The Rap GTPases mediate CXCL13- and sphingosine1-phosphate-induced chemotaxis, adhesion, and Pyk2 tyrosine phosphorylation in B lymphocytes.
The localization of B cells to lymphoid organs where they can become activated and differentiate into antibody-secreting plasma cells is controlled by multiple chemoattractants that promote cell migration and integrin-mediated adhesion. CXCL13 and sphingosine 1-phosphate (S1P) are two important chemoattractants that control the trafficking of B cells. CXCL13 directs B lymphocytes to lymphoid follicles where they receive survival signals and, if activated, undergo a germinal center response. In contrast, S1P allows B cells and plasma cells to exit lymphoid organs and re-enter the circulation. The Rap1 GTPase is a key regulator of cell adhesion and cell migration in a number of systems. We now show that Rap activation is required for CXCL13 and S1P to induce B cell migration as well as adhesion to ICAM-1 and VCAM-1. We also show that Pyk2, a tyrosine kinase involved in cytoskeleton rearrangements and B cell migration, is a downstream target of both CXCL13 and S1P signaling and that Rap activation is important for CXCL13 and S1P to stimulate tyrosine phosphorylation of Pyk2, a modification that increases Pyk2 kinase activity. This suggests that the ability of CXCL13 and S1P to direct the trafficking and localization of B cells in vivo may be dependent on Rap activation.
Durand
Caylib A
CA
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
Westendorf
Jens
J
Tse
Kathy W K
KW
Gold
Michael R
MR
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D054382:Chemokine CXCL13; D019743:Chemokines, CXC / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D020668:rap GTP-Binding Proteins / Q000378:metabolism*
D054382:Chemokine CXCL13; D019743:Chemokines, CXC; C486386:Cxcl13 protein, mouse; D008246:Lysophospholipids; D016755:Proto-Oncogene Proteins c-jun; D049349:Receptors, Lysosphingolipid; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D019000:Phosphotyrosine; C060506:sphingosine 1-phosphate; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020668:rap GTP-Binding Proteins; D013110:Sphingosine