Ludwig Institute for Cancer Research, Biomedical Centre, Box 595, S-751 24 Uppsala, Sweden

Correspondence to: Lars Rönnstrand, Ludwig Institute for Cancer Research, Biomedical Centre, Box 595, S-751 24 Uppsala, Sweden

^aCurrent address: Department of Medical Pharmacology, Biomedical Centre, Box 593, S-751 24 Uppsala, Sweden

Activation of the -receptor for platelet-derived growth factor (PDGF) by its ligand leads to autophosphorylation on a number of tyrosine residues. Here we show that Tyr763 in the kinase insert region is a novel autophosphorylation site, which after phosphorylation binds the protein tyrosine phosphatase SHP-2. SHP-2 has also previously been shown to bind to phosphorylated Tyr1009 in the PDGF -receptor. Porcine aortic endothelial (PAE) cells transfected with a PDGF -receptor in which Tyr763 and Tyr1009 were mutated to phenylalanine residues failed to associate with SHP-2 after ligand stimulation. Morover, PDGF-BB-induced Ras GTP-loading and Erk2 activation were severely compromised in the receptor mutant. Whereas the mitogenic response to PDGF-BB remained at the same level as in cells expressing wild-type PDGF -receptor, chemotaxis induced by PDGF-BB was significantly decreased in the case of the Y763F/Y1009F mutant cells, suggesting an important role for SHP-2 in chemotactic signaling.

PDGF -receptor; SHP-2; chemotaxis; Ras/MAP kinase pathway