WO2004013177A1 - Modulation de fonctions a mediation par upa au moyen du fragment aminoterminal du recepteur de mannose-6-phosphate/facteur de croissance insulinoide 2 (cd222) - Google Patents

Modulation de fonctions a mediation par upa au moyen du fragment aminoterminal du recepteur de mannose-6-phosphate/facteur de croissance insulinoide 2 (cd222)

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Publication number
WO2004013177A1
WO2004013177A1 PCT/AT2003/000224 AT0300224W WO2004013177A1 WO 2004013177 A1 WO2004013177 A1 WO 2004013177A1 AT 0300224 W AT0300224 W AT 0300224W WO 2004013177 A1 WO2004013177 A1 WO 2004013177A1
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WO
WIPO (PCT)
Prior art keywords
cells
upa
activation
cell
plg
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PCT/AT2003/000224
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German (de)
English (en)
Inventor
Hannes Stockinger
Bernd Binder
Vladimir Leksa
Samuel Godar
Johannes Breuss
Original Assignee
Hannes Stockinger
Bernd Binder
Vladimir Leksa
Samuel Godar
Johannes Breuss
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.)
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Publication date
Application filed by Hannes Stockinger, Bernd Binder, Vladimir Leksa, Samuel Godar, Johannes Breuss filed Critical Hannes Stockinger
Priority to AU2003281845A priority Critical patent/AU2003281845A1/en
Publication of WO2004013177A1 publication Critical patent/WO2004013177A1/fr

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    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere

Definitions

  • the present invention relates to the molecular mechanism of how the functions of the TJrokinase type plasminogen activator receptor (uPA-R, CD87) are controlled by the marose-6-phosphate / insulin-like growth factor 2 receptor (CD222).
  • uPA-R TJrokinase type plasminogen activator receptor
  • CD222 marose-6-phosphate / insulin-like growth factor 2 receptor
  • BSA bovine serum albumin
  • FKS fetal calf serum
  • GPI glycosylphosphatidylinositol
  • HUVEC human umbilical cord endothelial cells
  • HUVSMC human smooth muscle cells from umbilical cord
  • IGF2 Insulin Growth Factor 2
  • LTGFß latent form of the transforming growth factor beta
  • M6-P mannose-6-phosphate
  • M6P / IGF2-R mannose-6-phosphate / insulin-like growth factor 2 receptor
  • Mini plg mini plasminogen
  • MLEC mink length epithelial cells
  • PBMCs peripheral blood mononuclear cells
  • pepA peptide A
  • pepB peptide B
  • pepBscr permuted peptide B
  • pepC peptide C
  • Plg plasminogen
  • TGFß transforming growth factor beta
  • uPA urokinase type plasminogen activator
  • uPA-R urokinase type plasminogen activator receptor
  • Reagents - Peptide B (pepB, ANDTKNNNLYKTNIAGSN), the permuted version of PepB (pepBscr, DILN ⁇ GAKNATKIN ⁇ Y ⁇ S) and Peptide C (pepC, HDLKTRTYHSNGDSNLRS) were developed by Genosphere Biotechnologies (Paris, France), Peptide, Q, Graz, A, P (B) Austria.) Manufactured. Vitronectin, pro-uPA, uPA, Glu-Plg, Kl -3, mini-Plg and PAI-1, all of human origin, are products from Technoclone (Vienna, Austria).
  • Human fibronectin, rat collagen-1 and mouse laminin are products from Upstate (Lake Placid, ⁇ Y).
  • Aprotinin, crystal violet, polybrene, Triton X-100 and tranexamic acid (TA) are from Sigma Chemical Co. (St. Louis, MO).
  • the piasmin substrate S-2251 was manufactured by Chromogenix (Milan, Italy).
  • BSA is a product of Behring (Marburg, Germany).
  • the CD222-negative mouse fibroblasts were developed by Dr. E. Wagner (1) provided and cultivated in RPMI-1640 medium with penicillin, streptomycin, glutamine and 10% FCS.
  • the ecotropic nerpack cell line Phoenix was developed by Dr. G. P. ⁇ olan (2) was made available and was cultivated in DMEM medium under standard conditions.
  • Human peripheral blood mononuclear cells (PBMCs) were isolated from the blood of healthy individuals using Ficoll Hypaque density gradients. Monocytes were obtained from this by incubating on a plastic surface for one hour.
  • FIUVEC and HUVSMC were isolated from umbilical cord.
  • FfUVSMC were cultivated in DMEM medium with 10% FCS.
  • HUVEC were cultured in DMEM with 20% BSA, 10 ng / ml basic fibroblast growth factor and 100 ⁇ g / ml heparin.
  • the 8 kb fragment of the complete human CD222 cDNA and the 1.4 kb fragment of the complete human CD 87 cDNA were cloned into the retroviral vector BMN-Z (3). All transfection and transduction processes have been described previously (2, 4).
  • the retroviral plasmids were transiently transfected into the ecotropic packaging cell line Phoenix using the Superfect transfection method (Qiagen, Germany). 3 days after the transfection, the supernatant-containing viral particles were treated with polybrene (4 ⁇ g / ml) mixed and the mixtures were used to infect mouse fibroblasts from CD222 deficient embryos (- / -).
  • Plasminogen activation test We slightly changed the method described above (5). After trypsinization, mouse fibroblasts were placed in a 96-well plate (Nunc. Denmark) at a density of 2 ⁇ 10 3 cells / well and then grown in RPMI-1640 medium containing 10% FCS until subconfluence. Monocytes were separated from human PBMCs by adhesion for 1 hour and then transferred to a 96-well plate (1 ⁇ 10 6 / well). The cells were washed with serum-free medium and incubated with 3 nM Pro-uPA at 37 ° C for 20 min. After washing twice, Plg (50 nM) and the chromogenic piasmin substrate S-2251 (0.8 mM) were added. The cells were incubated at 37 ° C. and after various time intervals the absorption at 405 nm was determined using an ELISA reader (Anthos Labtec Instr., Salzburg, Austria).
  • Adhesion examination The test cells were washed in serum-free medium and resuspended. A 96-well plate (Nunc) was coated with various matrix proteins in RPMI-1640 medium for 2 hours at 37 ° C. The free binding sites of the cells were blocked using a 1% BSA solution. It was then washed and then incubated either with mouse fibroblasts (10 4 / well) or with human PBMCs (10 6 / well) in the presence or absence of 10 nM uPA. After a 10-minute incubation at 37 ° C., the wells were carefully washed by immersing them in a plastic dish filled with RPMI-1640 medium. Adherent cells were fixed with methanol and stained with crystal violet. After the washing process, the cells were soaked in 0.5 "> Triton X-100 and the number of cells was determined by measuring the absorbance at 595 nm using an ELISA reader.
  • Chemotaxis Examination was performed in a 24-well plate, using tissue culture polycarbonate filter inserts (10 mm diameter, 8 ⁇ m pore size, Nunc) coated with vitronectin (10 ⁇ g / ml) and blocked with BSA.
  • Mouse fibroblasts (5xl0 4 ) or human PBMCs (lxlO 6 ) were prepared for the adhesion test and resuspended in 300 ⁇ l serum-free medium and filled into the upper chamber of the insert. 10 nM uPA in 300 ul serum-free medium was added to the lower chamber. After 4 hours incubation at 37 ° C, the filters were removed, cleaned, the top of the filter cells and the number of cells that had migrated to the underside * using Crystal Violet as described above, is determined.
