Research ArticleImmunology

Inhibitory ITAM Signaling Traps Activating Receptors with the Phosphatase SHP-1 to Form Polarized “Inhibisome” Clusters

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Science Signaling  19 Apr 2011:
Vol. 4, Issue 169, pp. ra24
DOI: 10.1126/scisignal.2001309

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Inhibition by Diversion

Signaling by receptors containing activating motifs called ITAMs stimulates pathways that lead to cellular activation. Paradoxically, ITAM receptors, including the immunoglobulin receptor FcαRI, can also inhibit signaling. Pfirsch-Maisonnas et al. found that the binding of low-affinity ligand resulted in the recruitment of FcαRI and the phosphatase SHP-1 to membrane lipid rafts. In a second step, ligation of the activating receptor FcεRI resulted in its colocalization with FcαRI and SHP-1 in rafts, and the assembled proteins were internalized into intracellular structures called “inhibisomes,” which prevented FcεRI from activating its effectors. FcαRI also inhibited signaling by non–ITAM-containing receptors, which suggests that the recruitment of inhibitory ITAM receptors and SHP-1 to lipid rafts may constitute a general mechanism for the inhibition of activating receptors.

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