title: The FWD1/beta-TrCP-mediated degradation pathway establishes a 'turning off switch' of a Cdc42 guanine nucleotide exchange factor, FGD1.
abstract: 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 A mutant FGD1 protein, FGD1(SA), in which both of the critical serine residues in the DSGPsiXS motif have been replaced by alanines, does not interact with FWD1/beta-TrCP and exhibits increased stability.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.
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. hayakawa@ps.toyaku.ac.jp
authors.forename: Makio
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Kikugawa
mesh_terms: D020662:Guanine Nucleotide Exchange Factors; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D025821:Polyubiquitin / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: C471644:BTRC protein, human; C490796:FGD1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D011506:Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D025821:Polyubiquitin; D020764:cdc42 GTP-Binding Protein