Mechanisms by which cleaved kininogen inhibits endothelial cell differentiation and signalling

Summary

We have shown that cleaved high-molecular-weight kininogen inhibits endoththelial cell tube and vacuole formation in a concentration-dependent manner and this correlates with its recognised anti-angiogenic activity. The antibody against the urokinase plasminogen activator receptor (uPAR) mimicked the inhibitory effect of cleaved kininogen (HKa) on apoptosis (HKa: 30% and uPAR antibody: 26%) and tube formation. In tumour angiogenesis, cancer cells release angiogenic stimulators, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), thus stimulating the transformation of endogenous pro-uPA to uPA. The proteolytic enzyme urokinase plasminogen activator (uPA) then binds to its receptor in a complex with its inhibitor PAI-1, which results in the internalisation of this complex, and activates extracellular signal-regulated kinase (ERK). Recycling of the uPAR regulates the migration of endothelial cells (ECs). ERK activation stimulates migration and proliferation and suppresses apoptosis of ECs. HKa disrupted the uPA-uPAR complex, inhibited ERK activation, and blocked the internalization of uPAR, eventually resulting in cell death and cell motility arrest. Both are critical steps in angiogenesis.

Keywords

Urokinase / receptor - tissue factor / factor VII - endothelial cells - contact phase - cytokines

