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J. Biol. Chem., Vol. 278, Issue 37, 35710-35717, September 12, 2003

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The Protein-tyrosine Phosphatase SHP-1 Associates with the Phosphorylated Immunoreceptor Tyrosine-based Activation Motif of FcRIIa to Modulate Signaling Events in Myeloid Cells^*

Latha P. Ganesan, Huiqing Fang, Clay B. Marsh and Susheela Tridandapani 

From the Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, The Dorothy M. Davis Heart and Lung Institute, and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210

FcRIIa is a low affinity IgG receptor uniquely expressed in human cells that promotes phagocytosis of immune complexes and induces inflammatory cytokine gene transcription. Recent studies have revealed that phagocytosis initiated by FcRIIa is tightly controlled by the inositol phosphatase SHIP-1, and the protein-tyrosine phosphatase SHP-1. Whereas the molecular nature of SHIP-1 involvement with FcRIIa has been well studied, it is not clear how SHP-1 is activated by FcRIIa to mediate its regulatory effect. Here we report that FcRIIa clustering induces SHP-1 phosphatase activity in THP-1 cells. Using synthetic phosphopeptides, and stable transfectants expressing immunoreceptor tyrosine-based activation motif (ITAM) tyrosine mutants of FcRIIa, we demonstrate that SHP-1 associates with the phosphorylated amino-terminal ITAM tyrosine of FcRIIa, whereas the tyrosine kinase Syk associates with the carboxyl-terminal ITAM tyrosine. Association of SHP-1 with FcRIIa ITAM appears to suppress total cellular tyrosine phosphorylation. Furthermore, FcRIIa clustering results in the association of SHP-1 with key signaling molecules such as Syk, p85 subunit of PtdIns 3-kinase, and p62dok, suggesting that these molecules may be substrates of SHP-1 in this system. Finally, overexpression of wild-type SHP-1 but not catalytically deficient SHP-1 led to a down-regulation of NFB-dependent gene transcription in THP-1 cells activated by clustering FcRIIa.

Received for publication, May 14, 2003 , and in revised form, June 24, 2003.

^* This work was supported in part by National Institutes of Health Grants P30 CA16058, P01 CA095426, HL63800, HL6176, and HL70294. 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.

Fellow of the Leukemia and Lymphoma Society. To whom correspondence should be addressed: Rm. 405B HLRI, 473 W. 12th Ave., Columbus, OH 43210. Tel.: 614-247-6768; Fax: 614-688-4662; E-mail: tridandapani.2{at}osu.edu.

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