CDC42 AND FGD1 CAUSE DISTINCT SIGNALING AND TRANSFORMING ACTIVITIES

Activated forms of different Rho family members (CDC42, Rac1, RhoA, Rh oB, and RhoG) have been shown to transform NIH 3T3 cells as well as co ntribute to Ras transformation. Rho family guanine nucleotide exchange factors (GEFs) (also known as Dbl family proteins) that activate CDC4 2, Rad, and RhoA also demonstrate oncogenic potential. The faciogenita l dysplasia gene product, FGD1, is a Dbl family member that has recent ly been shown to function as a CDC42-specific GEF. Mutations within th e FGD1 locus cosegregate with faciogenital dysplasia, a multisystemic disorder resulting in extensive growth impairments throughout the skel etal and urogenital systems. Here we demonstrate that FGD1 expression is sufficient to cause tumorigenic transformation of NIH 3T3 fibroblas ts. Although both FGD1 and constitutively activated CDC42 cooperated w ith Raf and showed synergistic focus-forming activity, both quantitati ve and qualitative differences in their functions were seen. FGD1 and CDC42 also activated common nuclear signaling pathways. However, where as both showed comparable activation of c-Jun, CDC42 showed stronger a ctivation of serum response factor and FGD1 was consistently a better activator of Elk-1. Although coexpression of FGD1 with specific inhibi tors of CDC42 function demonstrated the dependence of FGD1 signaling a ctivity on CDC42 function, FGD1 signaling activities were not always c onsistent 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 acti vities through non-CDC42 targets.