Novel hepatocyte growth factor (HGF) binding domains on fibronectin and vitronectin coordinate a distinct and amplified Met-integrin induced signalling pathway in endothelial cells.
BACKGROUND
The growth of new blood vessels in adult life requires the initiation of endothelial cell migration and proliferation from pre-existing vessels in addition to the recruitment and differentiation of circulating endothelial progenitor cells. Signals emanating from growth factors and the extracellular matrix are important in regulating these processes.


RESULTS
Here we report that fibronectin (FN) and vitronectin (VN) modulate the responses of endothelial cells to HGF (Scatter Factor), an important pro-angiogenic mediator. Novel binding sites for HGF were identified on both FN and VN that generate molecular complexes with enhanced biological activity and these were identified in the supernatants of degranulated platelet suspensions implicating their release and formation in vivo. In the absence of co-stimulation with an ECM glycoprotein, HGF could not promote endothelial cell migration but retained the capacity to induce a proliferative response utilising the Map kinase pathway. Through promoting Met-Integrin association, HGF-FN and HGF-VN complexes coordinated and enhanced endothelial cell migration through activation of the PI-3 kinase pathway involving a Ras-dependent mechanism whereas a Ras-independent and attenuated migratory response was promoted by co-stimulation of cells with HGF and a non-binding partner ECM glycoprotein such as collagen-1.


CONCLUSIONS
These studies identify a novel mechanism and pathway of HGF signalling in endothelial cells involving cooperation between Met and integrins in a Ras dependent manner. These findings have implications for the regulation of neovascularization in both health and disease.
Rahman
Salman
S
Coagulation Research Laboratory, Division of Cardiovascular Medicine, GKT School of Medicine, St, Thomas' Hospital, London, UK. salman.rahman@kcl.ac.uk
Patel
Yatin
Y
Murray
Jacqueline
J
Patel
Kirti V
KV
Sumathipala
Rushika
R
Sobel
Michael
M
Wijelath
Errol S
ES
D001665:Binding Sites; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D005109:Extracellular Matrix; D005353:Fibronectins / Q000378:metabolism*; D006133:Growth Substances; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor; D015398:Signal Transduction; D019096:Vitronectin / Q000378:metabolism*
D005353:Fibronectins; D006133:Growth Substances; D016023:Integrins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D019096:Vitronectin; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
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