and the start and stop codons are in bold letters.
  • a variant sequence can include a single nucleotide polymorphism (SNP).
  • SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA.
  • the NOV1 protein (SEQ ID NO:2) encoded by SEQ ID NO.T is 856 amino acid residues in length and is presented using the one-letter amino acid code in Table IB. Psort analysis predicts the NO VI protein of the invention to be localized in the cytoplasm with a certainty of 0.4500.
  • the "E- value” or “Expect” value is a numeric indication of the probability that the aligned sequences could have achieved their similarity to the BLAST query sequence by chance alone, within the database that was searched.
  • the Expect value (E) is a parameter that describes the number of hits one can "expect” to see just by chance when searching a database of a particular size. It decreases exponentially with the Score (S) that is assigned to a match between two sequences. Essentially, the E value describes the random background noise that exists for matches between sequences.
  • the Expect value is used to create a significance threshold for reporting results.
  • the default value used for blasting is typically set to 0.0001, with the filter to remove low complexity sequence turned off.
  • the Expect value is also used instead of the P value (probability) to report the significance of matches.
  • P value probability
  • an E value of one assigned to a hit can be interpreted as meaning that in a database of the current size one might expect to see one match with a similar score simply by chance.
  • An E value of zero means that one would not expect to see any matches with a similar score simply by chance. See, e.g., http://www.ncbi.nlm.nih.gov/Education/BLASTinfo/.
  • nucleic acid sequence of this invention has 2063 of 2508 bases (82%) identical to a gb:GENBANK-ID:MMPAL
  • the full amino acid sequence of the protein of the invention was found to have 695 of 859 amino acid residues (80%) identical to, and 754 of 859 amino acid residues (87%) similar to, the 859 amino acid residue ptnr:SPTREMBL-ACC:P70261 protein ⁇ xom Mus musculus (PALADIN GENE).
  • NOV1 also has homology to the proteins shown in the BLASTP data in Table ID. Table ID. BLAST results for NOVl
  • Table IE A multiple sequence alignment is given in Table IE, with the NOVl protein being shown on line 1 in Table IE in a ClustalW analysis, and comparing the NOVl protein with the related protein sequences shown in Table ID.
  • This BLASTP data is displayed graphically in the ClustalW in Table IE.
  • the NOVl Clustal W alignment shown in Table IE was modified to begin at amino residue 1050.
  • the data in Table IE includes all of the regions overlapping with the NOVl protein sequences.
  • NOVl has, for example, multiple Paladin gene signature sequences and homology to other members of the Paladin-like Protein Family.
  • NOV 1 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOVl nucleic acids and polypeptides can be used to identify proteins that are members of the Paladin like family of proteins.
  • the NOVl nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVl activity or function.
  • nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation, cellular metabolism and signal transduction.
  • These molecules can be used to treat, e.g., cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD),atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia, diabetes, Von Hippel-Lindau (NHL) syndrome, pancreatitis, obesity, hyperthyroidism and hypothyroidism, hypercalceimia, ulcers, cirrhosis, transplantation, inflammatory bowel disease, divertic
  • NOVl nucleic acids and polypeptides according to the invention are useful, inter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOVl nucleic acids and their encoded polypeptides include structural motifs that are characteristic of proteins belonging to the Paladin-like protein family.
  • Paladin proteins are a family of protein-tyrosine phosphatases.
  • the protein phosphatases can be divided into 2 large families: the serine/threonine phosphatases, which are metalloproteins, and the protein-tyrosine phosphatases, which proceed via a thiol-phosphate enzyme intermediate.
  • the protein-tyrosine phosphatase family includes the VHl-like dual- specificity phosphatases. These phosphatases dephosphorylate phosphotyrosine- as well as phosphoserine- and phosphothreonine-containing substrates. Members of the dual-specificity phosphatase protein family inactivate mitogen-activated protein (MAP) kinase through dephosphorylation of critical threonine and tyrosine residues. Members of the MAP kinase family play a pivotal role in cellular signal transduction. Using a subtractive screen of mouse gastrulation, Pearce et al. (1996) identified a novel mouse gene, paladin, with similarity to the dual specificity protein phosphatase family.
  • MAP mitogen-activated protein
  • the NOVl nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of cardiac and endocrine physiology.
  • the NOVl nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat muscle and nervous system disorders, e.g., cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD),atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia, diabetes, Von Hippel-Lindau (VHL) syndrome, pancreatitis, obesity, hyperthyroidism and hypothyroidism, hypercalceimia, ulcer
  • NOVl nucleic acids and polypeptides are useful for detecting specific cell types. For example, expression analysis has demonstrated that a NOVl nucleic acid is expressed in brown adipose, heart, aorta, vein, umbilical vein, adrenal gland/suprarenal gland, pancreas, thyroid, salivary glands, parotid salivary glands, stomach, liver, gall bladder, small intestine, colon, bone marrow, lymphoid tissue, spleen, lymph node, tonsils, thymus, cartilage, muscle, brain, thalamus, hypothalamus, pituitary gland, amygdala, substantia nigra, hippocampus, spinal chord, cervix, mammary gland/breast, ovary, placenta, uterus, vulva, prostate, testis, lung, lung pleura, kidney, retina, dermis. Additional utilities for NOVl nucleic acids and polypeptides according to
  • a NOV2 polypeptide has been identified as a Plasma Membrane Ring Finger-like protein (also referred to as CG93210-01).
  • the disclosed novel NOV2 nucleic acid (SEQ ID NO:3) of 1205 nucleotides is shown in Table 2A.
  • the novel NOV2 nucleic acid sequences maps to the chromosome 22.
  • An ORF begins with an ATG initiation codon at nucleotides 17-19 and ends with a ATT codon at nucleotides 1149-1151.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 2A, and the start and stop codons are in bold letters.
  • the NOV2 protein (SEQ ID NO:4) encoded by SEQ ID NO:3 is 378 amino acid residues in length and is presented using the one-letter amino acid code in Table 2B. Psort analysis predicts the NOV2 protein of the invention to be localized at the plasma membrane with a certainty of 0.6400.
  • nucleic acid sequence of this invention has 287 of 489 bases (58%) identical to a gb:GENBANK-ID:SSI132828]acc:AJ132828.1 mRNA from Spermatozopsis similis (mRNA for p210 protein, partial).
  • the full amino acid sequence of the protein of the invention was found to have 341 of 379 amino acid residues (89%>) identical to, and 355 of 379 amino acid residues (93%) similar to, the 379 amino acid residue ptnr:SPTREMBL-ACC:Q9DCWl protein from Mus musculus (0610009 J22RTK PROTEIN).
  • NOV2 also has homology to the proteins shown in the BLASTP data in Table 2D.
  • NOV2 has, for example, a Ring Finger signature sequence and homology to other members of the Plasma Membrane Ring Finger-like Protein Family.
  • NOV 2 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOV2 nucleic acids and polypeptides can be used to identify proteins that are members of the Plasma Membrane Ring Finger-like Protein Family.
  • the NOV2 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVl activity or function.
  • nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation, cellular metabolism and signal transduction.
  • small molecules that modulate or inhibit, e.g., cellular activation, cellular metabolism and signal transduction.
  • These molecules can be used to treat, e.g., anemia, ataxia-telangiectasia, autoimmume disease, immunodeficiencies, diabetes, autoimmune disease, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, hypercalceimia, Lesch-Nyhan syndrome, cancer, trauma, regeneration (in vitro and in vivo), viral/bacterial/parasitic infections, as well as other diseases, disorders and conditions.
  • anemia e.g.,
  • NOV2 nucleic acids and polypeptides according to the invention are useful, inter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOV2 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of proteins belonging to the Plasma Membrane Ring Finger-like Protein Family .
  • the NOV2 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of immune and renal physiology.
  • the NOV2 nucleic acids and polypeptides, antibodies and related compounds according to the mvention may be used to treat muscle and nervous system disorders, e.g., anemia, ataxia-telangiectasia, autoimmume disease, immunodeficiencies, diabetes, autoimmune disease, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, hypercalceimia, Lesch-Nyhan syndrome, cancer, trauma, regeneration (in vitro and in vivo), viral/bacterial/parasitic infections, as well as other diseases, disorders and conditions.
  • muscle and nervous system disorders e.g., anemia, ataxia-
  • the NOV2 nucleic acids and polypeptides are useful for detecting specific cell types.
  • expression analysis has demonstrated that a NOV2 nucleic acid is expressed in peripheral blood, and a pool of various mammalian tissues.
  • Expression information was derived from the tissue sources of the sequences that were included in the derivation of the sequence of CuraGen Aec. No. CG93210-01.
  • the sequence is predicted to be expressed in the following tissues because of the expression pattern of (GENBANK-ID: gb:GENBANK- ID:SSI132828
  • NOV2 nucleic acids and polypeptides according to the invention are disclosed herein.
  • NOV3 A NOV3 polypeptide has been identified as a Thrombospondin type 1 (tsp_l) domain containing protein (also referred to as CG93275-01).
  • the disclosed novel NOV3 nucleic acid (SEQ ID NO:5) of 799 nucleotides is shown in Table 3 A.
