EP1192174A4 - Antagonists of bmp and tgf beta signalling pathways - Google Patents
Antagonists of bmp and tgf beta signalling pathwaysInfo
- Publication number
- EP1192174A4 EP1192174A4 EP00941398A EP00941398A EP1192174A4 EP 1192174 A4 EP1192174 A4 EP 1192174A4 EP 00941398 A EP00941398 A EP 00941398A EP 00941398 A EP00941398 A EP 00941398A EP 1192174 A4 EP1192174 A4 EP 1192174A4
- Authority
- EP
- European Patent Office
- Prior art keywords
- smurf1
- bmp
- tgfβ
- signalling
- smurf2
- 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- Withdrawn
Links
- 230000019491 signal transduction Effects 0.000 title abstract 2
- 239000005557 antagonist Substances 0.000 title 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 title 1
- 101100477839 Drosophila melanogaster Smurf gene Proteins 0.000 abstract 5
- 102000004887 Transforming Growth Factor beta Human genes 0.000 abstract 4
- 108090001012 Transforming Growth Factor beta Proteins 0.000 abstract 4
- 230000011664 signaling Effects 0.000 abstract 4
- 108010059616 Activins Proteins 0.000 abstract 3
- 102100026818 Inhibin beta E chain Human genes 0.000 abstract 3
- 239000000488 activin Substances 0.000 abstract 3
- 230000037361 pathway Effects 0.000 abstract 3
- 102100025744 Mothers against decapentaplegic homolog 1 Human genes 0.000 abstract 2
- 102100030608 Mothers against decapentaplegic homolog 7 Human genes 0.000 abstract 2
- 101700032040 SMAD1 Proteins 0.000 abstract 2
- 101700026522 SMAD7 Proteins 0.000 abstract 2
- 210000002257 embryonic structure Anatomy 0.000 abstract 2
- 210000003716 mesoderm Anatomy 0.000 abstract 2
- 230000034512 ubiquitination Effects 0.000 abstract 2
- 238000010798 ubiquitination Methods 0.000 abstract 2
- 102000003960 Ligases Human genes 0.000 abstract 1
- 108090000364 Ligases Proteins 0.000 abstract 1
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 abstract 1
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 abstract 1
- 241000269370 Xenopus <genus> Species 0.000 abstract 1
- 230000008512 biological response Effects 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 230000015556 catabolic process Effects 0.000 abstract 1
- 230000033026 cell fate determination Effects 0.000 abstract 1
- 230000033081 cell fate specification Effects 0.000 abstract 1
- 238000006731 degradation reaction Methods 0.000 abstract 1
- 230000003828 downregulation Effects 0.000 abstract 1
- 210000003981 ectoderm Anatomy 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 230000013020 embryo development Effects 0.000 abstract 1
- 210000004962 mammalian cell Anatomy 0.000 abstract 1
- 102000004169 proteins and genes Human genes 0.000 abstract 1
- 108090000623 proteins and genes Proteins 0.000 abstract 1
- 230000007261 regionalization Effects 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 230000008685 targeting Effects 0.000 abstract 1
- 230000007306 turnover Effects 0.000 abstract 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/93—Ligases (6)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Physical Education & Sports Medicine (AREA)
- Wood Science & Technology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- General Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Neurology (AREA)
- Microbiology (AREA)
- Rheumatology (AREA)
- Ophthalmology & Optometry (AREA)
- Biochemistry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Enzymes And Modification Thereof (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
This invention provides unique members of the Hect family of ubiquitin ligases that specifically target BMP and TGFβ/activin pathway-specific Smads. The novel ligases have been named Smurf1 and Smurf2. They directly interact with Smads1 and 5 and Smad7, respectively, and regulate the ubiquitination, turnover and activity of Smads and other proteins of these pathways. Smurf1 interferes with biological responses to BMP, but not activin signalling. In amphibian embryos Smurf1 inhibits endogenous BMP signals, resulting in altered pattern formation and cell fate specification in the mesoderm and ectoderm. The present invention provides a unique regulatory link between the ubiquitination pathway and the control of cell fate determination by the TGFβ superfamily during embryonic development. Thus, Smurf1 is a negative regulator of Smad1 signal transduction, by targeting Smad1, Smurf1 blocks BMP signalling. In mammalian cells, Smurf2 suppresses TGFβ signalling, and in Xenopus, blocks formation of dorsal mesoderm and causes anterior truncation of the embryos. Smurf2 forms a stable complex with Smad7, which induces degradation and downregulation of TGFβ/activin signalling.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13896999P | 1999-06-11 | 1999-06-11 | |
| US138969P | 1999-06-11 | ||
| PCT/US2000/016250 WO2000077168A2 (en) | 1999-06-11 | 2000-06-12 | ANTAGONISTS OF BMP AND TGFβ SIGNALLING PATHWAYS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP1192174A2 EP1192174A2 (en) | 2002-04-03 |
| EP1192174A4 true EP1192174A4 (en) | 2002-08-28 |
Family
ID=22484504
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00941398A Withdrawn EP1192174A4 (en) | 1999-06-11 | 2000-06-12 | Antagonists of bmp and tgf beta signalling pathways |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1192174A4 (en) |
