Vav transformation requires activation of multiple GTPases and regulation of gene expression.
Although Vav can act as a guanine nucleotide exchange factor for RhoA, Rac1, and Cdc42, its transforming activity has been ascribed primarily to its ability to activate Rac1. However, because activated Vav, but not Rac-specific guanine nucleotide exchange factors, exhibits very potent focus-forming transforming activity when assayed in NIH 3T3 cells, Vav transforming activity must also involve activation of Rac-independent pathways. In this study, we determined the involvement of other Rho family proteins and their signaling pathways in Vav transformation. We found that RhoA, Rac1, and Cdc42 functions are all required for Vav transforming activity. Furthermore, we determined that Vav activation of nuclear factor-kappaB and the Jun NH2-terminal kinase mitogen-activated protein kinase (MAPK) is necessary for full transformation by Vav, whereas p38 MAPK does not seem to play an important role. We also determined that Vav is a weak activator of Elk-1 via a Ras- and MAPK/extracellular signal-regulated kinase kinase-dependent pathway, and this activity was essential for Vav transformation. Thus, we conclude that full Vav transforming activation is mediated by the activation of multiple small GTPases and their subsequent activation of signaling pathways that regulate changes in gene expression. Because Vav is activated by the epidermal growth factor receptor and other tyrosine kinases involved in cancer development, defining the role of aberrant Vav signaling may identify activities of receptor tyrosine kinases important for human oncogenesis.
Palmby
Todd R
TR
Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB 7295, Chapel Hill, NC 27599-7295, USA.
Abe
Karon
K
Karnoub
Antoine E
AE
Der
Channing J
CJ
D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D018929:Cell Culture Techniques; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D017930:Genes, Reporter; D005822:Genetic Vectors; D020935:MAP Kinase Signaling System; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D002070:Butadienes; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C494113:Elk1 protein, mouse; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D014157:Transcription Factors; C113580:U 0126; C496619:Vav1 protein, mouse; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein