Mechanistic analysis of the amplification and diversification events induced by Vav proteins in B-lymphocytes.
Vav proteins participate in the assembly of a multibranched signal transduction pathway in lymphocytes, including the stimulation of the phosphatidylinositol 3-kinase/protein kinase B and the phospholipase C-gamma/Ras GDP-releasing protein/Ras/Erk routes. In the present work, we used a genetic approach in chicken DT40 B-cell lines to investigate additional elements of the Vav route, the synergisms existing among the different Vav signaling branches, and the activities exerted by wild-type and oncogenic Vav proteins in B-lymphocytes. We show here that the Vav pathway is ramified in B-lymphocytes in additional diacylglycerol-dependent signaling branches such as those involving protein kinase C, protein kinase D, and phospholipase D. By using side-by-side comparisons of the activation levels of those signal transduction pathways in inhibitor-treated and knockout DT40 cells, we show that B-cells have different requirements regarding Vav proteins for the activation of antigen receptor downstream elements. Furthermore, we have detected interpathway cross-talk at the level of the most proximal elements but not among the most distal effector molecules of the Vav route. Finally, we show that the oncogenic versions of Vav1 and RhoA can activate alternative routes that could contribute to signal amplification and diversification events in transformed lymphocytes.
Caloca
María J
MJ
Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas, University of Salamanca, Campus Unamuno, Salamanca E-37007, Spain.
Zugaza
José L
JL
Bustelo
Xosé R
XR
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D002645:Chickens; D005786:Gene Expression Regulation; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008954:Models, Biological; D010739:Phospholipase D / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000737:chemistry
D051567:Proto-Oncogene Proteins c-vav; C089212:protein kinase D; D011493:Protein Kinase C; D010739:Phospholipase D; D020742:rhoA GTP-Binding Protein