  • TGFß-Detection The cell culture supernatants from test cells were diluted 10-fold with DMEM medium (0.1% BSA and 2 ⁇ g / ml aprotinin). Twelve hours before the test, the MLEC cells which carry the luciferase gene under the control of the PAI-1 (TGFß-responsive plasminogen activator inhibitor 1) promoter were sown in a 96-well plate (2 ⁇ 10 4 cell wells). The MLEC reporter cells were incubated overnight with the diluted supernatants from the test cells. After the incubation, the MLEC cells were washed, lysed and analyzed for luciferase activity.
  • DMEM medium 0.1% BSA and 2 ⁇ g / ml aprotinin
  • PAI-1 TGFß-responsive plasminogen activator inhibitor 1
  • Apoptosis-Nac white - The cells were sown in a 96-well plate (5 ⁇ 10 cells / well) and incubated in DMEM medium with 10% BSA, 2 ng / ml basic fibroblast growth factor and 100 ⁇ g / ml heparin. After 24 hours, the medium was replaced by 150 ⁇ l of the same medium with the addition of the molecules to be examined. After incubation for 24 hours, the apoptosis of the cells was detected using the Cell Death ELISA kit (Röche, Penzberg, Germany).
  • CD222 regulates CD87 -dependent functions - Numerous studies confirm the role of CD87 in the fibrinolytic system and in cell migration. None of these indicate the role of CD222 in these biological processes. Using a retroviral system, human CD222 (CD222 +), human CD87 (CD87 +) or both molecules (CD222 + / CD87 +) were expressed in fibroblasts from CD222-deficient mice (CD222 - / -) (see Materials and Methods). These cells were then used to analyze the effect of CD222 on CD87 mediated Plg activation, cell adhesion, chemotaxis and TGFß activation. The ability of these cells to test Plg activation was first tested.
  • the cells were preincubated with human Pro-uPA, washed and then incubated with Plg together with the chromogenic piasmin substrate S-2251. Under these conditions, Plg was activated efficiently after 3 hours.
  • CD87 + cells showed significantly stronger Plg activation compared to basal Plg activation by - / - cells.
  • CD222 expression reduced basal activity.
  • Plg activation was significantly reduced compared to the CD87 single transductants (Fig. 1).
  • Plg activation was destroyed by tranexamic acid (TA), a lysine analog. Since TA is an inhibitor of Plg binding to the cell surface, this experiment shows that cell-bound Plg is necessary for activation.
  • the uPA inhibitor PAI-1 also inhibited Plg activation, which indicates the uPA dependence of this process (Fig. 1).
  • the discovery that the coexpression of human CD222 reduces the ability of CD87 + cells to activate Plg was the first indication that CD222 has a regulatory effect on CD 87 -edicated functions.
  • the adhesive capacity of the transductants produced was examined.
  • the cells were incubated in wells which were coated with various matrix proteins in the presence or absence of human uPA. After washing, the number of adherent cells was determined (Fig. 2).
  • Adhesion to fibronectin was weaker (19 ⁇ 1%) and adhesion to laminin was weak (8 ⁇ 1%).
  • the CD87H cells showed stronger adhesion to vitronectin (52 ⁇ 2%, Fig.
  • the uPA inhibitor PAI-1 inhibited CD87 / uPA induced adhesion to vitronectin, which confirms the specificity of the system (Fig. 2C).
  • the impact of CD87 and CD222 on uPA-induced chemotaxis was assessed. Modified Boyden gobs coated with Vitronectin were used for this (Fig. 3).
  • the - / - cells showed little basal migration.
  • CD87 was expressed, approximately 2 times more cells migrated (28 ⁇ 2% versus 14 ⁇ 1%).
  • CD87 + cells increased their migratory response (50 ⁇ 3% of the cells); this effect was canceled by PAI-1.
  • the N-terminal region of CD222 is similar to the Plg binding region in streptokinase and a peptide derived from this region in CD222 can modulate CD 87 -dependent functions.
  • Comparison of the amino acid sequence of CD222 with proteins known to bind and activate Plg showed similarity to streptokinase (Fig. 4).
  • Streptokinase is a protein secreted by streptococci and has the ability to digest tissue barriers by binding and activating Plg (6).
  • the region of the N-terminal region of streptokinase, which is similar to the N-terminus of CD222 was shown to contain an epitope, which is also found in the putative Plg binding site of fibronectin (7).
  • sequence comparisons showed a 21% identity and a 55 similarity between the corresponding regions of CD222 and streptokinase. This sequence context prompted us to analyze peptides based on the N-terminal sequence of CD222 for their influence on CD87 functions.
  • peptide B (pepB) "was derived from the region in CD222 that is similar to the described Plg binding site in streptokinase (8); peptide C (pepC) is derived from the sequence in CD222 that corresponds to the known Plg - Activation site in streptokinase similar to (9) (Fig. 4).
  • the peptides were designed to include the conserved amino acid residues and the lysines suspected of Plg binding, to prevent cyclic or intermolecular peptide complexes avoid (such observations were made in previous studies with cysteine-containing peptides, unpublished data), the cysteine of CD222 in pepB was replaced by alanine (Fig. 4).
  • pepA permuted form of pepB - pepBscr and peptide A (pepA), the latter peptide being derived from domain 15 of CD222, was used as a control.
  • the peptides were checked for their ability to modulate the functions of CD87. For this purpose, they were used in the methods described above. These experiments have shown that pepB suppresses uPA-induced Plg activation in CD87 + cells, as well as adhesion to and chemotaxis by vitronectin (FIG. 5). The other peptides had little or no effect.
  • pepB also inhibits uPA-induced Plg activation, adhesion to, and chemotaxis to vitronectin in human monocytes / PBMCs.
  • PepB was also able to inhibit the uPA-induced migration of human smooth muscle cells (data not shown). These results are in agreement with those that we obtained with transduced mouse fibroblasts.
  • a peptide (pepB) derived from the N-terminus of CD222 mimics the effect of CD222 on CD 87 mediated Plg activation, cell adhesion and chemotaxis.
  • An agonistic peptide from CD222 has been established that mimics the regulatory effect of CD222 on CD 87.
  • CD222 regulates TGFß activation -
  • a mechanism for the activation of LTGFß by a protein complex consisting of CD222 and CD87 (10).
  • TGFß activation in - / -, CD222 + , CD87 + and CD222 + / CD87 + fibroblasts were tested the effects of CD222-derived peptides on LTGFß activation.
  • TGFß concentration of TGFß was dependent on the proteolytic activity of Plm, as could be shown by the partial inhibition by the serine protease inhibitor aprotinin.
  • TGFß activation of CD222 + / CD87 + cells was also inhibited by PepB (Fig. 6). This shows that CD222, and especially its N-terminal part, also plays an important role in the activation of TGFß, a central cytokine for the regulation of cell migration, immune responses and apoptosis.
  • the selective influence of TGFß on the apoptosis of cells is clearly shown in FIG.
  • TGFß induces apoptosis in HUVEC but not in HUVSMC
  • Mini-Flg induces apoptosis in endothelial cells -
  • Plg the proteolytic fragments of Plg, Kl -3 and mini-Plg.
  • Plg the proteolytic fragments of Plg, Kl -3 and mini-Plg.
  • CD87 / CD222 complex induces an anti-angiogenic mechanism that has not yet been described, and anti-angiogenic signaling pathways are potential target structures for tumor therapy in order to starve the tumor by blocking the supply by the vessels.
  • CD222 circulates very quickly between the Trans-Golgi network, lysosomes, plasma membrane and endosomes. This cellular transport can be regulated by various factors including CD222 ligands, growth factors, retinoic acid, phorholester (11-14). The number of CD222 molecules in the plasma membrane can therefore be quickly changed by various stimulations. In view of our data, this process could enable cells under various physiological circumstances (e.g. monocyte differentiation / activation during inflammation) to quickly control cell surface-associated proteolysis, adhesion, chemotaxis, TGFß activation and apoptosis. Furthermore, loss of CD222 function, such as due to mutation in various tumors (15), and consequently loss of control over CD87 could not only lead to uncontrolled tumor growth, but also to increased pericellular proteolysis and uncontrolled infiltration of tumor cells.
  • Plg activation test The cells (- / -, CD87 +, CD222 +, CD222H- / CD87 + mouse fibroblasts) were placed in a 96-well plate and cultured to confluence for 24 hours. The cells were preincubated for 20 min at 37 ° C with serum-free medium containing 3nM pro-uPA, washed and then with Plg (50r ⁇ VI) and the chromogenic plasmin-specific substrate S-2251 (0.8 mM). The piasmin activity was determined at various time intervals by measuring the absorbance at 405 nm. Some experiments were carried out in the presence of 5 mM TA or 10 U / ml PAI-1. (The data obtained are shown for CD87 + cells.) The experiments were repeated 3 times in duplicates.
  • FiG 3 Cell chemotaxis examination.
  • the chemotaxis analyzes were carried out in a 24-well plate using tissue culture polycarbonate filter inserts. The bottom sides of the filters used were coated with Vitronectin and blocked with BSA.
  • Cells (- / -, CD87 +, CD222 +, CD222 + / CD87 + mouse fibroblasts) were harvested, washed, resuspended in serum-free medium and placed in the upper chamber. Medium with either 10 nM uPA, uPA plus PAH (10 nM plus 10 U / ml) or no additive was placed in the lower chamber.
  • the filters were washed, the top of the filters were scraped free of cells and the adherent cells were fixed on the underside and stained with crystal violet.
  • the cell number was determined by measuring the absorbance at 595 nm.
  • the migration of the cells to the bottom of the filter is expressed as a percentage of the total amount of cells used.
  • the experiments were repeated 4 times in duplicates; the mean values +/- SD (* P ⁇ 0.05) are shown.
  • FiG 4 Comparison of the N-terminal region of CD222 (amino acids 53-105) with the Plg-binding region of streptokinase (SK, amino acid 7-59) and fibronectin (FN, amino acid 1733-1785). The conserved amino acid residues between the sequences are boxed, a conservative exchange is indicated by a dot or brackets. The peptides derived from this region (pepB and pepC) are listed. Alanine, which was exchanged for cysteine within the pepB sequence, is underlined.
  • the cell culture supernatants were analyzed for their TGF ⁇ concentration using MLEC reporter cells.
  • the results are shown as relative TGFß activity compared to untreated cells (100%).
  • the mean values +/- SD (* P ⁇ 0.05) are shown.
  • FIG. 7 Apoptosis induction in HUVEC and HUVSMC by TGFß.
  • the cells were placed in a 96-well plate (5000 cells / well) and incubated in the presence of purified TGFßl, TGFß2 and TGFß3 preparations (50, 10 and 2ng / ml). The cells were then washed with culture medium and lysed. Intact DNA was removed by centrifugation and the presence of soluble nucleosomes in the supernatant was detected using the Death ELISA kit. The relative apoptosis units were determined by the standard in the kit.
  • FlG 8 Apoptosis induction by mini-Plg in HUVEC. HUVEC were placed in a 96-well plate (5000 cells / well) and incubated for 24 hours with 240 nM of Plg or its fragments. Apoptosis was measured as described in Fig. 7.

