The small GTPase Ral mediates SDF-1-induced migration of B cells and multiple myeloma cells

Chemokine-controlled migration plays a critical role in B-cell development, differentiation, and function, as well as in the pathogenesis of B-cell malignancies, including the plasma cell neoplasm multiple myeloma (MM). Here, we demonstrate that stimulation of B cells and MM cells with the chemokine stromal cell-derived factor-1 (SDF-1) induces strong migration and activation of the Ras-like GTPase Rai. Inhibition of Rai, by expression of the dominant negative RaIN28 mutant or of RaIBP Delta GAP, a RaI effector mutant that sequesters active RaI, results in impaired SDF-1-induced migration of B cells and MM cells. Of the 2 RaI isoforms, RaIA and RaIB, RaIB was found to mediate SDF-1-induced migration. We have recently shown that Btk, PLC gamma 2, and Lyn/Syk mediate SDF-1-controlled B-cell migration; however, SIDIF-1-induced RaI activation is not affected in B cells deficient in these proteins. In addition, treatment with pharmacological inhibitors against PI3K and PLC or expression of dominant-negative Ras did not impair SDF-1-induced RaI activation. Taken together, these results reveal a novel function for RaI, that is, regulation of SDF-1induced migration of B cells and MM cells, thereby providing new insights into the control of B-cell homeostasis, trafficking, and function, as well as into the pathogenesis of MM.