| JP (1) | JP2003502064A (en) |
| CN (1) | CN100379752C (en) |
| AU (1) | AU782355B2 (en) |
| CA (1) | CA2376675A1 (en) |
| IL (1) | IL147005A0 (en) |
| WO (1) | WO2000077168A2 (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7358056B1 (en) | 1999-08-30 | 2008-04-15 | Signal Pharmaceuticals | Methods for modulating signal transduction mediated by TGF-β and related proteins |
| US20030092603A1 (en) * | 2001-10-09 | 2003-05-15 | Mundy Gregory R. | Identification of specific modulators of bone formation |
| EP1639008A1 (en) * | 2003-07-01 | 2006-03-29 | VIB vzw | Ubiquitinated tnf receptor 2 and its uses |
| ATE557087T1 (en) * | 2003-09-11 | 2012-05-15 | Hubit Genomix Inc | Procedure and KIT for the detection of sclerosis proliferative diseases and/or remedies against sclerosis proliferative diseases as well as procedures and KIT to identify proliferative diseases caused by the prevention and/or treatment of sclerosis. |
| GB0526664D0 (en) * | 2005-11-30 | 2006-02-08 | Plasticell Ltd | Method |
| KR100959050B1 (en) | 2006-03-01 | 2010-05-20 | 소프트맥스 인코퍼레이티드 | System and method for generating a separated signal |
| JP2010519274A (en) | 2007-02-21 | 2010-06-03 | フラームス・インテルウニフェルシタイル・インステイチュート・フォール・ビオテヒノロヒー・ヴェーゼットウェー（ヴェーイーベー・ヴェーゼットウェー） | Combination therapy using TNF and α-galactosylceramide |
| US20100183514A1 (en) * | 2007-05-29 | 2010-07-22 | President And Fellows Of Harvard College | Molecules involved in regulation of osteoblast activity and osteoclast activity, and methods of use thereof |
| US9745589B2 (en) | 2010-01-14 | 2017-08-29 | Cornell University | Methods for modulating skeletal remodeling and patterning by modulating SHN2 activity, SHN3 activity, or SHN2 and SHN3 activity in combination |
| US9403833B2 (en) * | 2014-05-14 | 2016-08-02 | Novartis Ag | Carboxamide derivatives |
| US9403810B2 (en) * | 2014-05-14 | 2016-08-02 | Novartis Ag | Carboxamide derivatives |
| KR102360028B1 (en) * | 2014-12-26 | 2022-02-08 | 삼성전자주식회사 | Composition for reducing senescence of a cell or a subject comprising Smurf2 inhibitor and use thereof |
| CN110196326A (en) * | 2019-06-05 | 2019-09-03 | 武汉合研生物医药科技有限公司 | A kind of TGF β R1(T204D) enzymatic activity rapid detection method and its application |
| CN110592032B (en) * | 2019-10-14 | 2021-04-13 | 北京理工大学 | Ubiquitin ligase Smurf1 mutant, coding gene and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997012962A1 (en) * | 1995-10-04 | 1997-04-10 | Cold Spring Harbor Laboratory | Ubiquitin ligases, and uses related thereto |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6103869A (en) * | 1997-05-20 | 2000-08-15 | Ludwig Institute For Cancer Research | Smad2 phosphorylation and interaction with Smad4 |
| US5976849A (en) * | 1998-02-05 | 1999-11-02 | Zeneca Limited | Human E3 ubiquitin protein ligase |
-
2000
- 2000-06-12 CA CA002376675A patent/CA2376675A1/en not_active Abandoned
- 2000-06-12 IL IL14700500A patent/IL147005A0/en unknown
- 2000-06-12 EP EP00941398A patent/EP1192174A4/en not_active Withdrawn
- 2000-06-12 WO PCT/US2000/016250 patent/WO2000077168A2/en active IP Right Grant
- 2000-06-12 CN CNB008113548A patent/CN100379752C/en not_active Expired - Fee Related
- 2000-06-12 AU AU56107/00A patent/AU782355B2/en not_active Ceased
- 2000-06-12 JP JP2001504003A patent/JP2003502064A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997012962A1 (en) * | 1995-10-04 | 1997-04-10 | Cold Spring Harbor Laboratory | Ubiquitin ligases, and uses related thereto |
Also Published As
| Publication number | Publication date |
|---|---|
| AU782355B2 (en) | 2005-07-21 |
| WO2000077168A2 (en) | 2000-12-21 |
| AU5610700A (en) | 2001-01-02 |
| EP1192174A2 (en) | 2002-04-03 |
| WO2000077168A3 (en) | 2001-05-03 |
| CN100379752C (en) | 2008-04-09 |
| JP2003502064A (en) | 2003-01-21 |
| IL147005A0 (en) | 2002-08-14 |
| CA2376675A1 (en) | 2000-12-21 |
| CN1409722A (en) | 2003-04-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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| 17P | Request for examination filed |
Effective date: 20020111 |
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| AK | Designated contracting states |
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| AX | Request for extension of the european patent |
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| A4 | Supplementary search report drawn up and despatched |
Effective date: 20020716 |
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| AK | Designated contracting states |
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| RIC1 | Information provided on ipc code assigned before grant |
Free format text: 7C 07H 21/04 A, 7C 12N 15/00 B, 7C 07K 14/00 B, 7C 12N 9/00 B |
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| 17Q | First examination report despatched |
Effective date: 20050524 |
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| GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
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| GRAS | Grant fee paid |
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| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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| 18D | Application deemed to be withdrawn |
Effective date: 20100105 |