Vav is required for cyclin D2 induction and proliferation of mouse B lymphocytes activated via the antigen receptor

B lymphocytes from mice null for the Rho-family guanine-nucleotide exchange factor, Vav, are defective in their ability to proliferate in response to BCR crosslinking, but are able to proliferate normally in response to LPS. In addition, they have a depletion of CD5(+) (B1) lymphocytes and defective IgG class switching. This phenotype is reminiscent of that observed in mic e null for the cell cycle regulatory protein, cyclin D2. We demonstrate her e that the inability of vav(-/-) B cells to proliferate in response to BCR ligation is due to an inability to induce cyclin D2. In addition, we show t hat the proliferative defect of these cells occurs after the cells have ent ered early Gl phase. Analyses of potential downstream signaling intermediat es revealed differential activation of the stress-activated MAP kinases in the absence of Vav, normal activation of the ERK, MAPK, and phosphatidylino sitol 3-kinase pathways, and defective intracellular calcium mobilization. We further demonstrate that intracellular calcium homeostasis is required f or cyclin D2 induction, implicating a possible link with the defective calc ium response of vav(-/-) B cells and their inability to induce cyclin D2.