Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/5819
Title: Endothelial cell adhesion to the extracellular matrix induces c-Src-dependent VEGFR-3 phosphorylation without the activation of the receptor intrinsic kinase activity.
Authors: Galvagni, Federico 
Pennacchini, S
Salameh, A
Rocchigiani, Marina
Neri, F
Orlandini, Maurizio 
Petraglia, F
Gotta, S
SARDONE G., L
Matteucci, G
TERSTAPPEN G., C
Oliviero, Salvatore 
Keywords: Angiogenesis; VEGFR3; SRC; INTEGRINS
Issue Date: 2010
Project: None 
Journal: CIRCULATION RESEARCH
Abstract: 
RATIONALE: Integrins cooperate with growth factor receptors to promote downstream signaling for cell proliferation and migration. However, the mechanism of receptor activation is still unknown. OBJECTIVE: To analyze the mechanism of phosphorylation of the vascular endothelial growth factor receptor (VEGFR)-3 by cell adhesion. METHODS AND RESULTS: We show that VEGFR-3 phosphorylation, induced by cell attachment to the extracellular matrix, is independent from the intrinsic kinase activity of the receptor, as evidenced from phosphorylation cell adhesion experiments with a mutant kinase dead receptor or in the presence of the specific kinase inhibitor MAZ 51. Cell adhesion experiments in the presence of the c-Src inhibitor PP2 or in fibroblast triple knockout for c-Src, Yes, and Fyn (SYF) demonstrate that VEGFR-3 phosphorylation, induced by extracellular matrix, is mediated by c-Src. Kinase assays in vitro with recombinant c-Src show that VEGFR-3 is a direct c-Src target and mass spectrometry analysis identified the sites phosphorylated by c-Src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated VEGFR-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins CRKI/II and SHC inducing activation of JNK. CONCLUSIONS: These data suggest that cell adhesion to extracellular matrix induces a downstream signaling using the tyrosine kinase receptor VEGFR-3 as scaffold.
Description: 
34990
URI: http://hdl.handle.net/20.500.12779/5819
ISSN: 0009-7330
DOI: 10.1161/CIRCRESAHA.109.206326
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