Generation of novel cytoplasmic forms of protein tyrosine phosphatase epsilon by proteolytic processing and translational control

Two protein forms of tyrosine phosphatase epsilon (PTPε) are known - receptor-like (tm-PTPε) and non receptor-like (cyt-PTPε), with each form possessing unique tissue-specific expression patterns, subcellular localization, and physiological functions. We describe two additional forms of PTPε protein - p67 and p65. p67 is produced by initiation of translation at an internal initiation codon of PTPε mRNA molecules, while p65 is produced by specific proteolytic cleavage of larger PTPε proteins. Cleavage is inhibited by MG132, but is proteasome-independent. In contrast with full-length tm-PTPε and cyt-PTPε, p67 and p65 are exclusively cytoplasmic, are not phosphorylated by Neu, and do not associate with Grb2 in unstimulated cells, p67 and p65 are catalytically active and can reduce Src-mediated phosphorylation of the Kv2.1 voltage-gated potassium channel, albeit with reduced efficiency which most likely results from their cytoplasmic localization. We also show that full-length cyt-PTPε protein can be found at the cell membrane and in the nucleus and that it is the first 27 residues of cyt-PTPε which determine this localization. p67 and p65 provide mechanisms for removing PTPε activity from the cell membrane, possibly serving to down-regulate PTPε activity there. PTPε emerges as a family of four related proteins whose expression, subcellular localization and most likely physiological roles are subject to complex regulation at the transcriptional, translational and post-translational levels.