  • the novel NOV3 nucleic acid sequences maps to the chromosome 16.
  • An ORF begins with an ATG initiation codon at nucleotides 51-53 and ends with a TGA codon at nucleotides 744-746.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 3 A, and the start and stop codons are in bold letters.
  • the NOV3 protein (SEQ ID NO:6) encoded by SEQ TD NO:5 is 231 amino acid residues in length and is presented using the one-letter amino acid code in Table 3B. Psort analysis predicts the NOV3 protein of the invention to be localized in the cytoplasm with a certainty of 0.4500.
  • nucleic acid sequence of this invention has 392 of 396 bases (98%) identical to an EST AA057409 mRNA from human).
  • the full amino acid sequence of the protein of the invention was found to have 74 of 216 amino acid residues (34%) identical to, and 107 of 216 amino acid residues (49%) similar to, the 237 amino acid residue ptnr:SPTREMBL-ACC:Q9HBS6 protein from Homo sapiens (HYPOTHETICAL 25.7 KDA PROTEIN).
  • NOV3 also has homology to the proteins shown in the BLASTP data in Table 3D.
  • ADAMTS-10 precursor A disintegrin and metalloproteinase with thrombospondin motifs 10) (ADAM-TS 10) (ADAM-TSIO) (Fragment); SEQ ID NO:49
  • the NOV3 Clustal W alignment shown in Table 3E was modified to begin at amino residue 1321.
  • the data in Table 3E includes all of the regions overlapping with the NOV3 protein sequences.
  • the presence of identifiable domains in the protein disclosed herein was determined by searches using algorithms such as PROSITE, Blocks, Pfam, ProDomain, Prints and then determining the Interpro number by crossing the domain match (or numbers) using the Interpro website (http:www.ebi.ac.uk/interpro/).
  • Table 3F lists the domain description from DOMAIN analysis results against NOV3.
  • NOV3 has, for example, tliree tsp_l domain signature sequences and homology to other members of the tsp_l Domain-containing Protein Family.
  • NOV 3 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOV3 nucleic acids and polypeptides can be used to identify proteins that are members of the tsp_l Domain-containing Protein Family.
  • the NOV3 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOV3 activity or function.
  • nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation, cellular metabolism, and signal transduction. These molecules can be used to treat, e.g., Von Hippel-Lindau (VHL) syndrome, diabetes, tuberous sclerosis, fertility, hypogonadism, as well as other diseases, disorders and conditions.
  • VHL Von Hippel-Lindau
  • various NOV3 nucleic acids and polypeptides according to the invention are useful, ter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOV3 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of proteins belonging to the tsp_l Domain-containing Protein Family.
  • Thrombospondin type 1 domain (TSP1, IPR000884) is a repeat found in the thrombospondin protein where it is repeated 3 times.
  • the tsp_l domain is repeated three times in the NOV3 polypeptide.
  • proteins involved in the complement pathway properdin, C6, C7, C8A, C8B, C9 (Patthy,L., J. Mol. Biol.
  • the NOV3 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of urogenital physiology.
  • the NOV3 nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat reproductive and metabolic disorders, e.g., Von Hippel-Lindau (VHL) syndrome, diabetes, tuberous sclerosis, fertility, hypogonadism, as well as other diseases, disorders and conditions.
  • VHL Von Hippel-Lindau
  • the NOV3 nucleic acids and polypeptides are useful for detecting specific cell types.
  • NOV3 nucleic acid is expressed in eye and testis.
  • a NOV4 polypeptide has been identified as a Protocadherin Alpha C2 Short Form-like protein (also referred to as CG93187-01).
  • the disclosed novel NOV4 nucleic acid (SEQ ID NO: 7) of 600 nucleotides is shown in Table 4A.
  • the novel NOV4 nucleic acid sequences maps to the chromosome 11.
  • An ORF begins with an ATG initiation codon at nucleotides 41-43 and ends with a
  • TAG codon at nucleotides 2546-2548.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 4A, and the start and stop codons are in bold letters.
  • the NOV4 protein (SEQ LD NO:8) encoded by SEQ ID NO:7 is 835 amino acid residues in length and is presented using the one-letter amino acid code in Table 4B. Psort analysis predicts the NOV4 protein of the invention to be localized at the plasma membrane with a certainty of 0.7900.
  • nucleic acid sequence of this invention has 273 of 415 bases (65%) identical to a gb:GENBANK-ID:AF061573
  • the full amino acid sequence of the protein of the invention was found to have 273 of 415 amino acid residues (65%) identical to, and 273 of 415 amino acid residues (65%) similar to, the 4076 amino acid residue gb:GENBANK- ID:AF061573jacc:AF061573.2 protein from Homo sapiens (protocadherin (PCDH8) mRNA, complete eds).
  • PCDH8 protocadherin
  • NOV4 also has homology to the proteins shown in the BLASTP data in Table 4D.
  • EGF LAG seven-pass G-type receptor 2 >gi
  • N0V4 492 FE DESSBTLRL ⁇ HAL 542 gi 1 17461472 I 936 TTjVDSYTgEIRVgRSP 987 gi
  • the NOV4 Clustal W alignment shown in Table 4E was modified to begin at amino residue 1201 and end at amino acid residue 2760.
  • the data in Table IE includes all of the regions overlapping with the NOV4 protein sequences.
  • NOV4 has, for example, seven Cadherin domain signature sequences and homology to other members of the Protocadherin Alpha C2 Short Form
  • NOV4 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOV4 nucleic acids and polypeptides can be used to identify proteins that are members of the Protocadherin Alpha C2 Short Form Protein-like Protein Family.
  • the NOV4 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOV4 activity or function.
  • the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation, cellular metabolism, and signal transduction.
  • VHL Von Hippel-Lindau
  • Alzheimer's disease stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, Lesch- Nyhan syndrome, multiple sclerosis, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neurodegeneration, systemic lupus erythematosus, autoimmune disease, asthma, emphysema, scleroderma, allergy, ARDS, fertility, endometriosis, hypogonadism, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, autoimmune disease, allergies, immunodeficiencies, transplantation, graft versus host disease (GVHD), lymphaedema, as well as other diseases, disorders and conditions.
  • VHL Von Hippel-Lindau
  • NOV4 nucleic acids and polypeptides according to the invention are useful, inter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOV4 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of proteins belonging to the Protocadherin Alpha C2 Short Form Protein-like Protein Family. Cadherins (Takeichi, Annu. Rev. Biochem. 59: 237-252 (1990); Takeichi Trends
  • cadherin expression causes morphological changes involving the positional segregation of cells into layers, suggesting they may play an important role in the sorting of different cell types during morphogenesis, histogenesis and regeneration. They may also be involved in the regulation of tight and gap junctions, and in the control of intercellular spacing.
  • Cadherins are evolutionary related to the desmogleins which are component of intercellular desmosome junctions involved in the interaction of plaque proteins.
  • cadherins comprise a number of domains: these include a signal sequence; a propeptide of around 130 residues; an extracellular domain of around 600 residues; a single transmembrane domain; and a well-conserved C-terminal cytoplasmic domain of about 150 residues.
  • the extracellular domain can be subdivided into 5 parts, 4 of which are repeats of about 110 residues, and the fifth contains 4 conserved cysteines.
  • the calcium-binding region of cadherins is thought to be located in the extracellular domain. This indicates that the sequence of the invention has properties similar to those of other proteins known to contain this/these domain(s) and similar to the properties of these domains.
  • Maniatis et al. has identified 52 novel human cadherin-like genes organized into three closely linked clusters (Wu and Maniatis, Cell 97(6):779-90 (1999).) Comparison of the genomic DNA sequences with those of representative cDNAs reveals a striking genomic organization similar to that of immunoglobulin and T cell receptor gene clusters.
  • the N- terminal extracellular and transmembrane domains of each cadherin protein are encoded by a distinct and unusually large exon. These exons are organized in a tandem array.
  • the C-terminal cytoplasmic domain of each protein is identical and is encoded by three small exons located downstream from the cluster of N-terminal exons. This unusual organization has interesting implications regarding the molecular code required to establish complex networks of neuronal connections in the brain and the mechanisms of cell-specific cadherin- like gene expression.
  • the NOV4 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of urogenital, nerve, and endocrine physiology.
  • the NOV4 nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat reproductive and nervous system disorders, e.g., Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, Lesch-Nyhan syndrome, multiple sclerosis, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neurodegeneration, systemic lupus erythematosus, autoimmune disease, asthma, emphysema, scleroderma, allergy, ARDS, fertility, endometriosis, hypogonadism, hemophilia, hypercoagulation
  • NOV4 nucleic acids and polypeptides are useful for detecting specific cell types.
  • expression analysis has demonstrated that a NOV4 nucleic acid is expressed in Heart, Aorta, Umbilical Vein, Thyroid, Colon, Peripheral Blood, Spleen, Lymph node, Bone, Cartilage, Brain, Left cerebellum, Right Cerebellum, Parietal Lobe, Temporal Lobe, Cerebral Medulla/Cerebral white matter, Hippocampus, Cervix, Mammary glandBreast, Ovary, Placenta, Uterus, Testis, Lung, and Retina.
