Journal of Biological Chemistry
Volume 278, Issue 42, 17 October 2003, Pages 40923-40932
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Mechanisms of Signal Transduction
The Tyrosine Phosphatase 1B Regulates Linker for Activation of T-cell Phosphorylation and Platelet Aggregation upon FcγRIIa Cross-linking*

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Human platelets express the receptor for immunoglobulin G, FcγRIIa, that triggers cell aggregation upon interaction with immune complexes. Here, we report that the rapid tyrosine phosphorylation of the Linker for Activation of T-cell (LAT) in human platelets stimulated by FcγRIIa cross-linking was followed by its complete dephosphorylation in an αIIb/β3 integrin-dependent manner. Concomitant to LAT dephosphorylation, the protein tyrosine phosphatase 1B (PTP1B) was activated through a mechanism involving its proteolysis by calpains downstream of integrins. Both PTP1B and LAT were associated with the actin cytoskeleton complex formed during platelet aggregation. Moreover, phospho-LAT appeared as a good substrate of activated PTP1B in vitro and these two proteins interacted upon platelet activation by FcγRIIa cross-linking. The permeant substrate-trapping PTP1B (TAT-PTP1B D181A) partly inhibited LAT dephosphorylation in human platelets, strongly suggesting that this tyrosine phosphatase was involved in this regulatory pathway. Using a pharmacological inhibitor, we provide evidence that PTP1B activation and LAT dephosphorylation processes were required for irreversible platelet aggregation. Altogether, our results demonstrate that PTP1B plays an important role in the integrin-mediated dephosphorylation of LAT in human platelets and is involved in the control of irreversible aggregation upon FcγRIIa stimulation.

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This work was supported by grants from the Association pour la Recherche contre le Cancer (contract 4794) and Alliance des Recherches sur le Cancer-Toulouse. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.