SHP-2 binds to Tyr763 and Tyr1009 in the PDGF beta-receptor and mediates PDGF-induced activation of the Ras MAP kinase pathway and chemotaxis

Activation of the beta-receptor for platelet-derived growth factor (PDGF) b y its ligand leads to autophosphorylation on a number of tyrosine residues. Here me show that Tyr763 in the kinase insert region is a novel autophosph orylation site, which after phosphorylation binds the protein tyrosine phos phatase SHP-2. SHP-2 has also previously been shown to bind to phosphorylat ed Tyr1009 in the PDGF beta-receptor. Porcine aortic endothelial (PAE) cell s transfected with a PDGF beta-receptor in which Tyr763 and Tyr1009 were mu tated to phenylalanine residues failed to associate with SHP-2 after ligand stimulation. Moreover, PDGF-BB-induced Ras GTP-loading and Erk2 activation were severely compromised in the receptor mutant. Whereas the mitogenic re sponse to PDGF-BB remained at the same level as in cells expressing wild-ty pe PDGF beta-receptor, chemotaxis induced by PDGF-BB was significantly decr eased in the case of the Y763F/Y1009F mutant cells, suggesting an important role for SHP-2 in chemotactic signaling.