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Abstract

La présente invention concerne des mécanismes moléculaires du contrôle des fonctions du récepteur d'activateur de plasminogène de type urokinase (uPA-R, CD87). Il a été montré que le mannose-6-phosphate/facteur de croissance insulinoïde 2 (M6P/IGF2-R, CD222) régule l'activation du plasminogène à médiation par uPA/CD87 (Plg), l'adhésion cellulaire, la migration cellulaire, l'activation de TGFβ et l'apoptose. De plus, la région N-terminale de CD222 est la partie fonctionnelle de contrôle du système uPA/CD87. Un peptide dérivé de cette région dans CD222 reproduit les effets inhibiteurs de CD222 sur des fonctions de CD87. Cette invention permet ainsi de démontrer un nouveau rôle de CD222 dans la régulation de la fibrinolyse, de l'adhésion cellulaire, de la migration cellulaire, de l'activation de TGFβ et de l'apoptose et de mettre au point de nouveaux outils et structures cibles pour influencer de manière thérapeutique ces fonctions cellulaires dans des conditions pathologiques telles qu'une métastase tumorale et des inflammations.
PCT/AT2003/000224 2002-08-06 2003-08-05 Modulation de fonctions a mediation par upa au moyen du fragment aminoterminal du recepteur de mannose-6-phosphate/facteur de croissance insulinoide 2 (cd222) WO2004013177A1 (fr)

