CDC42 and FGD1 cause distinct signaling and transforming activities.
Activated forms of different Rho family members (CDC42, Rac1, RhoA, RhoB, and RhoG) have been shown to transform NIH 3T3 cells as well as contribute to Ras transformation. Rho family guanine nucleotide exchange factors (GEFs) (also known as Dbl family proteins) that activate CDC42, Rac1, and RhoA also demonstrate oncogenic potential. The faciogenital dysplasia gene product, FGD1, is a Dbl family member that has recently been shown to function as a CDC42-specific GEF. Mutations within the FGD1 locus cosegregate with faciogenital dysplasia, a multisystemic disorder resulting in extensive growth impairments throughout the skeletal and urogenital systems. Here we demonstrate that FGD1 expression is sufficient to cause tumorigenic transformation of NIH 3T3 fibroblasts. Although both FGD1 and constitutively activated CDC42 cooperated with Raf and showed synergistic focus-forming activity, both quantitative and qualitative differences in their functions were seen. FGD1 and CDC42 also activated common nuclear signaling pathways. However, whereas both showed comparable activation of c-Jun, CDC42 showed stronger activation of serum response factor and FGD1 was consistently a better activator of Elk-1. Although coexpression of FGD1 with specific inhibitors of CDC42 function demonstrated the dependence of FGD1 signaling activity on CDC42 function, FGD1 signaling activities were not always consistent with the direct or exclusive stimulation of CDC42 function. In summary, FGD1 and CDC42 signaling and transformation are distinct, thus suggesting that FGD1 may be mediating some of its biological activities through non-CDC42 targets.
Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7295, USA.
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D016475:3T3 Cells; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D026362:Serum Response Factor; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014170:Transformation, Genetic; D020764:cdc42 GTP-Binding Protein; D050807:ets-Domain Protein Elk-1
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C494113:Elk1 protein, mouse; C097489:Fgd1 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D026362:Serum Response Factor; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D019908:Proto-Oncogene Proteins c-raf; D019204:GTP-Binding Proteins; D020764:cdc42 GTP-Binding Protein