title: Proline-rich domain plays a crucial role in extracellular stimuli-responsive translocation of a Cdc42 guanine nucleotide exchange factor, FGD1.
abstract: We previously demonstrated that FGD1, the Cdc42 guanine nucleotide exchange factor (GEF) responsible for faciogenital dysplasia, and its homologue FGD3 are targeted by the ubiquitin ligase SCF(FWD1) upon phosphorylation of two serine residues in their DSGIDS motif and subsequently degraded by the proteasome. FGD1 and FGD3 share highly homologous Dbl homology (DH) and adjacent pleckstrin homology (PH) domains, both of which are responsible for GEF activity. However, their function and regulation are remarkably different. Here we demonstrate extracellular signal-responsive translocation of FGD1, but not FGD3. During the wound-healing process, translocation of FGD1 to the leading edge membrane occurs in cells facing to the wound. Furthermore, epidermal growth factor (EGF) stimulates the membrane translocation of FGD1, but not FGD3. As the most striking difference, FGD3 lacks the N-terminal proline-rich domain that is conserved in FGD1, indicating that proline-rich domain may play a crucial role in signal-responsive translocation of FGD1. Indeed, there is a faciogenital dysplasia patient who has a missense mutation in proline-rich domain of FGD1, by which the serine residue at position 205 is substituted with isoleucine. When expressed in cells, the mutant FGD1 with S(205)/I substitution fails to translocate to the membrane in response to the mitogenic stimuli. Thus we present a novel mechanism by which the activity of FGD1, a GEF for Cdc42, is temporally and spatially regulated in cells.
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Oshima
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Fujino
authors.forename: Ken
authors.initials: K
authors.lastname: Ando
authors.forename: Makio
authors.initials: M
authors.lastname: Hayakawa
mesh_terms: D001692:Biological Transport / Q000502:physiology; D002462:Cell Membrane / Q000502:physiology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007532:Isoleucine / Q000378:metabolism; D009154:Mutation; D011392:Proline / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014178:Translocation, Genetic; D014945:Wound Healing / Q000502:physiology*
chemical_list: C490796:FGD1 protein, human; C549833:FGD3 protein, human; D020662:Guanine Nucleotide Exchange Factors; D007532:Isoleucine; D012694:Serine; D004815:Epidermal Growth Factor; D011392:Proline