title: Fibronectin induces endothelial cell migration through β1 integrin and Src-dependent phosphorylation of fibroblast growth factor receptor-1 at tyrosines 653/654 and 766.
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 AKT and 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.
authors.affiliation: Gastroenterology Research Unit and Cancer Cell Biology Program, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zou
authors.forename: Sheng
authors.initials: S
authors.lastname: Cao
authors.forename: Ningling
authors.initials: N
authors.lastname: Kang
authors.forename: Robert C
authors.initials: RC
authors.lastname: Huebert
authors.forename: Vijay H
authors.initials: VH
authors.lastname: Shah
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002633:Chemotaxis / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D010766:Phosphorylation / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D019012:Integrin beta1; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D019061:src-Family Kinases