蛋白酶激活接受器一（Protease-activated receptor 1）是一個凝血蛋白酶（thrombin）所激活之G蛋白連結接受器 (G protein-coupled receptor)。酪氨酸激酶Src 已知是蛋白酶激活接受器一所調控之訊號傳遞中重要的傳遞者。但是目前酪氨酸激酶Src之活性調控仍不明確。此處將蛋白酶激活接受器一對酪氨酸激酶Src之活化、去活化、降解、及再合成之機轉加以研究。在大量表達b-制動素一（b-arrestin1）或是抑制表達b-制動素二（b-arrestin2）的情況下，蛋白酶激活接受器一快速地活化酪氨酸激酶Src，而抑制表達b-制動素一或大量表達b-制動素二時會抑制或消除酪氨酸激酶Src的活化。再者，在蛋白酶激活接受器一的刺激下，酪氨酸激酶Src會經由溶酶體降解，而抑制表達b-制動素二會抑制此降解。而後，長時間刺激蛋白酶激活接受器一會導致酪氨酸激酶Src和蛋白酶激活接受器一之再合成，以及血管內皮增生激素(vascular endothelial growth factor)之生成與分泌。酪氨酸激酶Src之再合成會增加其活性，抑制其活性亦會阻斷其再合成。抑制酪氨酸激酶Src之活性也會降低血管內皮增生激素之生成。而刺激蛋白酶激活接受器一所增加之細胞存活性可被血管內皮增生激素之抗體中和。這些結果指出，蛋白酶激活接受器一可引發□-制動素一或□-制動素二分別調節之酪氨酸激酶Src活化及去活化。□-制動素二同時也參與蛋白酶激活接受器一所導致的酪氨酸激酶Src降解。而蛋白酶激活接受器一所導致的酪氨酸激酶Src再合成及血管內皮增生激素生成也都與酪氨酸激酶Src的酵素活性有關。生成的血管內皮增生激素會被分泌至細胞外並參與蛋白酶激活接受器一所促進的細胞增生。因此，酪氨酸激酶Src之降解與再合成對於蛋白酶激活接受器一引發訊號之終止及再活化提供了一個可能的調控機制。此研究證明在刺激蛋白酶激活接受器一後，酪氨酸激酶Src會快速被活化，之後會經由降解而去活化，最後會再被合成而導致再活化。而蛋白酶激活接受器一可能是經由調控酪氨酸激酶Src之活性變化進而參與凝血蛋白酶所引發之血液凝結及血管新生。

Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor for thrombin. Src has been reported to be a signaling transducer of PAR1-mediated signal pathways. However, the regulation of Src kinase activity in these signal pathways is still unclear. The mechanisms of PAR1-mediated activation, de-activation, degradation, and re-expression of Src in HEK 293 cells were investigated. PAR1-mediated rapid activation of Src was increased with overexpression of □-arrestin1 or depletion of □-arrestin2. This activation of Src was decreased or eliminated with depletion of □-arrestin1 or overexpression of □-arrestin2. Of interest, stimulation of PAR1 induced lysosomal degradation of Src, and this degradation was blocked by depletion of □-arrestin2. Furthermore, long-term stimulation of PAR1 caused the re-expression of Src and PAR1 as well as the synthesis and secretion of vascular endothelial growth factor (VEGF). The re-expression of Src enhanced its kinase activity and was abolished by inhibiting its kinase activity. The synthesis of VEGF was also blocked by the inhibition of Src activity. Neutralization of secreted VEGF by anti-VEGF antibody reduced PAR1-mediated enhancement of cell viability. Collectively, these results indicate that Src is activated and de-activated by PAR1 through □-arrestin1- and □-arrestin2-dependent mechanisms, respectively. □-arrestin2 also appears to promote PAR1-induced lysosomal degradation of Src. Kinase activity of Src is involved in PAR1-mediated re-expression of Src and synthesis of VEGF. Synthesized VEGF is then secreted and participates in PAR1-mediated cell proliferation. Therefore, degradation and re-expression of Src provide a possible mechanism for terminating and re-activating PAR1 signaling. This work demonstrates that after stimulation of PAR1, Src was activated rapidly, then deactivated with degradation mechanism, and re-activated by re-expression of itself. The modulation of Src activity implies that PAR1 may manipulate Src activity to mediate thrombin-induced blood coagulation and angiogenesis.

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References
1. Coughlin S.R. (1999). How the protease thrombin talks to cells. Proc. Natl.
Acad. Sci. U. S. A 96: 11023-11027.
2. Macfarlane S.R., Seatter M.J., Kanke T., Hunter G.D., and Plevin R. (2001).
Proteinase-activated receptors. Pharmacol. Rev. 53: 245-282.
3. Vu T.K., Hung D.T., Wheaton V.I., and Coughlin S.R. (1991). Molecular
cloning of a functional thrombin receptor reveals a novel proteolytic
mechanism of receptor activation. Cell 64: 1057-1068.
4. Gerszten R.E., Chen J., Ishii M., Ishii K., Wang L., Nanevicz T., Turck C.W.,
Vu T.K., and Coughlin S.R. (1994). Specificity of the thrombin receptor for
agonist peptide is defined by its extracellular surface. Nature 368: 648-651.
5. Nanevicz T., Ishii M., Wang L., Chen M., Chen J., Turck C.W., Cohen F.E.,
and Coughlin S.R. (1995). Mechanisms of thrombin receptor agonist
specificity. Chimeric receptors and complementary mutations identify an
agonist recognition site. J. Biol. Chem. 270: 21619-21625.
6. Henn V., Slupsky J.R., Grafe M., Anagnostopoulos I., Forster R.,
80
Muller-Berghaus G., and Kroczek R.A. (1998). CD40 ligand on activated
platelets triggers an inflammatory reaction of endothelial cells. Nature 391:
591-594.
7. McNamara C.A., Sarembock I.J., Gimple L.W., Fenton J.W., Coughlin S.R.,
and Owens G.K. (1993). Thrombin stimulates proliferation of cultured rat
aortic smooth muscle cells by a proteolytically activated receptor. J. Clin.
Invest 91: 94-98.
8. Mohle R., Green D., Moore M.A., Nachman R.L., and Rafii S. (1997).
Constitutive production and thrombin-induced release of vascular endothelial
growth factor by human megakaryocytes and platelets. Proc. Natl. Acad. Sci.
U. S. A 94: 663-668.
9. Hung D.T., Wong Y.H., Vu T.K., and Coughlin S.R. (1992). The cloned
platelet thrombin receptor couples to at least two distinct effectors to stimulate
phosphoinositide hydrolysis and inhibit adenylyl cyclase. J. Biol. Chem. 267:
20831-20834.
10. Baffy G., Yang L., Raj S., Manning D.R., and Williamson J.R. (1994). G
protein coupling to the thrombin receptor in Chinese hamster lung fibroblasts.
81
J. Biol. Chem. 269: 8483-8487.
11. Benka M.L., Lee M., Wang G.R., Buckman S., Burlacu A., Cole L., DePina A.,
Dias P., Granger A., Grant B. et al. (1995). The thrombin receptor in human
platelets is coupled to a GTP binding protein of the G alpha q family. FEBS
Lett. 363: 49-52.
12. Offermanns S., Laugwitz K.L., Spicher K., and Schultz G. (1994). G proteins
of the G12 family are activated via thromboxane A2 and thrombin receptors in
human platelets. Proc. Natl. Acad. Sci. U. S. A 91: 504-508.
13. Barr A.J., Brass L.F., and Manning D.R. (1997). Reconstitution of receptors
and GTP-binding regulatory proteins (G proteins) in Sf9 cells. A direct
evaluation of selectivity in receptor．G protein coupling. J. Biol. Chem. 272:
2223-2229.
14. Ogino Y., Tanaka K., and Shimizu N. (1996). Direct evidence for two distinct
G proteins coupling with thrombin receptors in human neuroblastoma SH-EP
cells. Eur. J. Pharmacol. 316: 105-109.
15. Chen Y.H., Pouyssegur J., Courtneidge S.A., and Van Obberghen-Schilling E.
82
(1994). Activation of Src family kinase activity by the G protein-coupled
thrombin receptor in growth-responsive fibroblasts. J. Biol. Chem. 269:
27372-27377.
16. Ellis C.A., Malik A.B., Gilchrist A., Hamm H., Sandoval R.,
Voyno-Yasenetskaya T., and Tiruppathi C. (1999). Thrombin induces
proteinase-activated receptor-1 gene expression in endothelial cells via
activation of Gi-linked Ras/mitogen-activated protein kinase pathway. J. Biol.
Chem. 274: 13718-13727.
17. Tsopanoglou N.E. and Maragoudakis M.E. (2004). Role of thrombin in
angiogenesis and tumor progression. Semin. Thromb. Hemost. 30: 63-69.
18. Yin Y.J., Salah Z., Maoz M., Ram S.C., Ochayon S., Neufeld G., Katzav S.,
and Bar-Shavit R. (2003). Oncogenic transformation induces tumor
angiogenesis: a role for PAR1 activation. FASEB J. 17: 163-174.
19. Yin Y.J., Salah Z., Grisaru-Granovsky S., Cohen I., Even-Ram S.C., Maoz M.,
Uziely B., Peretz T., and Bar-Shavit R. (2003). Human protease-activated
receptor 1 expression in malignant epithelia: a role in invasiveness.
Arterioscler. Thromb. Vasc. Biol. 23: 940-944.
83
20. Ferguson S.S., Barak L.S., Zhang J., and Caron M.G. (1996).
G-protein-coupled receptor regulation: role of G-protein-coupled receptor
kinases and arrestins. Can. J. Physiol Pharmacol. 74: 1095-1110.
21. Krupnick J.G. and Benovic J.L. (1998). The role of receptor kinases and
arrestins in G protein-coupled receptor regulation. Annu. Rev. Pharmacol.
Toxicol. 38: 289-319.
22. Pitcher J.A., Freedman N.J., and Lefkowitz R.J. (1998). G protein-coupled
receptor kinases. Annu. Rev. Biochem. 67: 653-692.
23. Penn R.B., Pronin A.N., and Benovic J.L. (2000). Regulation of G
protein-coupled receptor kinases. Trends Cardiovasc. Med. 10: 81-89.
24. Kohout T.A. and Lefkowitz R.J. (2003). Regulation of G protein-coupled
receptor kinases and arrestins during receptor desensitization. Mol. Pharmacol.
63: 9-18.
25. Claing A., Laporte S.A., Caron M.G., and Lefkowitz R.J. (2002). Endocytosis
of G protein-coupled receptors: roles of G protein-coupled receptor kinases
and beta-arrestin proteins. Prog. Neurobiol. 66: 61-79.
84
26. Goodman O.B., Jr., Krupnick J.G., Santini F., Gurevich V.V., Penn R.B.,
Gagnon A.W., Keen J.H., and Benovic J.L. (1996). Beta-arrestin acts as a
clathrin adaptor in endocytosis of the beta2-adrenergic receptor. Nature 383:
447-450.
27. Laporte S.A., Oakley R.H., Zhang J., Holt J.A., Ferguson S.S., Caron M.G.,
and Barak L.S. (1999). The beta2-adrenergic receptor/betaarrestin complex
recruits the clathrin adaptor AP-2 during endocytosis. Proc. Natl. Acad. Sci. U.
S. A 96: 3712-3717.
28. Ishii K., Chen J., Ishii M., Koch W.J., Freedman N.J., Lefkowitz R.J., and
Coughlin S.R. (1994). Inhibition of thrombin receptor signaling by a G-protein
coupled receptor kinase. Functional specificity among G-protein coupled
receptor kinases. J. Biol. Chem. 269: 1125-1130.
