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

Two protein forms of tyrosine phosphatase epsilon (PTP epsilon) are known - receptor-like (tm-PTP epsilon) and non receptor-like (cyt-PTP epsilon), wi th each form possessing unique tissue-specific expression patterns, subcell ular localization, and physiological functions. We describe two additional forms of PTP epsilon: protein - p67 and p65, p67 is produced by initiation of translation at an internal initiation codon of PTP epsilon mRNA molecule s, while p65 is produced by specific proteolytic cleavage of larger PTP eps ilon proteins. Cleavage is inhibited by MG132, but is proteasome-independen t. In contrast with full-length tm-PTP epsilon and cyt-PTP epsilon, 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 a ctive and can reduce Src-mediated phosphorylation of the Kv2.1 voltage-gate d potassium channel, albeit with reduced efficiency which most likely resul ts from their cytoplasmic localization. We also show that full-length cyt-P TP epsilon protein can be found at the cell membrane and in the nucleus and that it is the first 27 residues of cyt-PTP epsilon which determine this l ocalization. p67 and p65 provide mechanisms for removing PTP epsilon activi ty from the cell membrane, possibly serving to down-regulate PTP epsilon ac tivity there. PTP epsilon emerges as a family of four related proteins whos e expression, subcellular localization and most likely physiological roles are subject to complex regulation at the transcriptional, translational and post-translational levels.