title: How ITAMs inhibit signaling.
abstract: Immunoreceptor tyrosine-based activation motifs (ITAMs) are used by multiple receptors to activate immune cells. However, ITAM-associated receptors can have paradoxically inhibitory effects, which have been implicated in regulation of inflammatory responses, but mechanisms of inhibitory signaling are poorly understood. New evidence shows that low avidity ligation of the ITAM-associated immunoglobulin A receptor FcαRI (transient engagement of small numbers of FcαRIs) results in translocation of FcαRI and the associated inhibitory Src homology 2 (SH2) domain-containing phosphatase-1 (SHP-1) to membrane lipid rafts. Subsequent ligation of activating receptors results in their colocalization with FcαRI and SHP-1 and trafficking to an inhibitory intracellular compartment termed the inhibisome. Thus, ITAM suppressive signals subvert the activating function of rafts to promote incorporation of receptors into supramolecular domains where signaling molecules are deactivated by SHP-1.
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, 535 East 70th Street, New York, NY 10021, USA. ivashkivl@hss.edu
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D021962:Membrane Microdomains / Q000276:immunology; D018448:Models, Immunological; D054730:Protein Interaction Domains and Motifs / Q000276:immunology*; D021381:Protein Transport / Q000276:immunology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000276:immunology*; D011961:Receptors, Fc / Q000235:genetics*; D015398:Signal Transduction / Q000276:immunology*; D014443:Tyrosine / Q000276:immunology
chemical_list: D015703:Antigens, CD; C036832:Fc(alpha) receptor; D007070:Immunoglobulin A; D011961:Receptors, Fc; D014443:Tyrosine; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6