title: Calpain-catalyzed cleavage and subcellular relocation of protein phosphotyrosine phosphatase 1B (PTP-1B) in human platelets.
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.
authors.affiliation: Molecular Medicine Unit, Beth Israel Hospital, Boston, MA 02215.
authors.forename: J V
authors.initials: JV
authors.lastname: Frangioni
authors.forename: A
authors.initials: A
authors.lastname: Oda
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: E W
authors.initials: EW
authors.lastname: Salzman
authors.forename: B G
authors.initials: BG
authors.lastname: Neel
mesh_terms: D001792:Blood Platelets / Q000201:enzymology*; D002154:Calpain / Q000378:metabolism*; D002384:Catalysis; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007700:Kinetics; D010766:Phosphorylation; D010974:Platelet Aggregation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016023:Integrins; D017027:Protein Tyrosine Phosphatases; D002154:Calpain