RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling.
The RasGRPs are a family of Ras activators that possess diacylglycerol-binding C1 domains. In T cells, RasGRP1 links TCR signaling to Ras. B cells coexpress RasGRP1 and RasGRP3. Using Rasgrp1 and Rasgrp3 single and double null mutant mice, we analyzed the role of these proteins in signaling to Ras and Erk in B cells. RasGRP1 and RasGRP3 both contribute to BCR-induced Ras activation, although RasGRP3 alone is responsible for maintaining basal Ras-GTP levels in unstimulated cells. Surprisingly, RasGRP-mediated Ras activation is not essential for B cell development because this process occurs normally in double-mutant mice. However, RasGRP-deficient mice do exhibit humoral defects. Loss of RasGRP3 led to isotype-specific deficiencies in Ab induction in immunized young mice. As reported previously, older Rasgrp1-/- mice develop splenomegaly and antinuclear Abs as a result of a T cell defect. We find that such mice have elevated serum Ig levels of several isotypes. In contrast, Rasgrp3-/- mice exhibit hypogammaglobulinemia and show no signs of splenomegaly or autoimmunity. Double-mutant mice exhibit intermediate serum Ab titers, albeit higher than wild-type mice. Remarkably, double-mutant mice exhibit no signs of autoimmunity or splenomegaly. B cell proliferation induced by BCR ligation with or without IL-4 was found to be RasGRP1- and RasGRP3-dependent. However, the RasGRPs are not required for B cell proliferation per se, because LPS-induced proliferation is unaffected in double-mutant mice.
Coughlin
Jason J
JJ
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Stang
Stacey L
SL
Dower
Nancy A
NA
Stone
James C
JC
D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D018631:ras Proteins / Q000276:immunology* / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; D007132:Immunoglobulin Isotypes; C112278:Rasgrp1 protein, mouse; D011947:Receptors, Antigen, B-Cell; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins