Physical and functional interactions between receptor-like protein-tyrosine phosphatase alpha and p59fyn.

We have examined the in vivo activity of receptor-like protein-tyrosine phosphatase alpha (PTPalpha) toward p59(fyn), a widely expressed Src family kinase. In a coexpression system, PTPalpha effected a dose-dependent tyrosine dephosphorylation and activation of p59(fyn), where maximal dephosphorylation correlated with a 5-fold increase in kinase activity. PTPalpha expression resulted in increased accessibility of the p59(fyn) SH2 domain, consistent with a PTPalpha-mediated dephosphorylation of the regulatory C-terminal tyrosine residue of p59(fyn). No p59(fyn) dephosphorylation was observed with an enzymatically inactive mutant form of PTPalpha or with another receptor-like PTP, CD45. Many enzyme-linked receptors are complexed with their substrates, and we examined whether PTPalpha and p59(fyn) underwent association. Reciprocal immunoprecipitations and assays detected p59(fyn) and an appropriate kinase activity in PTPalpha immunoprecipitates and PTPalpha and PTP activity in p59(fyn) immunoprecipitates. No association between CD45 and p59(fyn) was detected in similar experiments. The PTPalpha-mediated activation of p59(fyn) is not prerequisite for association since wild-type and inactive mutant PTPalpha bound equally well to p59(fyn). Endogenous PTPalpha and p59(fyn) were also found in association in mouse brain. Together, these results demonstrate a physical and functional interaction of PTPalpha and p59(fyn) that may be of importance in PTPalpha-initiated signaling events.