Regulation of Protein-tyrosine Phosphatases α and ε by Calpain-mediated Proteolytic Cleavage

The precise subcellular localization of non-receptor tyrosine phosphatases is a major factor in regulating their physiological functions. We have previously shown that cellular processing of protein-tyrosine phosphatase ε (PTPε) generates a physiologically distinct, cytoplasmic form of this protein, p65 PTPε. Here we describe a novel protein form of the related receptor-type tyrosine phosphatase α (RPTPα), p66 PTPα, which is detected in nearly all cell types where RPTPα is expressed. Both p66 PTPα and p65 PTPε are produced by calpain-mediated proteolytic cleavage in vivo. Cleavage is inhibited in living cells by a variety of calpain inhibitors, can be induced in primary cortical neurons treated with calcium chloride, and is observed in lysates of brain or of cultured cells following addition of purified calpain. Cleavage occurs within the intracellular juxtamembrane domain of RPTPα, releasing the phosphatase catalytic domains from their membranal anchors and translocating them to the cytoplasm. Translocation reduces the ability of PTPα to act on membrane-associated substrates, as it loses its ability to dephosphorylate Src at its C-terminal regulatory site, and its ability to dephosphorylate the Kv2.1 voltage-gated potassium channel is severely impaired. In all, the data indicate that control of phosphatase function via post-translational processing occurs also among receptor-type phosphatases, and demonstrate the molecular complexity of regulating these parameters within the PTPα/PTPε phosphatase subfamily.