Two distinct tyrosine-based motifs enable the inhibitory receptor FcgammaRIIB to cooperatively recruit the inositol phosphatases SHIP1/2 and the adapters Grb2/Grap

J Biol Chem. 2004 Dec 10;279(50):51931-8. doi: 10.1074/jbc.M410261200. Epub 2004 Sep 28.

Abstract

FcgammaRIIB are low-affinity receptors for IgG that contain an immunoreceptor tyrosine-based inhibition motif (ITIM) and inhibit immunoreceptor tyrosine-based activation motif (ITAM)-dependent cell activation. When coaggregated with ITAM-bearing receptors, FcgammaRIIB become tyrosyl-phosphorylated and recruit the Src homology 2 (SH2) domain-containing inositol 5'-phosphatases SHIP1 and SHIP2, which mediate inhibition. The FcgammaRIIB ITIM was proposed to be necessary and sufficient for recruiting SHIP1/2. We show here that a second tyrosine-containing motif in the intracytoplasmic domain of FcgammaRIIB is required for SHIP1/2 to be coprecipitated with the receptor. This motif functions as a docking site for the SH2 domain-containing adapters Grb2 and Grap. These adapters interact via their C-terminal SH3 domain with SHIP1/2 to form a stable receptor-phosphatase-adapter trimolecular complex. Both Grb2 and Grap are required for an optimal coprecipitation of SHIP with FcgammaRIIB, but one adapter is sufficient for the phosphatase to coprecipitate in a detectable manner with the receptors. In addition to facilitating the recruitment of SHIPs, the second tyrosine-based motif may confer upon FcgammaRIIB the properties of scaffold proteins capable of altering the composition and stability of the signaling complexes generated following receptor engagement.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Line
  • Chickens
  • GRB2 Adaptor Protein
  • In Vitro Techniques
  • Inositol Polyphosphate 5-Phosphatases
  • Mice
  • Molecular Sequence Data
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases / chemistry
  • Phosphoric Monoester Hydrolases / metabolism*
  • Protein Binding
  • Receptors, IgG / chemistry*
  • Receptors, IgG / genetics
  • Receptors, IgG / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transfection
  • Tyrosine / chemistry
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • Fcgr2b protein, mouse
  • GRB2 Adaptor Protein
  • Grb2 protein, mouse
  • Receptors, IgG
  • Recombinant Proteins
  • Tyrosine
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases
  • Inpp5d protein, mouse
  • Inppl1 protein, mouse
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases