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  • Title: Two distinct tyrosine-based motifs enable the inhibitory receptor FcgammaRIIB to cooperatively recruit the inositol phosphatases SHIP1/2 and the adapters Grb2/Grap.
    Author: Isnardi I, Lesourne R, Bruhns P, Fridman WH, Cambier JC, Daëron M.
    Journal: J Biol Chem; 2004 Dec 10; 279(50):51931-8. PubMed ID: 15456754.
    Abstract:
    FcgammaRIIB 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, FcgammaRIIB become tyrosyl-phosphorylated and recruit the Src homology 2 (SH2) domain-containing inositol 5'-phosphatases SHIP1 and SHIP2, which mediate inhibition. The FcgammaRIIB 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 FcgammaRIIB 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 FcgammaRIIB, 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 FcgammaRIIB the properties of scaffold proteins capable of altering the composition and stability of the signaling complexes generated following receptor engagement.
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