How ITAMs Inhibit Signaling

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 Fc alpha RI (transient engagement of small numbers of Fc alpha RIs) results in translocation of Fc alpha RI 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 Fc alpha RI 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.