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.

Fig. 1

Contrasting mechanisms of inhibition of signaling by ITIM- and ITAM-containing receptors. (A) Model of classical ITIM-mediated inhibition. The inhibitory ITIM-containing FcγRIIb and the activating FcγRIII are coaggregated by joint recognition of IgG Fc regions in immune complexes. The tyrosine-phosphorylated ITIM in the FcγRIIb cytoplasmic domain recruits SHIP (and in some ITIM-containing receptors SHP-1 and SHP-2), which inhibit signaling by dephosphorylating activating receptors and downstream signaling intermediates. PIP₂, phosphatidylinositol 4,5-bisphosphate; PI3K, phosphatidylinositol 3-kinase; P, phosphate; Y, tyrosine. (B) Model of ITAM-mediated inhibition. Dimerization of FcαRI by monomeric IgA or monovalent ligation by Fab fragments (not depicted) induces association of SHP-1 and translocation in to rafts. Various receptors that typically use rafts for positive signaling localize to rafts after ligation by their respective ligands and thus colocalize with FcαRI and SHP-1. These include FcεRI, FcγRIII, TNF receptor, chemokine (CC-motif) receptor 2 (CCR2), and TLRs. Deactivation of receptor signaling by SHP-1 is likely initiated in rafts and is completed after translocation to an intracellular inhibisome compartment.