期刊
SCIENCE SIGNALING
卷 4, 期 169, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2001309
关键词
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资金
- French Research Ministry, Agence National pour la Recherche (ANR) Mime2006
- ANR Mie2009
- Association pour l'Utilisation du Rein Artificiel (AURA)
- INSERM
The ability of immunoreceptor tyrosine-based activation motif (ITAM)-bearing receptors to inhibit, rather than activate, signaling by other receptors is a regulatory mechanism of immune homeostasis. However, it remains unclear how inhibitory ITAM (ITAMi) receptor signaling and Src homology 2 (SH2) domain-containing phosphatase-1 (SHP-1), which is recruited to ITAMs, target multiple heterologous activating responses without coaggregating with the associated activating receptors. We found that ITAMi signaling triggered by the binding of monomeric ligands to the type I immunoglobulin A (IgA) Fc receptor (Fc alpha RI) induced its dynamic cosegregation with heterologous activating receptors, signaling effectors, and the inhibitory phosphatase SHP-1 into polarized intracellular clusters that we call inhibisomes. Formation of inhibisomes was preceded by the recruitment of Fc alpha RI and SHP-1 into lipid rafts. Cosegregation required the depolymerization of actin, which depended on SHP-1, and inhibisome formation was abolished by knockdown of SHP-1 and by actin-depolymerizing drugs. Thus, SHP-1- and actin depolymerization-dependent spatiotemporal compartmentalization of ITAMi-containing receptors into lipid rafts, regions associated with intracellular signaling, represents a key event in the integration of ITAMi-mediated inhibitory signals.
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