  • NOV5 nucleic acids and polypeptides according to the invention are disclosed herein.
  • a NOV5 polypeptide has been identified as a Nuclear protein-like protein (also referred to as CG95083-01).
  • the disclosed novel NOV5 nucleic acid (SEQ ID NO:9) of 2322 nucleotides is shown in Table 5 A.
  • An ORF begins with an ATG initiation codon at nucleotides 70-72 and ends with a TAA codon at nucleotides 2320-2322.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 5 A, and the start and stop codons are in bold letters.
  • a variant sequence can include a single nucleotide polymorphism (SNP).
  • SNP can, in some instances, be referred to as a "cSNP” to denote that the nucleotide sequence containing the SNP originates as a cDNA.
  • the NOV5 protein (SEQ ID NO: 10) encoded by SEQ ID NO:9 is 750 amino acid residues in length and is presented using the one-letter amino acid code in Table 5B. Psort analysis predicts the NOV5 protein of the invention to be localized in the nucleus with a certainty of 0.3000.
  • nucleic acid sequence of this invention has 443 of 754 bases (58%) identical to a gb:GENBANK-ID:AB037783
  • NOV5 also has homology to the proteins shown in the BLASTP data in Table 5D. Table 5D. BLAST results for NOV5
  • NOV5 has, for example, an RhoGEF signature sequence and a FYVE Zinc Finger signature sequence, aw well as homology to other members of the Nuclear Protein-like Protein Family.
  • NOV5 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOV5 nucleic acids and polypeptides can be used to identify proteins that are members of the Nuclear Protein-like Protein Family.
  • the NOV5 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOV5 activity or function.
  • nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation, cellular replication, and signal transduction.
  • These molecules can be used to treat, e.g., Cardiovascular diseases, Cardiomyopathy, Atherosclerosis, Hypertension, Congenital heart defects, Aortic stenosis, Atrial septal defect (ASD), Atrioventricular (A-V) canal defect, Ductus arteriosus , Pulmonary stenosis, Subaortic stenosis, Ventricular septal defect (VSD), valve diseases, Tuberous sclerosis, Scleroderma, Obesity, Transplantation, DiabetesNon Hippel-Lindau (VHL) syndrome , Pancreatitis, Obesity, Von Hippel-Lindau (VHL) syndrome , Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's
  • NOV5 nucleic acids and polypeptides according to the invention are useful, inter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOV5 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of proteins belonging to the Nuclear Protein-like Protein Family.
  • NOV5 nucleic acids and polypeptides, antibodies and related compounds according to the mvention will be useful in therapeutic and diagnostic applications in the mediation of cardiac and nerve physiology.
  • the NOV5 nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat cardiovascular and nervous system disorders, e.g., Cardiovascular diseases,
  • Cardiomyopathy Atherosclerosis, Hypertension, Congenital heart defects, Aortic stenosis, Atrial septal defect (ASD), Atrioventricular (A-V) canal defect, Ductus arteriosus , Pulmonary stenosis, Subaortic stenosis, Ventricular septal defect (VSD), valve diseases, Tuberous sclerosis, Scleroderma, Obesity, Transplantation, DiabetesNon Hippel-Lindau (VHL) syndrome , Pancreatitis, Obesity, Von Hippel-Lindau (VHL) syndrome , Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy, Lesch-Nyhan syndrome, Multiple sclerosis, Ataxia-telangiectasia, Leukodystrophies, Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection as well as other diseases, disorders and conditions.
  • the NOV5 nucleic acids and polypeptides are useful for detecting specific cell types. For example, expression analysis has demonstrated that a NOV5 nucleic acid is expressed in Brown adipose, Vein, Umbilical Vein, Adrenal Gland/Suprarenal gland, Gall Bladder, Small Intestine, Colon, Lymphoid tissue, Spleen, Lymph node, Thymus, Brain, Temporal Lobe, Basal Ganglia Cerebral nuclei, Substantia Nigra, Spinal Chord, Cervix, Ovary, Uterus, Testis, Lung, Lung Pleura, Larynx, Urinary Bladder, Kidney.
  • a NOV6 polypeptide has been identified as a Secretory Protein-like protein (also referred to as CG94989-01).
  • the disclosed novel NOV6 nucleic acid (SEQ ID NO:ll) of 2372 nucleotides is shown in Table 6A.
  • the novel NOV6 nucleic acid sequences maps to the chromosome 17.
  • An ORF begins with an ATG initiation codon at nucleotides 99-101 and ends with a
  • TAA codon at nucleotides 1710-1712.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 6A, and the start and stop codons are in bold letters.
  • the NOV6 protein (SEQ ID NO:12) encodedby SEQ ID NO:11 is 537 amino acid residues in length and is presented using the one-letter amino acid code in Table 6B. Psort analysis predicts the NOV6 protein ofthe invention to be localized outside the cell with a certainty of0.6997.
  • the full amino acid sequence of the protein of the invention was found to have 395 of 395 amino acid residues (100%) identical to, and 395 of 395 amino acid residues (100%) similar to, the 468 amino acid residue ptnr:SPTREMBL-ACC:O60276 protein from Homo sapiens (KIAA0523 PROTEIN)(Fig. 3B).
  • NOV6 also has homology to the proteins shown in the BLASTP data in Table 6D.
  • the NOV6 Clustal W alignment shown in Table 6E was modified to begin at amino residue 841 and end at amino acid residue 1860.
  • the data in Table 6E includes all of the regions overlapping with the NOV6 protein sequences.
  • the presence of identifiable domains in the protein disclosed herein was determined by searches using algorithms such as PROSITE, Blocks, Pfam, ProDomain, Prints and then determining the Interpro number by crossing the domain match (or numbers) using the
  • NOV6 has, for example, has homology to other members of the Secretory Protein-like Protein Family.
  • NOV6 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOV6 nucleic acids and polypeptides can be used to identify proteins that are members of the Secretory Protein-like Protein Family.
  • the NOV6 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOV6 activity or function.
  • the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation and signal transduction.
  • NOV6 nucleic acids and polypeptides according to the invention are useful, inter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOV6 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of proteins belonging to the Secretory Protein-like Protein Family.
  • the NOV6 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of cardiac physiology.
  • the NOV6 nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat cardiac and vascular system disorders, e.g., Cardiovascular diseases, Cardiomyopathy, Atherosclerosis, Hypertension, Congenital heart defects, Aortic stenosis, Atrial septal defect (ASD), Atrioventricular (A-V) canal defect, Ductus arteriosus as well as other diseases, disorders and conditions
  • NOV6 nucleic acids and polypeptides are useful for detecting specific cell types. For example, expression analysis has demonstrated that a NOV6 nucleic acid is expressed in Aorta.
  • NOV7 A NOV7 polypeptide has been identified as a Transmission Blocking Target Antigen
  • S230 Precursor-like protein also referred to as CG94978-01.
  • the disclosed novel NOV7 nucleic acid (SEQ ID NO:13) of 1629 nucleotides is shown in Table 7A.
  • the novel NOV7 nucleic acid sequences maps to the chromosome 1.
  • An ORF begins with an ATG initiation codon at nucleotides 1-3 and ends with a TGA codon at nucleotides 1627- 1629.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 7A, and the start and stop codons are in bold letters.
  • the NOV7 protein (SEQ ID NO: 14) encoded by SEQ ID NO: 13 is 542 amino acid residues in length and is presented using the one-letter amino acid code in Table 7B. Psort analysis predicts the NOV7 protein of the invention to be localized in the cytoplasm with a certainty of 0.4500.
  • nucleic acid sequence of this invention has 874 of 876 bases (99%) identical to a gb:GENBANK-LD:AK022517
  • the full amino acid sequence of the protein of the invention was found to have 290 of 292 amino acid residues (99%) identical to, and 290 of 292 amino acid residues (99%) similar to, the 525 amino acid residue ptnr:SPTREMBL- ACC.Q9H9Z3 protein from Homo sapiens (CDNA FLJ12455 FIS, CLONE NT2RM1000563, WEAKLY SIMILAR TO TRANSMISSION- BLOCKING TARGET ANTIGEN S230 PRECURSOR).
  • NOV7 also has homology to the proteins shown in the BLASTP data in Table 7D.
  • Table 7E A multiple sequence alignment is given in Table 7E, with the NOV7 protein being shown on line 1 in Table 7E in a ClustalW analysis, and comparing the NOV7 protein with the select related protein sequences shown in Table 7D.
  • This BLASTP data is displayed graphically in the ClustalW in Table 7E.
  • N0V7 420 EARJSLLIVESRRRLVSILESRVLQLHREFL ⁇ A'LRL.
  • the presence of identifiable domains in the protein disclosed herein was determined by searches using algorithms such as PROSITE, Blocks, Pfam, ProDomain, Prints and then determining the Interpro number by crossing the domain match (or numbers) using the
  • NOV7 has, for example, three Blocking NT2RM1000563 Transmission-FIS Antigen Weakly Precursor Peptidase A2 signature sequences and homology to other members of the Transmission Blocking Target Antigen S230 Precursor-like Protein Family.
  • NOV7 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts. For example, NOV7 nucleic acids and polypeptides can be used to identify proteins that are members of the Transmission Blocking Target Antigen S230 Precursor-like Protein Family.
  • the NOV7 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOV7 activity or function.
  • the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation and signal transduction.
  • Cardiovascular diseases can be used to treat, e.g., Cardiovascular diseases, Cardiomyopathy, Atherosclerosis, Hypertension, Congenital heart defects, Aortic stenosis, Atrial septal defect (ASD), Atrioventricular (A-V) canal defect, Ductus arteriosus , Pulmonary stenosis, Subaortic stenosis, Ventricular septal defect (VSD), valve diseases, Tuberous sclerosis, Scleroderma, Obesity, Transplantation, DiabetesNon Hippel-Lindau (VHL) syndrome , Pancreatitis, Obesity, Von Hippel-Lindau (VHL) syndrome , Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy, Lesch- ⁇ yhan syndrome, Multiple sclerosis, Ataxia-telangiectasia, Leukodystrophies, Behavioral disorders, Addiction,
  • NOV7 nucleic acids and polypeptides according to the invention are useful, inter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOV7 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of proteins belonging to the Transmission Blocking Target Antigen S230 Precursor-like Protein Family.
  • the NOV7 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of cardiac and nerve physiology.
  • the NOV7 nucleic acids and polypeptides, antibodies and related compounds according to the mvention may be used to treat cardiovascular and nervous system disorders, e.g., Cardiovascular diseases,
  • Cardiomyopathy Atherosclerosis, Hypertension, Congenital heart defects, Aortic stenosis, Atrial septal defect (ASD), Atrioventricular (A-V) canal defect, Ductus arteriosus , Pulmonary stenosis, Subaortic stenosis, Ventricular septal defect (VSD), valve diseases, Tuberous sclerosis, Scleroderma, Obesity, Transplantation, DiabetesNon Hippel-Lindau (VHL) syndrome, Pancreatitis, Obesity, Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy, Lesch- ⁇ yhan syndrome, Multiple sclerosis, Ataxia-telangiectasia, Leukodystrophies, Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection
  • NOV7 nucleic acids and polypeptides are useful for detecting specific cell types.
  • expression analysis has demonstrated that a NOV7 nucleic acid is expressed in Adipose, Heart, Aorta, Coronary Artery, Umbilical Vein, Pancreas, Liver, Gall Bladder, Colon, Bone Marrow, Thymus, Bone, Cartilage, Synovium/Synovial membrane, Skeletal Muscle, Brain, Left cerebellum, Right Cerebellum, Thalamus, Hypothalamus, Pituitary Gland, Frontal Lobe, Parietal Lobe, Cerebral Medulla/Cerebral white matter, Basal Ganglia/Cerebral nuclei, Substantia Nigra, Hippocampus, Cervix, Mammary gland Breast, Uterus,
  • Oviduct/Uterine Tube/Fallopian tube Prostate, Testis, Lung, Bronchus, Larynx, Kidney, Retina, Skin, Epidermis.
  • a NOV8 polypeptide has been identified as a Nuclear Protein-like protein (also referred to as CG94713-01).
  • the disclosed novel NOV8 nucleic acid (SEQ ID NO:15) of 3807 nucleotides is shown in Table 8A.
  • the novel NOV8 nucleic acid sequences maps to the chromosome 1.
  • An ORF begins with an ATG initiation codon at nucleotides 16-18 and ends with a TGA codon at nucleotides 3793-3795.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 8 A, and the start and stop codons are in bold letters.
  • a variant sequence can include a single nucleotide polymorphism (SNP).
  • SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA.
  • the NOV8 protein (SEQ ID NO: 16) encoded by SEQ ID NO: 15 is 1259 amino acid residues in length and is presented using the one-letter amino acid code in Table 8B. Psort analysis predicts the NOV8 protein of the invention to be localized in the nucleus with a certainty of 0.7600.
  • nucleic acid sequence of a human ATIP isoform +1 2954 1.5e-307 In a BLAST search of public sequence databases, it was found, for example, that the nucleic acid sequence of this invention has 3751 of 3751 bases (100%) identical to a gb:GENBANK-ID:AB033114
  • the full amino acid sequence of the protein of the invention was found to have 1245 of 1245 amino acid residues (100%) identical to, and 1245 of 1245 amino acid residues (100%) similar to, the 1245 amino acid residue ptnr:SPTREMBL- ACC:Q9ULD2 protein from Homo sapiens (KIAA1288 PROTEIN).
  • NOV8 also has homology to the proteins shown in the BLASTP data in Table 8D.
  • Table 8E A multiple sequence alignment is given in Table 8E, with the NOV8 protein being shown on line 1 in Table 8E in a ClustalW analysis, and comparing the NOV8 protein with the related protein sequences shown in Table 8D.
  • This BLASTP data is displayed graphically in the ClustalW in Table 8E.
  • NOV8 has, for example, an RNA polymerase omega subunit signature sequence and homology to other members of the Nuclear Protein-like Protein Family.
  • NOV8 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOV8 nucleic acids and polypeptides can be used to identify proteins that are members of the Nuclear Protein-like Protein Family.
  • the NOV8 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOV8 activity or function.
  • nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation, cellular replication, and signal transduction.
  • These molecules can be used to treat, e.g., Cardiovascular diseases, Cardiomyopathy, Atherosclerosis, Hypertension, Congenital heart defects, Aortic stenosis, Atrial septal defect (ASD), Atrioventricular (A-V) canal defect, Ductus arteriosus , Pulmonary stenosis, Subaortic stenosis, Ventricular septal defect (VSD), valve diseases, Tuberous sclerosis, Scleroderma, Obesity, Transplantation, DiabetesNon Hippel-Lindau (VHL) syndrome , Pancreatitis, Obesity, Hyperparathyroidism, Hypoparathyroidism as well as other diseases, disorders and conditions.
  • Cardiovascular diseases e.g., Cardiomyopathy, Atherosclerosis, Hypertension,
  • NOV8 nucleic acids and polypeptides according to the invention are useful, inter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOV8 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of proteins belonging to the Nuclear Protein-like Protein Family.
  • NOV8 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of cardiac or endocrine physiology.
  • the NOV8 nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat infection, cardiovascular system, immune system, and nervous system disorders, e.g., Cardiovascular diseases, Cardiomyopathy, Atherosclerosis, Hypertension, Congenital heart defects, Aortic stenosis, Atrial septal defect (ASD), Atrioventricular (A-V) canal defect,
  • Ductus arteriosus Pulmonary stenosis, Subaortic stenosis, Ventricular septal defect (VSD), valve diseases, Tuberous sclerosis, Scleroderma, Obesity, Transplantation, DiabetesNon Hippel-Lindau (VHL) syndrome , Pancreatitis, Obesity, Hyperparathyroidism, Hypoparathyroidism as well as other diseases, disorders and conditions.
  • VSD Ventricular septal defect
  • VHL Ventricular septal defect
  • the NOV8 nucleic acids and polypeptides are useful for detecting specific cell types.
  • NOV8 nucleic acid is expressed in Heart, Aorta, Coronary Artery, Vein, Umbilical Vein, Adrenal Gland/Suprarenal gland, Pancreas, Islets of Langerhans, Parathyroid Gland, Thyroid, Pineal Gland, Tongue, Salivary Glands, Stomach, Liver, Small Intestine, Colon, Ascending Colon, Lymphoid tissue, Spleen, Brain, Thalamus, Hypothalamus, Temporal Lobe, Amygdala, Cerebral Medulla/Cerebral white matter, Basal Ganglia/Cerebral nuclei, Substantia Nigra, Hippocampus, Spinal Chord, Cervix, Mammary gland/Breast, Ovary, Placenta, Uterus, Prostate, Testis, Lung, Nasoepithelium, Larynx, Urinary Bladder, Kidney, Kidney Cortex, Re
  • ANOV9 polypeptide has been identified as a Hemicentin precursor-like protein (also referred to as CG94702-01).
  • the disclosed novel NOV9 nucleic acid (SEQ ID NO:17) of 11796 nucleotides is shown in Table 9A.
  • the novel NOV9 nucleic acid sequences maps to the chromosome 9.
  • An ORF begins with an ATG initiation codon at nucleotides 1-3 and ends with a TAA codon at nucleotides 11794-11796.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 9A, and the start and stop codons are inbold letters.
  • a variant sequence can include a single nucleotide polymorphism (SNP).
  • SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA.
  • the NOV9 protein (SEQ ID NO: 18) encoded by SEQ ID NO: 17 is 3931 amino acid residues in length and is presented using the one-letter amino acid code in Table 9B. Psort analysis predicts the NOV9 protein of the invention to be localized at the plasma membrane with a certainty of 0.7300.
  • nucleic acid sequence of this invention has 625 of 1067 bases (58%) identical to a gb:GENBANK-ID:HSLTGFBP4
  • the full amino acid sequence of the protein of the invention was found to have 502 of 1665 amino acid residues (30%) identical to, and 767 of 1665 amino acid residues (46%) similar to, the 5198 amino acid residue ⁇ tnr:SPTREMBL-ACC:O76518 protein from Caenorhabditis elegans (HEMICENTIN PRECURSOR).
  • NOV9 also has homology to the proteins shown in the BLASTP data in Table 9D.
  • the NOV9 Clustal W alignment shown in Table 9E was modified to begin at amino residue 4080.
  • the data in Table 9E includes all of the regions overlapping with the NOV9 protein sequences.
  • NON9 has, for example, thirty-three immunoglobulin (ig) signature sequences and four epidermal growth factor (EGF) signature sequences, as well as homology to other members of the Hemicentin Precursor-like Protein Family.
  • ⁇ ON9 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • ⁇ ON9 nucleic acids and polypeptides can be used to identify proteins that are members of the Hemicentin Precursor-like Protein Family.
  • the ⁇ ON9 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance ⁇ ON9 activity or function.
  • nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation, cellular differentiation, and signal transduction.
  • small molecules that modulate or inhibit, e.g., cellular activation, cellular differentiation, and signal transduction.
  • These molecules can be used to treat, e.g., Cardiovascular diseases, Hyperparathyroidism, Hypoparathyroidism, Lymphedema, Allergies as well as other diseases, disorders and conditions..
  • ⁇ ON9 nucleic acids and polypeptides according to the invention are useful, inter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the ⁇ ON9 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of proteins belonging to the Hemicentin Precursor-like Protein Family.
  • Hemicentrin is an extracellular matrix protein with a modular sturcture. Like ⁇ ON9, the hemicentrin structure includes many immunoglobulin domains flanked by EGF domains. The protein is likely involved in cellular differentiation of epithelial tissue.
  • the NON9 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of cardiac, immune and endocrine physiology. As such, the ⁇ ON9 nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat cardiovascular, immune, and endocrine disorders, e.g., Cardiovascular diseases,
  • Hyperparathyroidism Hypoparathyroidism, Lymphedema, Allergies as well as other diseases, disorders and conditions.
  • the ⁇ ON9 nucleic acids and polypeptides are useful for detecting specific cell types. For example, expression analysis has demonstrated that a ⁇ ON9 nucleic acid is expressed in Adipose, Thyroid, Colon, Lymph node, Bone, Myometrium, Prostate, Testis, Aorta, Nein.
  • ⁇ OV10 A ⁇ ON10 polypeptide has been identified as a Selectin-like protein.
  • the novel ⁇ ON10 nucleic acid sequences maps to the chromosome 9.
  • Two alternative novel ⁇ OV10, ⁇ ONlOa and ⁇ ONlOb, nucleic acids and encoded polypeptides are provided.
  • a ⁇ ON10 variant is ⁇ ONlOa (alternatively referred to herein as CG94661-01), which includes the 1268 nucleotide sequence (SEQ D ⁇ O:19) shown in Table 10A.
  • a NOVlOa ORF begins with a ATG initiation codon at nucleotides 145-147 and ends with a TGA codon at nucleotides 871-873. Putative untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 10A, and the start and stop codons are in bold letters.
  • the NOVlOa polypeptide (SEQ LD ⁇ O:20) encoded by SEQ ID NO:19 is 242 amino acid residues in length and is presented using the one-letter amino acid code in Table 10B.
  • the Psort profile for the NOVlOa predicts that this peptide is likely to be localized at the plasma membrane with a certainty of 0.7000.
  • NOV10 variant is the novel NOV 10b (alternatively referred to herein as CG94661-02), which includes the 887 nucleotide sequence (SEQ ID NO:21) shown in Table IOC.
  • NOV 10b was created by polymerase chain reaction (PCR) using the primers detailed in Example 1, Table 17. Primers were designed based on in silico predictions of the full length or some portion (one or more exons) of the cDNA/protein sequence of the invention. The PCR product derived by exon linking, covering the entire open reading frame, was cloned into the pCR2.1 vector from Invitrogen to provide clone 143260::COR100348691_extn.698976.C20.
  • the NOVl 0b ORF begins with a Kozak consensus ATG initiation codon at nucleotides 72-74 and ends with a TGA codon at nucleotides 1958-1960. Putative untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 10C, and the start and stop codons are in bold letters.
  • a variant sequence can include a single nucleotide polymorphism (SNP).
  • SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA.
  • the NOVlOb protein (SEQ ID NO:22) encoded by SEQ ID NO:21 is 242 amino acid residues in length and is presented using the one-letter code in Table 10D.
  • the Psort profile for NOVl Ob predicts that this sequence is likely to be localized at the plasma membrane with a certainty of 0.7000.
  • NOVlOa differs from NOVlOb at amino acid position 18 (T>M) and amino acid position 50 (S>P) as shown in Tables 10B and 10D.
  • NOVlOa nucleic acid sequence of this invention has 438 of 447 bases (97%) identical to a gb:GENBANK-ID:HSM802384
  • the full amino acid sequence of the protein of the invention was found to have 110 of 139 amino acid residues (79%) identical to, and 123 of 139 amino acid residues (88%) similar to, the 269 amino acid residue ptm:SPTREMBL- ACC:Q9D176 protein from Mus musculus (170001711 IRK PROTEIN).
  • the NOV 10b nucleic acid sequence of this invention has 438 of 447 bases (97%) identical to a gb:GENBANK-
  • the NOVIO Clustal W alignment shown in Table 10F was modified to begin at amino residue 1600 and end at amino acid residue 2000.
  • the data in Table 10F includes all of the regions overlapping with the NOVIO protein sequences.
  • the NOVIO Clustal W alignment shown in Table 10G was modified to begin at amino residue 1601.
  • the data in Table 10G includes all of the regions overlapping with the NOVIO protein sequences.
  • NOV10 has, for example, a Sushi domain (SCR repeat) signature sequences and homology to other members of the Selectin-like Protein Family.
  • SCR repeat Sushi domain
  • NOV10 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOV10 nucleic acids and polypeptides can be used to identify proteins that are members of the Selectin-like Protein Family.
  • the NOV10 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOV10 activity or function.
  • nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular adhesion and signal transduction.
  • These molecules can be used to treat, e.g., Cardiovascular diseases, Cardiomyopathy, Atherosclerosis, Hypertension, Congenital heart defects, Aortic stenosis, Atrial septal defect (ASD), Atrioventricular (A-V) canal defect, Ductus arteriosus , Pulmonary stenosis, Subaortic stenosis, Ventricular septal defect (VSD), valve diseases, Tuberous sclerosis, Scleroderma, Obesity, Transplantation, Von Hippel-Lindau (VHL) syndrome,
  • Cardiovascular diseases Cardiomyopathy, Atherosclerosis, Hypertension, Congenital heart defects, Aortic stenosis, Atrial septal defect (ASD), Atrioventricular (A-V) canal defect, Ductus arteriosus , Pul
  • Cirrhosis Transplantation, Diabetes, Autoimmune disease, Renal artery stenosis, Interstitial nephritis, Glomerulonephritis, Polycystic kidney disease, Systemic lupus erythematosus, Renal tubular acidosis, IgA nephropathy, Hypercalceimia, Lesch-Nyhan syndrome, Systemic lupus erythematosus, Autoimmune disease, Asthma, Emphysema, Scleroderma, allergy as well as other diseases, disorders and conditions.
  • NOV10 nucleic acids and polypeptides according to the invention are useful, inter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOV10 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of protems belonging to the Selectin-like Protein Family.
  • the NOV10 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of cardiac and immune physiology.
  • the NOV10 nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat cardiovascular and immune disorders, e.g., Cardiovascular diseases, Cardiomyopathy, Atherosclerosis, Hypertension, Congenital heart defects, Aortic stenosis, Atrial septal defect (ASD), Atrioventricular (A-V) canal defect, Ductus arteriosus , Pulmonary stenosis, Subaortic stenosis, Ventricular septal defect (VSD), valve diseases, Tuberous sclerosis, Scleroderma, Obesity, Transplantation, Von Hippel-Lindau (VHL) syndrome, Cirrhosis, Transplantation, Diabetes, Autoimmune disease, Renal artery stenosis, Interstitial nephritis, Glomerulonephriti
  • NOVIO nucleic acids and polypeptides are useful for detecting specific cell types.
  • expression analysis has demonstrated that a NOVIO nucleic acid is expressed in Heart, Thyroid, Parotid Salivary glands, Liver, Colon, Ascending Colon, Bone Marrow, Peripheral Blood, Lymphoid tissue, Spleen, Lymph node, Tonsils, Thymus, Cerebellum, Spinal Chord, Cervix, Mammary gland/Breast, Ovary, Placenta, Uterus, Oviduct/Uterine Tube/Fallopian tube, Vulva, Prostate, Testis, Lung, Kidney, Kidney Cortex, Retina, Skin.
  • a NOVl 1 polypeptide has been identified as a Nuclear Protein-like protein (also referred to as CG94325-01).
  • the disclosed novel NOV11 nucleic acid (SEQ ID NO:23) of 8670 nucleotides is shown in Table 11 A.
  • the novel NOVl 1 nucleic acid sequences maps to the chromosome 15.
  • An ORF begins with an ATG initiation codon at nucleotides 204-206 and ends with a TAA codon at nucleotides 7152-7154.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 11 A, and the start and stop codons are in bold letters.
  • a variant sequence can include a single nucleotide polymorphism (SNP).
  • SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA.
  • the NOVl 1 protein (SEQ ID NO:24) encoded by SEQ ID NO:23 is 2316 amino acid residues in length and is presented using the one-letter amino acid code in Table 1 IB. Psort analysis predicts the NOVl 1 protein of the invention to be localized at the nucleus with a certainty of 0.8800.
  • nucleic acid sequence of this invention has 5584 of 5584 bases (100%) identical to a gb:GENBANK-ID:AB046790
  • the full amino acid sequence of the protein of the invention was found to have 1790 of 1793 amino acid residues (99%) identical to, and 1792 of 1793 amino acid residues (99%) similar to, the 1833 amino acid residue ptnr:SPTREMBL- ACC:Q9NR92 protein from Homo sapiens (AF15Q14 PROTEIN).
  • NOVl 1 also has homology to the proteins shown in the BLASTP data in Table 1 ID.
  • Table 1 IE A multiple sequence alignment is given in Table 1 IE, with the NOVl 1 protein being shown on line 1 in Table 1 IE in a ClustalW analysis, and comparing the NOVl 1 protein with the related protein sequences shown in Table 1 ID.
  • This BLASTP data is displayed graphically in the ClustalW in Table 1 IE.
  • NOVll nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOVl 1 nucleic acids and polypeptides can be used to identify proteins that are members of the Nuclear Protein-like Protein Family.
  • the NOVl 1 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVl 1 activity or function.
  • the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation, cellular replication, and signal transduction. These molecules can be used to treat, e.g.
  • VHL Von Hippel-Lindau
  • VHL Cirrhosis, Transplantation, Hemophilia, hypercoagulation, Idiopathic thrombocytopenic purpura, autoimmume disease, allergies, immunodeficiencies, transplantation, Graft vesus host, Cardiovascular diseases, Von Hippel-Lindau (VHL) syndrome , Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy, Lesch-Nyhan syndrome, Multiple sclerosis, Ataxia-telangiectasia, Leukodystrophies, Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection, Systemic lupus erythematosus , Autoimmune disease, Asthma, Emphysema, Scleroderma, allergy, as well as other diseases, disorders and conditions.
  • NOVl 1 nucleic acids and polypeptides according to the invention are useful, ter alia, as novel members of the protein families according to the presence of sequence relatedness to previously described proteins.
  • the NOVll nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of cardiac, immune, and nerve physiology.
  • the NOVl 1 nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat cardiovascular, immune, and nervous system disorders, e.g., Von Hippel-Lindau (VHL) syndrome, Cirrhosis,
  • VHL Von Hippel-Lindau
  • Leukodystrophies Leukodystrophies, Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection, Systemic lupus erythematosus , Autoimmune disease, Asthma, Emphysema, Scleroderma, allergy, as well as other diseases, disorders and conditions.
  • the NOVl 1 nucleic acids and polypeptides are useful for detecting specific cell types.
  • expression analysis has demonstrated that a NOVl 1 nucleic acid is expressed in Adipose, Aorta, Artery, Coronary Artery, Umbilical Vein, Thyroid, Liver, Small Intestine, Duodenum, Colon, Ascending Colon, Bone Marrow, Lymph node, Tonsils, Thymus, Cartilage, Muscle, Brain, Cervix, Uterus, Vulva, Prostate, Testis, Lung, Bronchus, Urinary Bladder, Kidney, Skin, Epidermis, Dermis.
  • a NOV 12 polypeptide has been identified as a Plasma Membrane Protein-like protein (also referred to as CG94282-01).
  • the disclosed novel NOV12 nucleic acid (SEQ ID NO:25) of 8811 nucleotides is shown in Table 12 A.
  • the novel NOV 12 nucleic acid sequences maps to the chromosome 12.
  • An ORF begins with an ATG initiation codon at nucleotides 1-3 and ends with a TAG codon at nucleotides 4378-4380.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 12 A, and the start and stop codons are in bold letters.
  • a variant sequence can include a single nucleotide polymorphism (SNP).
  • SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA.
  • the NOV12 protein (SEQ ID NO:26) encoded by SEQ ID NO:25 is 1459 amino acid residues in length and is presented using the one-letter amino acid code in Table 12B. Psort analysis predicts the NOV12 protein of the invention to be localized at the plasma membrane with a certainty of 0.6500.
  • nucleic acid sequence of this invention has 6444 of 6447 bases (99%) identical to a gb:GENBANK-ID:AB033034
  • KIAA1208 protein partial eds.
  • the full amino acid sequence of the protein of the invention was found to have 663 of 663 amino acid residues (100%) identical to, and 663 of 663 amino acid residues (100%) similar to, the 663 amino acid residue ptnr:SPTREMBL-ACC:Q9ULL2 protein from Homo sapiens (KIAA1208 PROTEIN).
  • NOV 12 also has homology to the proteins shown in the BLASTP data in Table 12D.
  • Table 12E A multiple sequence alignment is given in Table 12E, with the NOV12 protein being shown on line 1 in Table 12E in a ClustalW analysis, and comparing the NOV 12 protein with the related protein sequences shown in Table 12D.
  • This BLASTP data is displayed graphically in the ClustalW in Table 12E.
  • the NOV 12 Clustal W alignment shown in Table 12E was modified to end at amino residue 1200.
  • the data in Table IE includes all of the regions overlapping with the NOV12 protein sequences.
  • NOV12 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOV12 nucleic acids and polypeptides can be used to identify proteins that are members of the Plasma Membrane Protein-like Protein Family.
  • the NOVl 2 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVl 2 activity or function.
  • the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation and signal transduction.
  • VHL DiabetesNon Hippel-Lindau
  • Pancreatitis Obesity
  • Cardiomyopathy Atherosclerosis
  • Hypertension Congenital heart defects
  • Aortic stenosis Atrial septal defect (ASD)
  • Atrioventricular (A-V) canal defect Ductus arteriosus
  • Pulmonary stenosis Subaortic stenosis
  • Ventricular septal defect VSD
  • valve diseases Tuberous sclerosis, Scleroderma, Obesity, Transplantation, Von Hippel-Lindau (NHL) syndrome, Cirrhosis, Transplantation, Non Hippel-Lindau (NHL) syndrome , Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy, Lesch- ⁇ yhan syndrome, Multiple sclerosis, Ataxia-telangiec
  • NOV 12 nucleic acids and polypeptides according to the invention are useful, ter alia, as novel members of the protein families according to the sequence relatedness to previously described proteins.
  • the NON12 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of cardiac, nerve, and immune physiology.
  • the ⁇ ON12 nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat cardiovascular, immune, and nervous system disorders, e.g., DiabetesNon Hippel-Lindau (VHL) syndrome, Pancreatitis, Obesity, Cardiomyopathy, Atherosclerosis, Hypertension, Congenital heart defects, Aortic stenosis, Atrial septal defect (ASD), Atrioventricular (A-V) canal defect, Ductus arteriosus , Pulmonary stenosis, Subaortic stenosis, Ventricular septal defect (VSD), valve diseases, Tuberous sclerosis, Scleroderma, Obesity, Transplantation, Von Hippel-Lindau (VHL) syndrome, Cirrhosis, Transplantation, Von Hippel-Lindau (VHL) syndrome , Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cere
  • NOV12 nucleic acids and polypeptides are useful for detecting specific cell types.
  • expression analysis has demonstrated that a NOV 12 nucleic acid is expressed in Pancreas, Uterus, Epidermis, Heart, Coronary Artery, Adrenal Gland/Suprarenal gland, Pancreas, Parathyroid Gland, Salivary Glands, Liver, Small Intestine, Bone Marrow, Peripheral Blood, Lymphoid tissue, Lymph node, Cartilage, Brain, Hypothalamus, Spinal Chord, Mammary gland/Breast, Uterus, Prostate, Testis, Lung, Kidney, Epidermis, Hair Follicle.
  • a NOVl 3 polypeptide has been identified as a BHLH Factor MATH6-like protein (also referred to as CG94399-01).
  • the disclosed novel NOV13 nucleic acid (SEQ ID NO:27) of 2244 nucleotides is shown in Table 13 A.
  • the novel NOV 13 nucleic acid sequences maps to the chromosome 2.
  • An ORF begins with an ATG initiation codon at nucleotides 105-107 and ends with a TGA codon at nucleotides 1062-1064.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 13 A, and the start and stop codons are in bold letters.
  • a variant sequence can include a single nucleotide polymorphism (SNP).
  • SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA.
  • the NOV13 protein (SEQ D NO:28) encoded by SEQ ID NO:27 is 319 amino acid residues in length and is presented using the one-letter amino acid code in Table 13B. Psort analysis predicts the NOVl 3 protein of the invention to be localized at the nucleus with a certainty of 0.7000.
  • nucleic acid sequence of this invention has 372 of 657 bases (56%) identical to a gb:GENBANK-ID:HSBBICP4A
  • Bovine herpesvirus 1 Bovine herpesvirus type 1 early-intermediate transcription control protein (BICP4) gene, complete eds).
