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J. Biol. Chem., Vol. 279, Issue 50, 51931-51938, December 10, 2004

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Two Distinct Tyrosine-based Motifs Enable the Inhibitory Receptor FcRIIB to Cooperatively Recruit the Inositol Phosphatases SHIP1/2 and the Adapters Grb2/Grap^*

Isabelle Isnardi¶, Renaud Lesourne||, Pierre Bruhns, Wolf H. Fridman, John C. Cambier**, and Marc Daëron

From the Laboratoire d'Immunologie Cellulaire et Clinique, INSERM U255, Institut de Recherches Biomédicales des Cordeliers, 75006 Paris, France, the ^**Department of Immunology, University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, Colorado 80262, and the Unité d'Allergologie Moléculaire et Cellulaire, Institut Pasteur, 75015 Paris, France

FcRIIB 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, FcRIIB become tyrosyl-phosphorylated and recruit the Src homology 2 (SH2) domain-containing inositol 5'-phosphatases SHIP1 and SHIP2, which mediate inhibition. The FcRIIB 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 FcRIIB 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 FcRIIB, 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 FcRIIB the properties of scaffold proteins capable of altering the composition and stability of the signaling complexes generated following receptor engagement.

Received for publication, September 7, 2004

^* 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 FcRIIB1.

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

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

To whom correspondence should be addressed: Unité d'Allergologie Moléculaire et Cellulaire, Dépt. d'Immunologie, Inst. Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France. Tel.: 33-1-4568-8642; Fax: 33-1-4061-3160; E-mail: daeron{at}pasteur.fr.

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