• References

• 1 Ratnoff OD, Colopy JE. A familial hemorrhagic trait associated with a deficiency of a clot-promoting fraction of plasma. J Clin Invest 1955; 34: 602-613.
• 2 Hathaway WE, Belhasen LP, Hathaway HS. Evidence for a new plasma thromboplastin factor. I. Case report, coagulation studies and physicochemical properties. Blood 1965; 26: 521-532.
• 3 Colman RW. Contributions of Mayme Williams to the Elucidation of the Multiple Functions of Plasma Kininogens. Thromb Haemost 1992; 68: 99-101.
• 4 Thompson RE, Mandle Jr R, Kaplan AP. Studies of binding of prekallikrein and factor XI to high molecular weight kininogen and its light chain. Proc Natl Acad Sci USA 1979; 76: 4862-4866.
• 5 Raja SN, Campbell JN, Mayer RA. et al. Role of kinins in pain and hyperalgesia: Psychophysical studies in a patient with kininogen deficiency. Clin Sci 1992; 83: 337-341.
• 6 Colman RW, Schmaier AH. Contact System: A vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997; 90: 3819-3843.
• 7 Zhao Y, Qiu Q, Mahdi F. et al. Assembly and activation of HK-PK complex on endothelial cells results in bradykinin liberation and NO formation. Am J Physiol Heart Circ Physiol. 2001; 280: H1821-H1829.
• 8 Colman RW, Jameson BA, Lin Y. et al. Domain 5 of high molecular weight kininogen (kininostatin) down-regulates endothelial cell proliferation and migration and inhibits angiogenesis. Blood 2000; 95: 543-550.
• 9 Cao DJ, Guo Y-L, Colman RW. Urokinase-type plasminogen activator receptor is involved in mediating the apoptotic effect of cleaved high molecular weight kininogen in human endothelial cells. Circ Res 2004; 94: 1227-1234.
• 10 Asakura SYW, Sottile J, Zhang Q. et al. Opposing effects of low and high molecular weight kininogens on cell adhesion. J Biochem (Tokyo) 1998; 124: 473-484.
• 11 Colman RW, Najamunnisa S, Yan W. et al. Binding of high molecular weight kininogen to human endothelial cells is mediated via a site within domains 2 and 3 of the urokinase receptor. J Clin Invest 1997; 100: 1481-1487.
• 12 Pike LJ. Rafts defined: a report on the Keystone Symposium on Lipid Rafts and Cell Function. J Lipid Res 2006; 47: 1597-1598.
• 13 Frank PG, Woodman SE, Park DS. et al. Caveolin, caveolae, and endothelial cell function. Arterioscler Thromb Vasc Biol 2003; 23: 1161-1168.
• 14 Sonveaux P, Martinive P, DeWever J. et al. Caveolin-1 expression is critical for vascular endothelial growth factor-induced ischemic hindlimb collateralization and nitric oxide-mediated angiogenesis. Circ Res 2004; 95: 154-161.
• 15 Griffoni CSE, Santi S, Riccio M. et al. Knockdown of caveolin-1 by antisense oligonucleotides impairs angiogenesis in vitro and in vivo. Biochem Biophys Res Commun 2000; 276: 756-761.
• 16 Stupack DG, Cheresh DA. Get a ligand, get a life: integrins, signaling and cell survival. J Cell Sci 2002; 115: 3729-3738.
• 17 Alain PRF, Monique L, Arbeillec B. et al. MMP-2 colocalizes with caveolae on the surface of endothelial cells. Exp Cell Res 2001; 262: 28-36.
• 18 Ikeda S, Ushio-Fukai M, Zuo L. et al. Novel role of ARF6 in vascular endothelial growth factor-induced signaling and angiogenesis. Circ Res 2005; 96: 467-475.
• 19 Wu Y, Rizzo V, Liu Y. et al. Kininostatin associated with membrane rafts and inhibits alpha(v)beta3 integrin activation in human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol 2007; 09: 1968-1975.
• 20 Chapman HA, Wei Y, Simon DI. et al. Role of urokinase receptor and caveolin in regulation of integrin signaling. Thromb Haemost 1999; 82: 291-297.
• 21 Pampori N, Hato T, Stupack DG. et al. Mechanisms and consequences of affinity modulation of integrin alpha Vbeta 3 detected with a novel patch-engineered monovalent ligand. J Biol Chem 1999; 274: 21609-21616.
• 22 Suehiro K, Gailit J, Plow EF. Fibrinogen is a ligand for integrin alpha5beta1 on endothelial cells. J Biol Chem 1997; 272: 5360-5366.
• 23 Simon DI, Wei Y, Zhang L. et al. Identification of a urokinase receptor-integrin interaction site. promiscuous regulator of integrin function. J Biol Chem 2000; 275: 10228-10234.
• 24 Degryse B, Resnati M, Czekay R-P. et al. Domain 2 of the urokinase receptor contains an integrin-interacting epitope with intrinsic signaling activity: generation of a new integrin inhibitor. J Biol Chem 2005; 280: 24792-24803.
• 25 Im E, Kazlauskas A. Src family kinases promote vessel stability by antagonizing the Rho/ROCK pathway. J Biol Chem 2007; 282: 29122-29129.
• 26 Werdich XQ, Penn JS. Specific involvement of SRC family kinase activation in the pathogenesis of retinal neovascularisation. Investig Ophthalmol Vis Sci 2006; 47: 5047-5056.
• 27 Arias-Salgado EG, Lizano S, Sarkar S. et al. Src kinase activation by direct interaction with the integrin beta cytoplasmic domain. Proc Natl Acad Sci USA 2003; 100: 13298-13302.
• 28 Brooks PC, Stromblad S, Klemke R. et al. Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 1995; 96: 1815-1822.