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AU2003281845A AU2003281845A1 (en) 2002-08-06 2003-08-05 Modulation of upa-mediated functions via the aminoterminal fragment of mannose-6-phosphate/insuline-like growth factor 2 receptor (cd222)

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AT11932002A AT413031B (de) 2002-08-06 2002-08-06 Verwendung von cd222 oder eines abgeleiteten peptids zur hemmung von fibrinolyse, zelladhäsion und zellmigration in vitro
ATA1193/2002 2002-08-06

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010146059A2 (fr) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarqueurs pour une thérapie par inhibiteur d'igf-1r

Citations (2)

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US5679350A (en) * 1992-05-28 1997-10-21 The University Of Toledo Method of delivery of a medicament to a cancer cell using a pathway of plasminogen activator material
WO1999045026A1 (fr) * 1998-03-05 1999-09-10 Chiron Corporation Procede d'augmentation de la demi-vie serique d'une molecule biologiquement active

Patent Citations (2)

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US5679350A (en) * 1992-05-28 1997-10-21 The University Of Toledo Method of delivery of a medicament to a cancer cell using a pathway of plasminogen activator material
WO1999045026A1 (fr) * 1998-03-05 1999-09-10 Chiron Corporation Procede d'augmentation de la demi-vie serique d'une molecule biologiquement active

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Title
DAHMS N M: "Insulin-like growth factor II/cation-independent mannose 6-phosphate receptor and lysosomal enzyme recognition.", BIOCHEMICAL SOCIETY TRANSACTIONS, vol. 24, no. 1, 1996, 656th Meeting of the Biochemical Society;Dublin, Ireland; September 11-15, 1995, pages 136 - 141, XP009017986, ISSN: 0300-5127 *
FAZIOLI F ET AL: "A urokinase-sensitive region of the human urokinase receptor is responsible for its chemotactic activity.", THE EMBO JOURNAL. ENGLAND 15 DEC 1997, vol. 16, no. 24, 15 December 1997 (1997-12-15), pages 7279 - 7286, XP002255622, ISSN: 0261-4189 *
GODÁR S ET AL: "M6P/IGFII-receptor complexes urokinase receptor and plasminogen for activation of transforming growth factor-beta1.", EUROPEAN JOURNAL OF IMMUNOLOGY. GERMANY MAR 1999, vol. 29, no. 3, March 1999 (1999-03-01), pages 1004 - 1013, XP002255623, ISSN: 0014-2980 *
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LEKSA VLADIMÍR ET AL: "The N terminus of mannose 6-phosphate/insulin-like growth factor 2 receptor in regulation of fibrinolysis and cell migration.", THE JOURNAL OF BIOLOGICAL CHEMISTRY. UNITED STATES 25 OCT 2002, vol. 277, no. 43, 25 October 2002 (2002-10-25), pages 40575 - 40582, XP002255624, ISSN: 0021-9258 *
LIU L ET AL: "Leucine 42 in the fibronectin motif of streptokinase plays a critical role in fibrin-independent plasminogen activation.", THE JOURNAL OF BIOLOGICAL CHEMISTRY. UNITED STATES 1 DEC 2000, vol. 275, no. 48, 1 December 2000 (2000-12-01), pages 37686 - 37691, XP001155068, ISSN: 0021-9258 *
NYKJAER A ET AL: "Mannose 6-phosphate/insulin-like growth factor-II receptor targets the urokinase receptor to lysosomes via a novel binding interaction.", THE JOURNAL OF CELL BIOLOGY. UNITED STATES 4 MAY 1998, vol. 141, no. 3, 4 May 1998 (1998-05-04), pages 815 - 828, XP002255621, ISSN: 0021-9525 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010146059A2 (fr) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarqueurs pour une thérapie par inhibiteur d'igf-1r

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ATA11932002A (de) 2005-03-15
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