Inhibitory ITAM signaling traps activating receptors with the phosphatase SHP-1 to form polarized "inhibisome" clusters

Sci Signal. 2011 Apr 19;4(169):ra24. doi: 10.1126/scisignal.2001309.


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 (FcαRI) 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 FcαRI 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Antigens, CD / immunology*
  • Antigens, CD / metabolism
  • Blotting, Western
  • Flow Cytometry
  • Gene Knockdown Techniques
  • Homeostasis / immunology*
  • Humans
  • Immunoglobulin A / immunology
  • Immunoprecipitation
  • Leukocytes, Mononuclear / metabolism
  • Membrane Microdomains / metabolism
  • Multiprotein Complexes / immunology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / immunology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • Receptors, Fc / immunology*
  • Receptors, Fc / metabolism
  • Signal Transduction / immunology*
  • beta-N-Acetylhexosaminidases


  • Actins
  • Antigens, CD
  • Fc(alpha) receptor
  • Immunoglobulin A
  • Multiprotein Complexes
  • Receptors, Fc
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • beta-N-Acetylhexosaminidases