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Research article

Src mediates stimulation by vascular endothelial growth factor of the phosphorylation of focal adhesion kinase at tyrosine 861, and migration and anti-apoptosis in endothelial cells

Robin ABU-GHAZALEH, Jahangir KABIR, Haiyan JIA, Mel LOBO, Ian ZACHARY
Biochemical Journal Nov 15, 2001, 360 (1) 255-264; DOI: 10.1042/bj3600255
Robin ABU-GHAZALEH
Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, U.K.
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Jahangir KABIR
Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, U.K.
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Haiyan JIA
Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, U.K.
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Mel LOBO
Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, U.K.
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Ian ZACHARY
Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, U.K.
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Abstract

Vascular endothelial growth factor (VEGF) stimulates the tyrosine phosphorylation of focal adhesion kinase (FAK), increases focal adhesion formation and is chemotactic for human umbilical-vein endothelial cells (HUVECs). In the present study we identified the major sites of VEGF-induced FAK tyrosine phosphorylation and investigated the mechanism mediating this pathway in the action of VEGF. VEGF increased the focal adhesion localization of FAK phosphorylated at Tyr-397 (Y397) and Y861 but stimulated a marked increase in phosphorylation at Y861 without significantly affecting the total level of phospho-Y397 FAK. Inhibition of Src with the specific inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) completely blocked VEGF-induced Y861 phosphorylation without decreasing the level of phospho-Y397 FAK. We also examined the role of Src in mediating endothelial functions of VEGF in which FAK has been implicated as having a role. PP2 markedly inhibited VEGF-induced chemotaxis and wound-healing cell migration. The Src inhibitor also decreased the anti-apoptotic effect of VEGF determined by surface staining of annexin V but did not increase FAK proteolysis or prevent the VEGF-dependent inhibition of FAK proteolysis. In contrast, the specific PtdIns 3-kinase inhibitor LY294002 induced apoptosis and markedly decreased p125FAK expression and increased FAK proteolysis but had little effect on Y861 phosphorylation. These findings identify Src-dependent FAK phosphorylation at Y861 as a novel VEGF-induced signalling pathway in endothelial cells and suggest that this pathway might be involved in the mechanisms mediating VEGF-induced endothelial cell migration and anti-apoptosis.

  • chemotaxis
  • endothelium
  • KDR
  • survival

Footnotes

  • Abbreviations used: DAPI, 4,6-diamidino-2-phenylindole; ERK, extracellular signal-regulated protein kinase; FAK, focal adhesion kinase; FBS, foetal-bovine serum; HUVECs, human umbilical-vein endothelial cells; PGI2, prostaglandin I2; PI 3-kinase, phosphoinositide 3-kinase; PKC, protein kinase C; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; PP3, 4-amino-7-phenylpyrazol[3,4-d]pyrimidine; SH, Src homology; VEGF, vascular endothelial growth factor.

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November 2001

Volume: 360 Issue: 1

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Src mediates stimulation by vascular endothelial growth factor of the phosphorylation of focal adhesion kinase at tyrosine 861, and migration and anti-apoptosis in endothelial cells
Robin ABU-GHAZALEH, Jahangir KABIR, Haiyan JIA, Mel LOBO, Ian ZACHARY
Biochemical Journal Nov 2001, 360 (1) 255-264; DOI: 10.1042/bj3600255
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Src mediates stimulation by vascular endothelial growth factor of the phosphorylation of focal adhesion kinase at tyrosine 861, and migration and anti-apoptosis in endothelial cells
Robin ABU-GHAZALEH, Jahangir KABIR, Haiyan JIA, Mel LOBO, Ian ZACHARY
Biochemical Journal Nov 2001, 360 (1) 255-264; DOI: 10.1042/bj3600255

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Keywords

chemotaxis
endothelium
KDR
survival

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