Calpain-catalyzed cleavage and subcellular relocation of protein phosphotyrosine phosphatase 1B (PTP-1B) in human platelets.

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Abstract
The non‐transmembrane phosphotyrosine phosphatase 1B (PTP‐1B) is an abundant enzyme, normally localized to the cytosolic face of the endoplasmic reticulum via a C‐terminal targeting sequence. We have found that agonist‐induced platelet activation results in proteolytic cleavage of PTP‐1B at a site upstream from this targeting sequence, causing subcellular relocation of its catalytic domain from membranes to the cytosol. PTP‐1B cleavage is catalyzed by the calcium‐dependent neutral protease calpain and is a general feature of platelet agonist‐induced aggregation. Moreover, PTP‐1B cleavage correlates with the transition from reversible to irreversible platelet aggregation in platelet‐rich plasma. Engagement of gpIIb‐IIIa is necessary for inducing PTP‐1B cleavage, suggesting that integrins regulate tyrosine phosphatases as well as tyrosine kinases. PTP‐1B cleavage is accompanied by a 2‐fold stimulation of its enzymatic activity, as measured by immune complex phosphatase assay, and correlates with discrete changes in the pattern of tyrosyl phosphorylation. Cleavage and subcellular relocation of PTP‐1B represents a novel mechanism for altering tyrosyl phosphorylation that may have important physiological implications in cell types other than platelets.