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 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.
de Gorter
David J J
DJ
Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands.
Reijmers
Rogier M
RM
Beuling
Esther A
EA
Naber
Hildegonda P H
HP
Kuil
Annemieke
A
Kersten
Marie José
MJ
Pals
Steven T
ST
Spaargaren
Marcel
M
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D054377:Chemokine CXCL12 / Q000378:metabolism* / Q000494:pharmacology; D002645:Chickens; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007952:Leukemia, Plasma Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D000072377:Syk Kinase; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; C483163:Ralb protein, human; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000606896:SYK protein, human; D000072377:Syk Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051966:Phospholipase C gamma; C492198:RALA protein, human; D015689:Oncogene Protein p21(ras); D020725:ral GTP-Binding Proteins