  • the full amino acid sequence of the protein of the invention was found to have 238 of 322 amino acid residues (73%) identical to, and 244 of 322 amino acid residues (75%) similar to, the 322 amino acid residue ⁇ tnr:TREMBLNEW-ACC:BAB39468 protein from Mus musculus (BHLH FACTOR MATH6).
  • NOV 13 also has homology to the proteins shown in the BLASTP data in Table 13D.
  • NOV 13 has, for example, a Helix-loop-helix domain and a Helix-loop-helix DNA binding domain (HLH) signature sequence as well as homology to other members of the BHLH Factor MATH6-like Protein Family.
  • HHL Helix-loop-helix DNA binding domain
  • NOV 13 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOV 13 nucleic acids and polypeptides can be used to identify proteins that are members of the BHLH Factor MATH6-like Protein Family.
  • the NOV13 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVl 3 activity or function.
  • the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation, cellular replication, and signal transduction.
  • small molecules that modulate or inhibit, e.g., cellular activation, cellular replication, and signal transduction.
  • VHL DiabetesNon Hippel-Lindau
  • Pancreatitis Obesity
  • Inflammatory bowel disease Diverticular disease
  • Non Hippel-Lindau (NHL) syndrome Non Hippel-Lindau
  • Alzheimer's disease, Stroke Tuberous sclerosis
  • hypercalceimia Parkinson's disease
  • Huntington's disease Cerebral palsy
  • Epilepsy Lesch- ⁇ yhan syndrome
  • Multiple sclerosis Ataxia-telangiectasia, Leukodystrophies, Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection, Systemic lupus erythematosus , Autoimmune
  • NOV13 nucleic acids and polypeptides according to the invention are useful, inter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOVl 3 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of protems belonging to the BHLH Factor MATH6-like Protein Family.
  • bHLH basic helix-loop-helix proteins
  • class A ubiquitous
  • class B tissue-specific
  • the HLH proteins lacking the basic domain (Emc, Id) function as negative regulators since they form heterodimers, but fail to bind DNA.
  • the hairy-related proteins hairy, E(spl), deadpan
  • the proteins of this subfamily act together with co-repressor proteins, like groucho, through their C-terminal motif WRPW.
  • MATH6 (Inoue, et al, Genes to Cells 6: 977-86 (2001)) is a distant homolog of Drosophila proneuronal gene Atonal Murine expression is higest in developing nervous system (ventricular zone and mantle layer, spinal cord, dorsal root ganglia). MATH6 is expressed by neuronal precursor cells and designated neurons, e.g., cerebellar Purkinje cells. The closest mammalian homolog to MATH6 is NeuroD. NeuroD point mutations and
  • NeuroD gene knockout animals have severe diabetes and die perinatally.
  • the NeuroD knockout animals lack beta-Islet cells and could not be rescued with insulin administration.
  • the NeuroD knockout animals are deaf due to a loss of inner ear sensory neurons.
  • the NON 13 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of metabolism as well as nerve and immune physiology.
  • the ⁇ ON13 nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat metabolic, hearing, nervous system, immune disorders, e.g., DiabetesNon Hippel-Lindau (NHL) syndrome , Pancreatitis, Obesity, Inflammatory bowel disease, Diverticular disease, Non Hippel-Lindau (NHL) syndrome , Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy, Lesch- ⁇ yhan syndrome, Multiple sclerosis, Ataxia-telangiectasia, Leukodystrophies, Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection, Systemic lupus erythematosus , Autoimmune disease, Asthma, Emphysema, Scleroderma, allergy as well as other diseases, disorders and conditions.
  • NDL DiabetesNon Hippel-Lind
  • the NON13 nucleic acids and polypeptides are useful for detecting specific cell types. For example, expression analysis has demonstrated that a ⁇ ON13 nucleic acid is expressed in Pancreas, Umbilical Nein, Small Intestine, Cartilage, Synovium Synovial membrane, Brain, Placenta, Oviduct/Uterine Tube/Fallopian tube, Lung, Brain, Uterus.
  • a NOV14 polypeptide has been identified as a Putative Protein-Tyrosine Phosphatase- like protein (also referred to as CG94366-01).
  • the disclosed novel NOV14 nucleic acid (SEQ ID NO:29) of nucleotides is shown in Table 14A.
  • the novel NOV14 nucleic acid sequences maps to the chromosome 22.
  • An ORF begins with an ATG initiation codon at nucleotides 248-250 and ends with a TAA codon at nucleotides 1679-1681.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 14 A, and the start and stop codons are in bold letters.
  • the NOV14 protein (SEQ ID NO:30) encoded by SEQ D NO:29 is 477 amino acid residues in length and is presented using the one-letter amino acid code in Table 14B. Psort analysis predicts the NOV14 protein ofthe invention to be localized at the plasma membrane with a certainty of0.6000.
  • nucleic acid sequence of this invention has 1105 of 1427 bases (77%) identical to a gb:GENBANK-ID:AF007118
  • the full amino acid sequence of the protein of the invention was found to have 369 of 462 amino acid residues (79%) identical to, and 402 of 462 amino acid residues (87%) similar to, the 551 amino acid residue ptn ⁇ SWISSNEW- ACC:P56180 protein from Homo sapiens (PUTATIVE PROTETN-TYROSINE PHOSPHATASE TPTE (EC 3.1.3.48)).
  • NOVl 4 also has homology to the proteins shown in the BLASTP data in Table 14D.
  • Table 14E A multiple sequence alignment is given in Table 14E, with the NOV 14 protein being shown on line 1 in Table 14E in a ClustalW analysis, and comparing the NOV14 protein with the related protein sequences shown in Table 14D.
  • This BLASTP data is displayed graphically in the ClustalW in Table 14E.
  • NOVl 4 has, for example, a dual specificity protein phosphatase signature sequence and homology to other members of the Putative Protein-Tyrosine Phosphatase-like Protein Family.
  • NOV14 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOV14 nucleic acids and polypeptides can be used to identify proteins that are members of the Putative Protein-Tyrosine Phosphatase-like Protein Family.
  • the NOV 14 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOV14 activity or function.
  • nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation, cellular replication, and signal transduction. These molecules can be used to treat, e.g., Cardiovascular diseases, cystitis, incontinence as well as other diseases, disorders and conditions hi addition, various NOV 14 nucleic acids and polypeptides according to the invention are useful, inter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOV14 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of proteins belonging to the Putative Protein-Tyrosine Phosphatase-like Protein Family.
  • PTPs protein tyrosine phosphatases
  • the protein tyrosine phosphatases which hydrolyze the phosphate monoesters of tyrosine residues, all share a common active site motif and are classified into 3 groups. These include the receptor-like PTPs, the intracellular PTPs, and the dual-specificity PTPs, which can dephosphorylate at serine and threonine residues as well as at tyrosines.
  • Diamond et al (1994) described a PTP from regenerating rat liver that is a member of a fourth class. The gene, which they designated Prll, was one of many immediate-early genes.
  • PTP(CAAXl) and PTP(CAAX2) represent a novel class of isoprenylated, oncogenic PTPs.
  • Peng et al. (1998) reported that the human PTP(CAAXl) gene, or PRL1, is composed of 6 exons and contains 2 promoters. The predicted mouse, rat, and human PRL1 proteins are identical. Zeng et al (1998) determined that the human PRL1 and PRL2 proteins share 87% amino acid sequence identity.
  • the NOV14 nucleic acids and polypeptides, antibodies and related compounds according to the mvention will be useful in therapeutic and diagnostic applications in the mediation of cardiac and renal physiology.
  • the NOVl 4 nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat cardiovascular and urogenital system disorders, e.g., Cardiovascular diseases, cystitis, incontinence as well as other diseases, disorders and conditions.
  • the NOV 14 nucleic acids and polypeptides are useful for detecting specific cell types. For example, expression analysis has demonstrated that a NOVl 4 nucleic acid is expressed in Urinary bladder.
  • NOV14 nucleic acids and polypeptides according to the invention are disclosed herein.
  • a NOVl 5 polypeptide has been identified as a Leucine Rich Repeat (LRR)-like protein (also referred to as CG95387-02).
  • LRR Leucine Rich Repeat
  • SEQ ID NO:31 The disclosed novel NOVl 5 nucleic acid (SEQ ID NO:31) of 3136 nucleotides is shown in Table 15A.
  • the novel NOV15 nucleic acid sequences maps to the chromosome 19.
  • An ORF begins with an ATG initiation codon at nucleotides 330-332 and ends with a TAA codon at nucleotides 2331-2333.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 15 A, and the start and stop codons are in bold letters.
  • a variant sequence can include a single nucleotide polymo ⁇ hism (SNP).
  • SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA.
  • the NOVl 5 protein (SEQ D NO:32) encoded by SEQ ID NO:31 is 667 amino acid residues in length and is presented using the one-letter amino acid code in Table 15B. Psort analysis predicts the NOVl 5 protein of the invention to be localized at the plasma membrane with a certainty of 0.7900.
