Receptor protein tyrosine phosphatase alpha activates Src-family kinases and controls integrin-mediated responses in fibroblasts.
BACKGROUND
Fyn and c-Src are two of the most widely expressed Src-family kinases. Both are strongly implicated in the control of cytoskeletal organization and in the generation of integrin-dependent signalling responses in fibroblasts. These proteins are representative of a large family of tyrosine kinases, the activity of which is tightly controlled by inhibitory phosphorylation of a carboxyterminal tyrosine residue (Tyr527 in chicken c-Src); this phosphorylation induces the kinases to form an inactive conformation. Whereas the identity of such inhibitory Tyr527 kinases has been well established, no corresponding phosphatases have been identified that, under physiological conditions, function as positive regulators of c-Src and Fyn in fibroblasts.


RESULTS
Receptor protein tyrosine phosphatase alpha (RPTPalpha) was inactivated by homologous recombination. Fibroblasts derived from these RPTPalpha-/- mice had impaired tyrosine kinase activity of both c-Src and Fyn, and this was accompanied by a concomitant increase in c-Src Tyr527 phosphorylation. RPTPalpha-/- fibroblasts also showed a reduction in the rate of spreading on fibronectin substrates, a trait that is a phenocopy of the effect of inactivation of the c-src gene. In response to adhesion on a fibronectin substrate, RPTPalpha-/- fibroblasts also exhibited characteristic deficiencies in integrin-mediated signalling responses, such as decreased tyrosine phosphorylation of the c-Src substrates Fak and p 130(cas), and reduced activation of extracellular signal regulated (Erk) MAP kinases.


CONCLUSIONS
These observations demonstrate that RPTPalpha functions as a physiological upstream activator of Src-family kinases in fibroblasts and establish this tyrosine phosphatase as a newly identified regulator of integrin signalling.
Su
J
J
Department of Pharmacology, Kaplan Cancer Center, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
Muranjan
M
M
Sap
J
J
D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D016391:Genes, src; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
D005353:Fibronectins; D016023:Integrins; D011956:Receptors, Cell Surface; D019061:src-Family Kinases; D017027:Protein Tyrosine Phosphatases; C516843:Ptpra protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4