SHEP1 partners with CasL to promote marginal zone B-cell maturation

Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18944-9. doi: 10.1073/pnas.1007558107. Epub 2010 Oct 18.

Abstract

The marginal zone is a cellular niche bordering the marginal sinus of the spleen that contains specialized B-cell and macrophage subsets poised to capture bloodborne antigens. Marginal zone B cells are retained in this niche by integrin-mediated signaling induced by G protein-coupled receptors (GPCRs) and, likely, the B-cell receptor (BCR). Sphingosine-1-phosphate (S1P) signaling via the S1P family of GPCRs is known to be essential for B-cell localization in the marginal zone, but little is known about the downstream signaling events involved. Here, we demonstrate that the adaptor protein SHEP1 is required for marginal zone B-cell maturation. SHEP1 functions in concert with the scaffolding protein CasL, because we show that SHEP1 and CasL are constitutively associated in B cells. SHEP1 association is required for the BCR or S1P receptor(s) to induce the conversion of CasL into its serine/threonine hyperphosphorylated form, which is important for lymphocyte adhesion and motility. Thus, SHEP1 orchestrates marginal zone B-cell movement and retention as a key downstream effector of the BCR and S1P receptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism*
  • Cell Movement / physiology*
  • Lysophospholipids / genetics
  • Lysophospholipids / metabolism
  • Mice
  • Mice, Knockout
  • Phosphorylation / physiology
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / metabolism
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism
  • Signal Transduction / physiology*
  • Sphingosine / analogs & derivatives
  • Sphingosine / genetics
  • Sphingosine / metabolism
  • Spleen / cytology
  • Spleen / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Lysophospholipids
  • NEDD9 protein, mouse
  • Receptors, Antigen, B-Cell
  • Receptors, Lysosphingolipid
  • Sh2d3c protein, mouse
  • sphingosine 1-phosphate
  • Sphingosine