Frangioni J V, Oda A, Smith M, Salzman E W, Neel B G
Molecular Medicine Unit, Beth Israel Hospital, Boston, MA 02215.
EMBO J. 1993 Dec;12(12):4843-56. doi: 10.1002/j.1460-2075.1993.tb06174.x.
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.
非跨膜磷酸酪氨酸磷酸酶1B（PTP-1B）是一种含量丰富的酶，通常通过C端靶向序列定位于内质网的胞质面。我们发现，激动剂诱导的血小板活化导致PTP-1B在该靶向序列上游的位点发生蛋白水解切割，使其催化结构域从膜上亚细胞定位到胞质溶胶中。PTP-1B的切割由钙依赖性中性蛋白酶钙蛋白酶催化，是血小板激动剂诱导聚集的一个普遍特征。此外，PTP-1B的切割与富含血小板血浆中血小板聚集从可逆转变为不可逆相关。gpIIb-IIIa的结合是诱导PTP-1B切割所必需的，这表明整合素不仅调节酪氨酸激酶，还调节酪氨酸磷酸酶。通过免疫复合物磷酸酶测定法测量，PTP-1B的切割伴随着其酶活性2倍的刺激，并与酪氨酸磷酸化模式的离散变化相关。PTP-1B的切割和亚细胞定位代表了一种改变酪氨酸磷酸化的新机制，这可能在血小板以外的细胞类型中具有重要的生理意义。