29. Trejo J., Altschuler Y., Fu H-W., Mostov K.E., and Coughlin S.R. (2000).
Protease-activated receptor-1 down-regulation: a mutant HeLa cell line
suggests novel requirements for PAR1 phosphorylation and recruitment to
clathrin-coated pits. J. Biol. Chem. 275: 31255-31265.
30. Hammes S.R., Shapiro M.J., and Coughlin S.R. (1999). Shutoff and
85
agonist-triggered internalization of protease-activated receptor 1 can be
separated by mutation of putative phosphorylation sites in the cytoplasmic tail.
Biochemistry 38: 9308-9316.
31. Hoxie J.A., Ahuja M., Belmonte E., Pizarro S., Parton R., and Brass L.F.
(1993). Internalization and recycling of activated thrombin receptors. J. Biol.
Chem. 268: 13756-13763.
32. Hein L., Ishii K., Coughlin S.R., and Kobilka B.K. (1994). Intracellular
targeting and trafficking of thrombin receptors. A novel mechanism for
resensitization of a G protein-coupled receptor. J. Biol. Chem. 269:
27719-27726.
33. Coughlin S.R. (2000). Thrombin signalling and protease-activated receptors.
Nature 407: 258-264.
34. Dale L.B., Bhattacharya M., Seachrist J.L., Anborgh P.H., and Ferguson S.S.
(2001). Agonist-stimulated and tonic internalization of metabotropic glutamate
receptor 1a in human embryonic kidney 293 cells: agonist-stimulated
endocytosis is beta-arrestin1 isoform-specific. Mol. Pharmacol. 60:
1243-1253.
86
35. Laporte S.A., Oakley R.H., Holt J.A., Barak L.S., and Caron M.G. (2000). The
interaction of beta-arrestin with the AP-2 adaptor is required for the clustering
of beta 2-adrenergic receptor into clathrin-coated pits. J. Biol. Chem. 275:
23120-23126.
36. Oakley R.H., Laporte S.A., Holt J.A., Caron M.G., and Barak L.S. (2000).
Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G
protein-coupled receptors delineate two major classes of receptors. J. Biol.
Chem. 275: 17201-17210.
37. Chen W., ten B.D., Brown J., Ahn S., Hu L.A., Miller W.E., Caron M.G.,
Barak L.S., Nusse R., and Lefkowitz R.J. (2003). Dishevelled 2 recruits
beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4.
Science 301: 1391-1394.
38. Chen W., Kirkbride K.C., How T., Nelson C.D., Mo J., Frederick J.P., Wang
X.F., Lefkowitz R.J., and Blobe G.C. (2003). Beta-arrestin 2 mediates
endocytosis of type III TGF-beta receptor and down-regulation of its signaling.
Science 301: 1394-1397.
39. Whitmarsh A.J. and Davis R.J. (1998). Structural organization of MAP-kinase
87
signaling modules by scaffold proteins in yeast and mammals. Trends
Biochem. Sci. 23: 481-485.
40. DeFea K.A., Zalevsky J., Thoma M.S., Dery O., Mullins R.D., and Bunnett
N.W. (2000). beta-arrestin-dependent endocytosis of proteinase-activated
receptor 2 is required for intracellular targeting of activated ERK1/2. J. Cell
Biol. 148: 1267-1281.
41. DeFea K.A., Vaughn Z.D., O'Bryan E.M., Nishijima D., Dery O., and Bunnett
N.W. (2000). The proliferative and antiapoptotic effects of substance P are
facilitated by formation of a beta -arrestin-dependent scaffolding complex.
Proc. Natl. Acad. Sci. U. S. A 97: 11086-11091.
