The Dok-3/Grb2 adaptor module promotes inducible association of the lipid phosphatase SHIP with the BCR in a coreceptor-independent manner

Eur J Immunol. 2016 Nov;46(11):2520-2530. doi: 10.1002/eji.201646431. Epub 2016 Sep 14.


The SH2 domain-containing inositol 5'-phosphatase (SHIP) plays a key role in preventing autoimmune phenomena by limiting antigen-mediated B cell activation. SHIP function is thought to require the dual engagement of the BCR and negative regulatory coreceptors as only the latter appear capable of recruiting SHIP from the cytosol to the plasma membrane by the virtue of phosphorylated immunoreceptor tyrosine-based inhibitory motifs. Here, we demonstrate a coreceptor-independent membrane recruitment and function of SHIP in B cells. In the absence of coreceptor ligation, SHIP translocates to sites of BCR activation through a concerted action of the protein adaptor unit Dok-3/Grb2 and phosphorylated BCR signaling components. Our data reveal auto-inhibitory SHIP activation by the activated BCR and suggest an unexpected negative-regulatory capacity of immunoreceptor tyrosine-based activation motifs in Igα and Igβ.

Keywords: BCR; B cell inhibition; Dok-3; Grb2; Plasma membrane recruitment; SHIP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • B-Lymphocytes / immunology
  • Cell Line
  • Cell Membrane / chemistry
  • Cell Membrane / genetics
  • Cell Membrane / immunology
  • Chickens
  • GRB2 Adaptor Protein / metabolism*
  • Lymphocyte Activation
  • Mice
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / genetics
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / immunology
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / metabolism*
  • Phosphorylation
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / immunology
  • Receptors, Antigen, B-Cell / metabolism*
  • Signal Transduction


  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • Receptors, Antigen, B-Cell
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases