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 Blood, 15 September 2007, Vol. 110, No. 6, pp. 1871-1878.
Prepublished online as a Blood First Edition Paper on May 30, 2007; DOI 10.1182/blood-2007-03-081414.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

The low-molecular-weight phosphotyrosine phosphatase is a negative regulator of Fc{gamma}RIIA-mediated cell activation

Francesca Mancini1, Stefania Rigacci2, Andrea Berti2, Cesare Balduini1, and Mauro Torti1

1 Department of Biochemistry, University of Pavia, Pavia; 2 Department of Biochemical Sciences, University of Florence, Florence, Italy

Activation of human platelets by cross-linking of the low-affinity receptor for immunoglobulin G (Fc{gamma}RIIA) is initiated by Src kinase–mediated phosphorylation of the immunoreceptor tyrosine–based activation motif (ITAM) within the receptor, but the identity of the enzyme responsible for its dephosphorylation and inactivation is unknown. Here we report that the 18-kDa low-molecular-weight phosphotyrosine phosphatase (LMW-PTP) is expressed in human platelets and undergoes subcellular redistribution upon Fc{gamma}RIIA cross-linking. In vitro, LMW-PTP was found to efficiently dephosphorylate activated Fc{gamma}RIIA and LAT, but not Syk or phospholipase C{gamma}2. In the megakaryocytic cell line DAMI, antibody-induced phosphorylation of Fc{gamma}RIIA was rapid and transient. The late dephosphorylation of Fc{gamma}RIIA was dramatically delayed upon reduction of LMW-PTP expression by siRNA. Strikingly, overexpression of LMW-PTP resulted in the inhibition of antibody-induced phosphorylation of Fc{gamma}RIIA, and caused a more rapid dephosphorylation. In addition, overexpression of LMW-PTP inhibited activation of Syk downstream of Fc{gamma}RIIA and reduced intracellular Ca2+ mobilization. These results demonstrate that LMW-PTP is responsible for Fc{gamma}RIIA dephosphorylation, and is implicated in the down-regulation of cell activation mediated by this ITAM-bearing immunoreceptor.


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