The FWD1/β‐TrCP‐mediated degradation pathway establishes a ‘turning off switch’ of a Cdc42 guanine nucleotide exchange factor, FGD1

FWD1/β-TrCP is the F-box protein that functions as the receptor subunit of the SCFFWD1/β-TrCP ubiquitin ligase and has been shown to be responsible for the degradation of important signaling molecules such as IκBs and β-catenin. Protein substrates of FWD1/β-TrCP contain a consensus DSGΨXS motif (where Ψ represents a hydrophobic residue and X represents any amino acid). Recognition by FWD1/β-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 SCFFWD1/β-TrCP ubiquitin ligase. A mutant FGD1 protein, FGD1(SA), in which both of the critical serine residues in the DSGΨXS motif have been replaced by alanines, does not interact with FWD1/β-TrCP and exhibits increased stability. Morphological changes induced by wild-type FGD1 (FGD1(WT)) are reduced by the co-expression of SCFFWD1/β-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.