The FWD1/beta-TrCP-mediated degradation pathway establishes a 'turning off switch' of a Cdc42 guanine nucleotide exchange factor, FGD1.

FWD1/beta-TrCP is the F-box protein that functions as the receptor subunit of the SCF(FWD1/beta-TrCP) ubiquitin ligase and has been shown to be responsible for the degradation of important signaling molecules such as IkappaBs and beta-catenin. Protein substrates of FWD1/beta-TrCP contain a consensus DSGPsiXS motif (where Psi represents a hydrophobic residue and X represents any amino acid). Recognition by FWD1/beta-TrCP requires phosphorylation of the conserved serines in that motif. Here we show that FGD1, a Cdc42 guanine nucleotide exchange factor (GEF), is a novel target of the SCF(FWD1/beta-TrCP) ubiquitin ligase. A mutant FGD1 protein, FGD1(SA), in which both of the critical serine residues in the DSGPsiXS motif have been replaced by alanines, does not interact with FWD1/beta-TrCP and exhibits increased stability. Morphological changes induced by wild-type FGD1 (FGD1(WT)) are reduced by the co-expression of SCF(FWD1/beta-TrCP) whereas those induced by FGD1(SA) are not affected. FGD1(SA)-expressing cells show a higher level of cell motility than FGD1(WT)-expressing cells. We present a novel 'turning off' mechanism for the inactivation of FGD1, an upstream regulator for Cdc42.