42. Wei H., Ahn S., Barnes W.G., and Lefkowitz R.J. (2004). Stable interaction
between beta-arrestin 2 and angiotensin type 1A receptor is required for
beta-arrestin 2-mediated activation of extracellular signal-regulated kinases 1
and 2. J. Biol. Chem. 279: 48255-48261.
43. McDonald P.H., Chow C.W., Miller W.E., Laporte S.A., Field M.E., Lin F.T.,
Davis R.J., and Lefkowitz R.J. (2000). Beta-arrestin 2: a receptor-regulated
MAPK scaffold for the activation of JNK3. Science 290: 1574-1577.
88
44. Sun Y., Cheng Z., Ma L., and Pei G. (2002). Beta-arrestin2 is critically
involved in CXCR4-mediated chemotaxis, and this is mediated by its
enhancement of p38 MAPK activation. J. Biol. Chem. 277: 49212-49219.
45. Luttrell L.M., Ferguson S.S., Daaka Y., Miller W.E., Maudsley S., la Rocca
G.J., Lin F., Kawakatsu H., Owada K., Luttrell D.K. et al. (1999).
Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein
kinase complexes. Science 283: 655-661.
46. Shenoy S.K., McDonald P.H., Kohout T.A., and Lefkowitz R.J. (2001).
Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic
receptor and beta-arrestin. Science 294: 1307-1313.
47. Jacob C., Cottrell G.S., Gehringer D., Schmidlin F., Grady E.F., and Bunnett
N.W. (2005). c-Cbl mediates ubiquitination, degradation, and down-regulation
of human protease-activated receptor 2. J. Biol. Chem. 280: 16076-16087.
48. Paing M.M., Stutts A.B., Kohout T.A., Lefkowitz R.J., and Trejo J. (2002).
beta -Arrestins regulate protease-activated receptor-1 desensitization but not
internalization or Down-regulation. J. Biol. Chem. 277: 1292-1300.
89
49. Goel R., Phillips-Mason P.J., Raben D.M., and Baldassare J.J. (2002).
alpha-Thrombin induces rapid and sustained Akt phosphorylation by
beta-arrestin1-dependent and -independent mechanisms, and only the
sustained Akt phosphorylation is essential for G1 phase progression. J. Biol.
Chem. 277: 18640-18648.
50. Goel R. and Baldassare J.J. (2002). beta-Arrestin 1 couples thrombin to the
rapid activation of the Akt pathway. Ann. N. Y. Acad. Sci. 973: 138-141.
51. Phillips-Mason P.J., Goel R., and Baldassare J.J. (2002). alpha-Thrombin
activates Akt via a nonreceptor tyrosine kinase in IIC9 cells. Ann. N. Y. Acad.
Sci. 973: 142-144.
52. Roskoski R., Jr. (2004). Src protein-tyrosine kinase structure and regulation.
Biochem. Biophys. Res. Commun. 324: 1155-1164.
53. Ma Y.C., Huang J., Ali S., Lowry W., and Huang X.Y. (2000). Src tyrosine
kinase is a novel direct effector of G proteins. Cell 102: 635-646.
54. Miller W.E., Maudsley S., Ahn S., Khan K.D., Luttrell L.M., and Lefkowitz
R.J. (2000). beta-arrestin1 interacts with the catalytic domain of the tyrosine
90
kinase c-SRC. Role of beta-arrestin1-dependent targeting of c-SRC in receptor
endocytosis. J. Biol. Chem. 275: 11312-11319.
55. Luttrell D.K. and Luttrell L.M. (2004). Not so strange bedfellows:
G-protein-coupled receptors and Src family kinases. Oncogene 23: 7969-7978.
56. Harris K.F., Shoji I., Cooper E.M., Kumar S., Oda H., and Howley P.M.
(1999). Ubiquitin-mediated degradation of active Src tyrosine kinase. Proc.
Natl. Acad. Sci. U. S. A 96: 13738-13743.
57. Magnifico A., Ettenberg S., Yang C., Mariano J., Tiwari S., Fang S., Lipkowitz
S., and Weissman A.M. (2003). WW domain HECT E3s target Cbl RING
finger E3s for proteasomal degradation. J. Biol. Chem. 278: 43169-43177.
58. Kim M., Tezuka T., Tanaka K., and Yamamoto T. (2004). Cbl-c suppresses
v-Src-induced transformation through ubiquitin-dependent protein degradation.
Oncogene 23: 1645-1655.
59. Cao W., Luttrell L.M., Medvedev A.V., Pierce K.L., Daniel K.W., Dixon T.M.,
Lefkowitz R.J., and Collins S. (2000). Direct binding of activated c-Src to the
beta 3-adrenergic receptor is required for MAP kinase activation. J. Biol.
91
Chem. 275: 38131-38134.
60. Liu J., Liao Z., Camden J., Griffin K.D., Garrad R.C., Santiago-Perez L.I.,
Gonzalez F.A., Seye C.I., Weisman G.A., and Erb L. (2004). Src homology 3
binding sites in the P2Y2 nucleotide receptor interact with Src and regulate
activities of Src, proline-rich tyrosine kinase 2, and growth factor receptors. J.
Biol. Chem. 279: 8212-8218.
61. Fan G., Shumay E., Malbon C.C., and Wang H. (2001). c-Src tyrosine kinase
binds the beta 2-adrenergic receptor via phospho-Tyr-350, phosphorylates
G-protein-linked receptor kinase 2, and mediates agonist-induced receptor
desensitization. J. Biol. Chem. 276: 13240-13247.
62. Ferguson S.S., Downey W.E., III, Colapietro A.M., Barak L.S., Menard L.,
and Caron M.G. (1996). Role of beta-arrestin in mediating agonist-promoted G
protein-coupled receptor internalization. Science 271: 363-366.
63. Zhang J., Barak L.S., Winkler K.E., Caron M.G., and Ferguson S.S. (1997). A
central role for beta-arrestins and clathrin-coated vesicle-mediated endocytosis
in beta2-adrenergic receptor resensitization. Differential regulation of receptor
resensitization in two distinct cell types. J. Biol. Chem. 272: 27005-27014.
92
64. Lefkowitz R.J. and Whalen E.J. (2004). beta-arrestins: traffic cops of cell
signaling. Curr. Opin. Cell Biol. 16: 162-168.
65. Shenoy S.K. and Lefkowitz R.J. (2003). Multifaceted roles of beta-arrestins in
the regulation of seven-membrane-spanning receptor trafficking and signalling.
Biochem. J. 375: 503-515.
66. Lefkowitz R.J. and Shenoy S.K. (2005). Transduction of receptor signals by
beta-arrestins. Science 308: 512-517.
67. Barlic J., Andrews J.D., Kelvin A.A., Bosinger S.E., DeVries M.E., Xu L.,
Dobransky T., Feldman R.D., Ferguson S.S., and Kelvin D.J. (2000).
Regulation of tyrosine kinase activation and granule release through
beta-arrestin by CXCRI. Nat. Immunol. 1: 227-233.
68. Fessart D., Simaan M., and Laporte S.A. (2005). c-Src regulates clathrin
adapter protein 2 interaction with beta-arrestin and the angiotensin II type 1
receptor during clathrin- mediated internalization. Mol. Endocrinol. 19:
491-503.
69. Mustelin T. and Tasken K. (2003). Positive and negative regulation of T-cell
93
activation through kinases and phosphatases. Biochem. J. 371: 15-27.
70. Rao N., Miyake S., Reddi A.L., Douillard P., Ghosh A.K., Dodge I.L., Zhou P.,
Fernandes N.D., and Band H. (2002). Negative regulation of Lck by Cbl
ubiquitin ligase. Proc. Natl. Acad. Sci. U. S. A 99: 3794-3799.