  • nucleic acid sequence of this invention has 2227 of 2228 bases (99%) identical to a gb:GENBANK-ID:AK027073
  • the full amino acid sequence of the protein of the invention was found to have 444 of 444 amino acid residues (100%) identical to, and 444 of 444 amino acid residues (100%) similar to, the 444 amino acid residue ptnr:SPTREMBL-ACC:Q9H5H8 protein from Homo sapiens (CDNA: FLJ23420 FIS, CLONE HEP22352).
  • NOV 15 also has homology to the proteins shown in the BLASTP data in Table 15D.
  • the NOVl 5 Clustal W alignment shown in Table 15E was modified to begin at amino residue 121.
  • the data in Table 15E includes all of the regions overlapping with the NOVl 5 protein sequences.
  • ⁇ OV15 has, for example, eight Leucine Rich Repeat (LRR) signature sequences and homology to other members of the LRR-like Protein Family.
  • LRR Leucine Rich Repeat
  • NOVl 5 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOVl 5 nucleic acids and polypeptides can be used to identify proteins that are members of the LRR-like Protein Family.
  • the NOV 15 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVl 5 activity or function.
  • nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation, cellular replication, and signal transduction.
  • These molecules can be used to treat, e.g., cancer, trauma, regeneration (in vitro and in vivo), viral/bacterial/parasitic infections, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, Lesch-Nyhan syndrome, multiple sclerosis, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neurodegeneration, Von Hippel-Lindau (VHL) syndrome, cirrhosis, transplantation, Hirschsprung's disease , Crohn's Disease, appendicitis, osteoporosis, hypercalceimia, arthritis, ankylosing spondylitis, scoliosis, systemic lupus
  • NOVl 5 nucleic acids and polypeptides according to the invention are useful, ter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOVl 5 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of proteins belonging to the LRR-like Protein Family.
  • LRR Proteins are a family of proteins characterized by a structural motif rich in leucine residues. They are either transmembrane or secreted proteins and are involved in protein- protein interactions. Members of this family have been implicated in extracellular matrix assembly and cellular growth.
  • LRRs are relatively short motifs (22-28 residues in length) found in a variety of cytoplasmic, membrane and extracellular proteins. Although these proteins are associated with widely different functions, a common property involves protein-protein interaction. Little is known about' the 3D structure of LRRs, although it is believed that they can form amphipathic structures with hydrophobic surfaces capable of interacting with membranes. In vitro studies of a synthetic LRR from Drosophila Toll protein have indicated that the peptides form gels by adopting beta-sheet structures that form extended filaments (Packman et al. FEBS Lett.1991; 291 : 87-91). These results are consistent with the idea that LRRs mediate protein-protein interactions and cellular adhesion. Other functions of LRR-containing proteins include, for example, binding to enzymes and vascular repair.
  • the NOVl 5 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications in the mediation of cardiac, immune, and nerve physiology.
  • the NOV 15 nucleic acids and polypeptides, antibodies and related compounds according to the invention may be used to treat cardiovascular, nervous, and immune system disorders, e.g., cancer, trauma, regeneration (in vitro and in vivo), viral/bacterial/parasitic infections, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, Lesch-Nyhan syndrome, multiple sclerosis, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neurodegeneration, Von Hippel-Lindau (VHL) syndrome, cirrhosis, transplantation, Hirschsprung's disease, Crohn's Disease, appendicitis, osteoporosis, hypercalceimia, arthritis, anky
  • NOV 15 nucleic acid is expressed in Coronary Artery, Parotid Salivary glands, Liver, Colon, Bone, Synovium/Synovial membrane, and Brain.
  • NOV 15 nucleic acids and polypeptides according to the invention are disclosed herein.
  • NOV16 is disclosed herein.
  • a NOVl 6 polypeptide has been identified as a RhoGEF-like protein (also referred to as CG95419-02).
  • the disclosed novel NOV16 nucleic acid (SEQ ID NO:33) of 5372 nucleotides is shown in Table 16A.
  • the novel NOVl 6 nucleic acid sequences maps to the chromosome 5.
  • Ail ORF begins with an ATG initiation codon at nucleotides 61-63 and ends with a TAA codon at nucleotides 5179-5181.
  • a putative untranslated region and/or downstream from the termination codon is underlined in Table 16 A, and the start and stop codons are in bold letters.
  • the NOV16 protein (SEQ ID NO:34) encoded by SEQ ID NO:33 is 1706 amino acid residues in length and is presented using the one-letter amino acid code in Table 16B. Psort analysis predicts the NOVl 6 protein of the invention to be localized in the cytoplasm with a certainty of 0.4500.
  • nucleic acid sequence of this invention has 4339 of 5274 bases (82%) identical to a gb:GENBANK-rD:MMU73199
  • the full amino acid sequence of the protein of the mvention was found to have 1350 of 1670 amino acid residues (80%) identical to, and 1460 of 1670 amino acid residues (87%) similar to, the 1693 amino acid residue ptnr:SWISSPROT-ACC:P97433 protein from as musculus (RHO-GUANINE NUCLEOTIDE EXCHANGE FACTOR (RHOGEF) (RIP2)).
  • NOVl 6 also has homology to the proteins shown in the BLASTP data in Table 16D.
  • Table 16D BLAST results for NOV16
  • Table 16E A multiple sequence alignment is given in Table 16E, with the NOV16 protein being shown on line 1 in Table 16E in a ClustalW analysis, and comparing the NOV16 protein with the related protein sequences shown in Table 16D.
  • This BLASTP data is displayed graphically in the ClustalW in Table 16E.
  • Rho interacting protein 2 > gi]7106395]/ Rho interacting protein 2; Rho specific exchange factor [Mus musculus]; SEQ ID NO: 1;
  • Rho interacting protein 2 > gi
  • NOV 16 has, for example, a RhoGEF signature sequence and homology to other members of the RhoGEF- like Protein Family.
  • NOVl 6 nucleic acids, and the encoded polypeptides, according to the invention are useful in a variety of applications and contexts.
  • NOVl 6 nucleic acids and polypeptides can be used to identify proteins that are members of the RhoGEF-like Protein Family.
  • the NOVl 6 nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVl 6 activity or function.
  • nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., cellular activation, cellular replication, and signal transduction. These molecules can be used to treat, e.g.
  • VHL Von Hippel-Lindau
  • graft versus host disease Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, Lesch-Nyhan syndrome, multiple sclerosis, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neurodegeneration, cirrhosis, transplantation, adrenoleukodystrophy , congenital adrenal hyperplasia, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, autoimmune disease, allergies, immunodeficiencies
  • NOV 16 nucleic acids and polypeptides according to the invention are useful, inter alia, as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
  • the NOVl 6 nucleic acids and their encoded polypeptides include structural motifs that are characteristic of proteins belonging to the RhoGEF-like Protein Family.
  • GEF Guide nucleotide exchange factor
  • Rho/Rac/Cdc42-like GTPases is also called Dbl-homologous (DH) domain.
  • DH Dbl-homologous domain.
  • PH pleckstrin homology domains invariably occur C-terminal to RhoGEF/DH domains.
  • binding to the beta/gamma subunit of heterotrimeric G proteins binding to lipids, e.g. phosphatidylinositol-4,5-bisphosphate, binding to phosphorylated Ser/Thr residues, attachment to membranes by an unknown mechanism.
  • the DAG_PE-binding domain binds two zinc ions; the ligands of these metal ions are probably the six cysteines and two histidines that are conserved in this domain and can regulate signal transduction by the PKC family of kinases.
  • NOVl 6 belongs to the guanine nucleotide exchange factor family of proteins which play a significant role in signal transduction.
  • the guanine nucleotide exchange factor (GEF) domain that regulates GTP binding protein signaling.
  • the GEF domain regulates positively the signaling cascades that utilize GTP-binding proteins (such as those of the ras superfamily) that function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking.
  • FGD1 farnesoid dyplasia protein
  • Rho family GTPase Cdc42Hs Rho family GTPase Cdc42Hs
  • the GEF domain of FGD1 has also been shown to activate 2 kinases involved in cell proliferation; the Jun NH2- terminal kinase and the p70 S6 kinase (Zheng et al; J. Biol. Chem 1996 Dec 27;271(52):33169-72).
  • NOV16 polypeptide may play an important role in normal development as well as disease.
  • This class of molecules (GEFs) is also being considered as a good drug target as the guanine nucleotide exchange factor RasGRP is a high -affinity target for diacylglycerol and phorbol esters and is bound by bryostatin 1, a compound currently in clinical trials (Lorenzo et al; Mol. Pharmacol 2000 May; 57(5):840-6).
  • the homolog of RhoGEF, DRhoGEF2 fail to gastrulate due to a defect in cell shape changes required for tissue invagination and the mRNA is found throughout oogenesis and embryogenesis (Barrett et al.
  • RhoGEF also interacts with c-Jun amino-terminal kinase (JNK) interacting protein- 1 (JIP-1).
  • JEP-1 might function as a scaffold protein by complexing specific components of the JNK signaling pathway, namely JNK, mitogen-activated protein kinase kinase 7, and mixed lineage kinase 3 (Meyer et al; J Biol Chem 1999; 274(49):35113-8).

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