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 Ral. Inhibition of Ral, by expression of the dominant negative RalN28 mutant or of RalBPDeltaGAP, a Ral effector mutant that sequesters active Ral, results in impaired SDF-1-induced migration of B cells and MM cells.
Of the 2 Ral isoforms, RalA and RalB, RalB was found to mediate SDF-1-induced migration.
We have recently shown that Btk, PLCgamma2, and Lyn/Syk mediate SDF-1-controlled B-cell migration; however, SDF-1-induced Ral 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 Ral activation.
Taken together, these results reveal a novel function for Ral, that is, regulation of SDF-1-induced 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.
2008-03-25
Eng.
Blood
Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands.
Blood. 2008 Apr;111(7):3364-72
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