Submitted August 10, 2007
Accepted January 16, 2008
The small GTPase Ral mediates SDF-1-induced migration of B cells and multiple myeloma cells
David J.J. de Gorter, Rogier M. Reijmers, Esther A. Beuling, Hildegonda P.H. Naber, Annemieke Kuil, Marie Jose Kersten, Steven T. Pals, and Marcel Spaargaren*
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
* Corresponding author; email: marcel.spaargaren{at}amc.uva.nl.
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 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 RalBP
GAP, a Ral effector mutant which sequesters active Ral, results in impaired SDF-1-induced migration of B cells and MM cells. Of the two Ral isoforms, RalA and RalB, RalB was found to mediate SDF-1-induced migration. We have recently shown that Btk, PLC
2 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. Also treatment with pharmacological inhibitors against PI3K and PLC, or expression of a dominant negative Ras mutant did not impair SDF-1-induced Ral activation. Taken together, these results reveal a novel function for Ral, i.e. 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.
