SHEP1 partners with CasL to promote marginal zone B-cell maturation.
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.
Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Cecille D
CD
Browne
Melanie M
MM
Hoefer
Suresh K
SK
Chintalapati
Matthew H
MH
Cato
Yann
Y
Wallez
Derek V
DV
Ostertag
Elena B
EB
Pasquale
Robert C
RC
Rickert
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D008246:Lysophospholipids; C505592:NEDD9 protein, mouse; D011947:Receptors, Antigen, B-Cell; D049349:Receptors, Lysosphingolipid; C405695:Sh2d3c protein, mouse; C060506:sphingosine 1-phosphate; D013110:Sphingosine