Fibronectin induces endothelial cell migration through β1 integrin and src-dependent phosphorylation of fibroblast growth factor receptor-1 at tyrosines 653/654 and 766

Li Zou, Sheng Cao, Ningling Kang, Robert C. Huebert, Vijay H. Shah

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

The extracellular matrix microenvironment regulates cell phenotype and function. One mechanism by which this is achieved is the transactivation of receptor tyrosine kinases by specific matrix molecules. Here, we demonstrate that the provisional matrix protein, fibronectin (FN), activates fibroblast growth factor (FGF) receptor-1 (FGFR1) independent of FGF ligand in liver endothelial cells. FN activation of FGFR1 requires β1 integrin, as evidenced by neutralizing antibody and siRNA-based studies. Complementary genetic and pharmacologic approaches identify that the non-receptor tyrosine kinase Src is required for FN transactivation of FGFR1. Whereas FGF ligand-induced phosphorylation of FGFR1 preferentially activates ERK, FN-induced phosphorylation of FGFR1 preferentially activates AKT, indicating differential downstream signaling of FGFR1 in response to alternate stimuli. Mutation analysis of known tyrosine residues of FGFR1 reveals that tyrosine 653/ 654 and 766 residues are required for FN-FGFR1 activation of AKTand chemotaxis. Thus, our study mechanistically dissects a new signaling pathway by which FN achieves endothelial cell chemotaxis, demonstrates how differential phosphorylation profiles of FGFR1 can achieve alternate downstream signals, and, more broadly, highlights the diversity of mechanisms by which the extracellular matrix microenvironment regulates cell behavior through transactivation of receptor tyrosine kinases.

Original languageEnglish (US)
Pages (from-to)7190-7202
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number10
DOIs
StatePublished - Mar 2 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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