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J. Biol. Chem., Vol. 275, Issue 48, 37357-37364, December 1, 2000

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Molecular Basis of the Recruitment of the SH2 Domain-containing Inositol 5-Phosphatases SHIP1 and SHIP2 by FcRIIB^*

Pierre Bruhns^§, Frédéric Vély^¶, Odile Malbec, Wolf H. Fridman, Eric Vivier^¶, and Marc Daëron

From the  Laboratoire d'Immunologie Cellulaire et Clinique, INSERM U255, Institut Curie, 75005 Paris, France and the ^¶ Centre d'Immunologie INSERM-CNRS de Marseille-Luminy, 13288 Marseille, France

FcRIIB are single-chain low affinity receptors for IgG that negatively regulate immunoreceptor tyrosine-based activation motif-dependent cell activation. They bear one immunoreceptor tyrosine-based inhibition motif (ITIM) that becomes tyrosyl-phosphorylated upon coaggregation of FcRIIB with immunoreceptor tyrosine-based activation motif-bearing receptors and that recruits SH2 domain-containing inositol 5-phosphatases (SHIPs) in vivo. Synthetic FcRIIB ITIM phosphopeptides, however, also bind SH2 domain-containing protein-tyrosine phosphatases (SHPs) in vitro. To identify SHIP-binding sites, we exchanged residues between the FcRIIB ITIM and the N-terminal ITIM of a killer cell Ig-like receptor that does not bind SHIPs. Loss of function and gain of function substitutions identified the Y+2 leucine, in the FcRIIB ITIM, as determining the binding of both SHIP1 and SHIP2, but not the binding of SHP-1 or SHP-2. Conversely, the Y2 isoleucine that determines the in vitro binding of SHP-1 and SHP-2 affected neither the binding nor the recruitment of SHIP1 or SHIP2. One hydrophobic residue, in the ITIM of FcRIIB therefore determines the affinity for SHIPs. This residue is symmetrical to the hydrophobic residue that determines the affinity of all ITIMs for SHPs. It defines a SHIP-binding site, distinct from a SHP-binding site, that enables FcRIIB to recruit SHIP1 and SHIP2 and that is preferentially used in vivo.

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