• 29 Wie Y, Czekay RP, Robillard L. et al. Regulation of {alpha}5{beta}1 integrin conformation and function by urokinase receptor binding. J Cell Biol 2005; 168: 501-511.
• 30 Liu Y, Sainz IM, Wu Y. et al. The inhibition of tube formation in a collagen-fibrinogen, three-dimensional gel by cleaved Kininogen (HKa) and HK domain 5 (D5) is dependent on Src family kinases. Exp Cell Res 2008; 314: 774-788.
• 31 Colman RW, Jameson BY, Lin Y. et al. Domain 5 of high molecular weight kininogen (kininostatin) down-regulates endothelial cell proliferation and migration and inhibits angiogenesis. Blood 2000; 95: 543-550.
• 32 Liu Y, Senger DR. Matrix-specific activation of Src and Rho initiates capillary morphogenesis of endothelial cells. FASEB J 2004; 18: 457-468.
• 33 Ischenko I, Guba M, Yezhelyev M. et al. Effect of Src kinase inhibition on metastasis and tumor angiogenesis in human pancreatic cancer. Angiogenesis 2007; 10: 167-182.
• 34 Boggon TJ, Eck MJ. Structure and regulation of Src family kinases. Oncogene 2004; 23: 7918-7927.
• 35 Roskoski Jr R. Src kinase regulation by phosphorylation and dephosphorylation. Biochem Biophys Res Commun 2005; 331: 1-14.
• 36 Duan LJ, Imamoto A, Fong GH. Dual roles of the C-terminal Src kinase (Csk) during developmental vascularisation. Blood 2004; 103: 1370-1372.
• 37 Fernandez PM, Patierno SR, Rickles FR. Tissue factor and fibrin in tumor angio-genesis. Semin Thromb Hemost 2004; 30: 31-44.
• 38 Herrick S, Blanc-Brude O, Gray A. et al. Fibrinogen. Int J Biochem Cell Biol 1999; 31: 741-746.
• 39 Wei Y, Tang CH, Kim Y. et al. Urokinase receptors are required for α5beta1 integrin-mediated signaling in tumor cells. J Biol Chem 2007; 282: 3929-3939.
• 40 Labrecque L, Nyalendo C, Langlois S. et al. Src-mediated tyrosine phosphorylation of caveolin-1 induces its association with membrane type 1 matrix metal-loproteinase. J Biol Chem 2004; 279: 52132-52140.
• 41 Tarui T, Akakura N, Majumdar M. et al. Direct interaction of the kringle domain of urokinase-type plasminogen activator (uPA) and integrin alpha v beta 3 induces signal transduction and enhances plasminogen activation. Thromb Haemost 2006; 95: 524-534.
• 42 Nguyen DH, Hussaini IM, Gonias SL. Binding of urokinase-type plasminogen activator to its receptor in MCF-7 cells activates extracellular signal-regulated kinase 1 and 2 which is required for increased cellular motility. J Biol Chem 1998; 273: 8502-8507.
• 43 Nguyen DH, Webb DJ, Catling AD. et al. Urokinase-type plasminogen activator stimulates the Ras/Extracellular signal-regulated kinase (ERK) signaling pathway and MCF-7 cell migration by a mechanism that requires focal adhesion kinase, Src, and Shc. Rapid dissociation of GRB2/Sps-Shc complex is associated with the transient phosphorylation of ERK in urokinase-treated cells. J Biol Chem 2000; 275: 19382-19388.
• 44 Tang H, Kerins DM, Hao Q. et al. The urokinase-type plasminogen activator receptor mediates tyrosine phosphorylation of focal adhesion proteins and activation of mitogen-activated protein kinase in cultured endothelial cells. J Biol Chem 1998; 273: 18268-18272.
• 45 Kaneko T, Konno H, Baba M. et al. Urokinase-type plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer. Cancer Sci 2003; 94: 43-49.
• 46 Conese M, Nykjaer A, Petersen CM. et al. α-2 Macroglobulin receptor/Ldl receptor-related protein (Lrp)-dependent internalization of the urokinase receptor. J Cell Biol 1995; 131: 1609-1622.
• 47 Nykjaer A, Conese M, Christensen EI. et al. Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. EMBO J 1997; 16: 2610-2620.
• 48 Barinka C, Parry G, Callahan J. et al. Structural basis of interaction between urokinase-type plasminogen activator and its receptor. J Mol Biol 2006; 363: 482-495.
• 49 Huai Q, Mazar AP, Kuo A. et al. Structure of human urokinase plasminogen activator in complex with its receptor. Science 2006; 311: 656-659.
• 50 Liu Y, Cao DJ, Sainz IM. et al. The inhibitory effect of HKa in endothelial cell tube formation is mediated by disrupting uPA-uPAR complex and inhibiting its signaling and internalization. Am J Physiol Cell Physiol 2008; 05: C257-267.
• 51 Prager GW, Breuss JM, Steurer S. et al. Vascular endothelial growth factor receptor-2-induced initial endothelial cell migration depends on the presence of the urokinase receptor. Circ Res 2004; 94: 1562-1570.
• 52 Sainz IM, Pixley RA, Colman RW. Fifty years of research on the plasma kallikreinkinin system. From protein structure and function to cell biology and in-vivo pathophysiology. Thromb Haemost 2007; 98: 77-83.
• 53 Hassan S, Sainz IM, Khan MM. et al. The Antithrombotic Activity of Kininogen is Mediated by Inhibitory Effects of Domain 3 During Arterial Injury In Vivo. Am J Physiol Heart Circ Physiol 2007; 292: H2959-2965.
• 54 Blat Y, Seiffert D. A renaissance for the contact system in blood coagulation. Thromb Haemost 2008; 99: 457-460.