Journal of Biological Chemistry
Volume 279, Issue 50, 10 December 2004, Pages 51931-51938
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Mechanisms of Signal Transduction
Two Distinct Tyrosine-based Motifs Enable the Inhibitory Receptor FcγRIIB to Cooperatively Recruit the Inositol Phosphatases SHIP1/2 and the Adapters Grb2/Grap*

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FcγRIIB are low-affinity receptors for IgG that contain an immunoreceptor tyrosine-based inhibition motif (ITIM) and inhibit immunoreceptor tyrosine-based activation motif (ITAM)-dependent cell activation. When coaggregated with ITAM-bearing receptors, FcγRIIB become tyrosyl-phosphorylated and recruit the Src homology 2 (SH2) domain-containing inositol 5′-phosphatases SHIP1 and SHIP2, which mediate inhibition. The FcγRIIB ITIM was proposed to be necessary and sufficient for recruiting SHIP1/2. We show here that a second tyrosine-containing motif in the intracytoplasmic domain of FcγRIIB is required for SHIP1/2 to be coprecipitated with the receptor. This motif functions as a docking site for the SH2 domain-containing adapters Grb2 and Grap. These adapters interact via their C-terminal SH3 domain with SHIP1/2 to form a stable receptor-phosphatase-adapter trimolecular complex. Both Grb2 and Grap are required for an optimal coprecipitation of SHIP with FcγRIIB, but one adapter is sufficient for the phosphatase to coprecipitate in a detectable manner with the receptors. In addition to facilitating the recruitment of SHIPs, the second tyrosine-based motif may confer upon FcγRIIB the properties of scaffold proteins capable of altering the composition and stability of the signaling complexes generated following receptor engagement.

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*

This work was supported in part by INSERM, the Université Pierre et Marie Curie, and the Institut Pasteur. 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.

The on-line version of this article (available at www.jbc.org) contains supplemental Figs. S1 and S2, which deal with the 16 C-terminal amino acids of the intracytoplasmic domain of FcγRIIB1.

Supported by a fellowship from the Université Pierre et Marie Curie.

Supported by a fellowship from the Association pour la Recherche contre le Cancer.