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¹ School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
² Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
³ Department of Biochemistry 1, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan

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 A mutant FGD1 protein, FGD1(SA), in which both of the critical serine residues in the DSGXS motif have been replaced by alanines, does not interact with FWD1/ß-TrCP and exhibits increased stability.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

^* Correspondence: E-mail: hayakawa{at}ps.toyaku.ac.jp

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