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 alpha (PTPalpha) in regulating the kinase activity of Src family members has been proposed because ectopic expression of PTPalpha enhances the dephosphorylation and activation of Src and Fyn [1] [2] [3]. We have generated mice lacking catalytically active PTPalpha to address the question of whether PTPalpha 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 PTPalpha allele (PTPalpha-/-) and lacking detectable PTPalpha protein exhibited no gross phenotypic defects. The kinase activities of Src and Fyn were significantly reduced in PTPalpha-/- mouse brain and primary embryonic fibroblasts, and this correlated with enhanced phosphorylation of the carboxy-terminal regulatory Tyr527 of Src in PTPalpha-/- mice. Thus, PTPalpha is a physiological positive regulator of the tyrosine kinases Src and Fyn. Increased tyrosine phosphorylation of several unidentified proteins was also apparent in PTPalpha-/- mouse brain lysates. These may be PTPalpha substrates or downstream signaling proteins. Taken together, the results indicate that PTPalpha 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.

RPTPα is required for rigidity-dependent inhibition of extension and differentiation of hippocampal neurons

“…Our group and others showed that Src and Fyn are activated by RPTP␣-mediated dephosphorylation both in fibroblasts (Ponniah et al, 1999;Su et al, 1999;von Wichert et al, 2003) and neurons (Bodrikov et al, 2005;Helmke et al, 1998;Zeng et al, 1999).…”

The interplay between Src and integrins in normal and tumor biology

“…The most likely tyrosine phosphatase involved in response to cell adhesion is the transmembrane phosphatase PTPa . Downregulation of Src and Fyn kinases has been observed in ptpaÀ/À cells, which correlated with enhanced tyrosine phosphorylation of the negative regulatory element (Ponniah et al, 1999). These fibroblasts lacking PTPa also exhibit defective tyrosine phosphorylation of substrates for cell adhesion-induced tyrosine phosphorylation (Ponniah et al, 1999;Su et al, 1999;Zeng et al, 2003).…”

Expression of protein tyrosine phosphatase alpha (RPTPα) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo

“…Third, RPTPa is an important regulator of SFK activity, by controlling dephosphorylation of the carboxy-terminal negative regulatory Y530 site of cSrc. Cells lacking RPTPa display reduced Fyn and cSrc kinase activities, and exhibit defects similar to those resulting from lack of c-Src (Ponniah et al, 1999;Su et al, 1999). Conversely, RPTPa overexpression results in elevated c-Src kinase activity (den Hertog et al, 1993;Zheng et al, 1992Zheng et al, , 2000.…”