Targeted disruption of the tyrosine phosphatase PTPα leads to constitutive downregulation of the kinases Src and Fyn

Abstract

A role for the receptor-like protein tyrosine phosphatase ? (PTP?) in regulating the kinase activity of Src family members has been proposed because ectopic expression of PTP?(enhances the dephosphorylation and activation of Src and Fyn [1-3]. We have generated mice lacking catalytically active PTP? to address the question of whether PTP? is a physiological activator of Src and Fyn, and to investigate its other potential functions in the context of the whole animal. Mice homozygous for the targeted PTP? allele (PTP?(-/-)) and lacking detectable PTP? protein exhibited no gross phenotypic defects. The kinase activities of Src and Fyn were significantly reduced in PTP?(-/-) mouse brain and primary embryonic fibroblasts, and this correlated with enhanced phosphorylation of the carboxy-terminal regulatory Tyr527 of Src in PTP?(-/-) mice. Thus, PTP? is a physiological positive regulator of the tyrosine kinases Src and Fyn. Increased tyrosine phosphorylation of several unidentified proteins was also apparent in PTP?(-/-) mouse brain lysates. These may be PTP? substrates or downstream signaling proteins. Taken together, the results indicate that PTP? has a dual function as a positive and negative regulator of tyrosine phosphorylation events, increasing phosphotyrosyl proteins through activation of Src and Fyn, and directly or indirectly removing tyrosine phosphate from other unidentified proteins.