71. Hung D.T., Vu T.H., Nelken N.A., and Coughlin S.R. (1992).
Thrombin-induced events in non-platelet cells are mediated by the unique
proteolytic mechanism established for the cloned platelet thrombin receptor. J.
Cell Biol. 116: 827-832.
72. Ahn S., Wei H., Garrison T.R., and Lefkowitz R.J. (2004). Reciprocal
regulation of angiotensin receptor-activated extracellular signal-regulated
kinases by beta-arrestins 1 and 2. J. Biol. Chem. 279: 7807-7811.
73. Maragoudakis M.E., Tsopanoglou N.E., and Andriopoulou P. (2002).
Mechanism of thrombin-induced angiogenesis. Biochem. Soc. Trans. 30:
173-177.
74. Uhlin M., Masucci M.G., and Levitsky V. (2005). Regulation of lck
degradation and refractory state in CD8+ cytotoxic T lymphocytes. Proc. Natl.
94
Acad. Sci. U. S. A 102: 9264-9269.
75. Ellis C.A., Tiruppathi C., Sandoval R., Niles W.D., and Malik A.B. (1999).
Time course of recovery of endothelial cell surface thrombin receptor (PAR-1)
expression. Am. J. Physiol 276: C38-C45.
76. Zhao Y.L., Takagawa K., Oya T., Yang H.F., Gao Z.Y., Kawaguchi M., Ishii Y.,
Sasaoka T., Owada K., Furuta I. et al. (2003). Active Src expression is induced
after rat peripheral nerve injury. Glia 42: 184-193.
77. Barr C.S. and Dokas L.A. (2001). Regulation of pp60(c-src) synthesis in rat
hippocampal slices by in vitro ischemia and glucocorticoid administration. J.
Neurosci. Res. 65: 340-345.
78. Irby R.B. and Yeatman T.J. (2000). Role of Src expression and activation in
human cancer. Oncogene 19: 5636-5642.
79. Tan M., Li P., Klos K.S., Lu J., Lan K.H., Nagata Y., Fang D., Jing T., and Yu
D. (2005). ErbB2 promotes Src synthesis and stability: novel mechanisms of
Src activation that confer breast cancer metastasis. Cancer Res. 65:
1858-1867.
95
80. Balezina O.P., Gerasimenko N.Y., Dugina T.N., and Strukova S.M. (2005).
Study of neurotrophic activity of thrombin on the model of regenerating
mouse nerve. Bull. Exp. Biol. Med. 139: 4-6.
81. Even-Ram S., Uziely B., Cohen P., Grisaru-Granovsky S., Maoz M., Ginzburg
Y., Reich R., Vlodavsky I., and Bar-Shavit R. (1998). Thrombin receptor
overexpression in malignant and physiological invasion processes. Nat. Med.
4: 909-914.
82. Maragoudakis M.E., Tsopanoglou N.E., Andriopoulou P., and Maragoudakis
M.M. (2000). Effects of thrombin/thrombosis in angiogenesis and tumour
progression. Matrix Biol. 19: 345-351.
83. Schlessinger J. (2000). New roles for Src kinases in control of cell survival
and angiogenesis. Cell 100: 293-296.
84. Munshi N., Groopman J.E., Gill P.S., and Ganju R.K. (2000). c-Src mediates
mitogenic signals and associates with cytoskeletal proteins upon vascular
endothelial growth factor stimulation in Kaposi's sarcoma cells. J. Immunol.
164: 1169-1174.
96
85. Evangelista V., Manarini S., Coller B.S., and Smyth S.S. (2003). Role of
P-selectin, beta2-integrins, and Src tyrosine kinases in mouse
neutrophil-platelet adhesion. J. Thromb. Haemost. 1: 1048-1054.
86. Tsopanoglou N.E. and Maragoudakis M.E. (1999). On the mechanism of
thrombin-induced angiogenesis. Potentiation of vascular endothelial growth
factor activity on endothelial cells by up-regulation of its receptors. J. Biol.
Chem. 274: 23969-23976.