title: Role of the guanine nucleotide exchange factor in Akt2-mediated plasma membrane translocation of GLUT4 in insulin-stimulated skeletal muscle.
abstract: The small GTPase Rac1 plays a key role in insulin-promoted glucose uptake mediated by the GLUT4 glucose transporter in skeletal muscle. Our recent studies have demonstrated that the serine/threonine protein kinase Akt2 is critically involved in insulin-dependent Rac1 activation. The purpose of this study is to clarify the role of the guanine nucleotide exchange factor FLJ00068 in Akt2-mediated Rac1 activation and GLUT4 translocation in mouse skeletal muscle and cultured myocytes. Constitutively activated FLJ00068 induced GLUT4 translocation in a Rac1-dependent and Akt2-independent manner in L6 myocytes. On the other hand, knockdown of FLJ00068 significantly reduced constitutively activated Akt2-triggered GLUT4 translocation. Furthermore, Rac1 activation and GLUT4 translocation induced by constitutively activated phosphoinositide 3-kinase were inhibited by knockdown of FLJ00068. In mouse gastrocnemius muscle, constitutively activated FLJ00068 actually induced GLUT4 translocation to the sarcolemma. GLUT4 translocation by constitutively activated FLJ00068 was totally abolished in rac1 knockout mouse gastrocnemius muscle. Additionally, we were successful in detecting the activation of Rac1 following the expression of constitutively activated FLJ00068 in gastrocnemius muscle by immunofluorescence microscopy using an activation-specific probe. Collectively, these results strongly support the notion that FLJ00068 regulates Rac1 downstream of Akt2, leading to the stimulation of glucose uptake in skeletal muscle.
authors.affiliation: Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takenaka
authors.affiliation: Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yasuda
authors.affiliation: Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Japan.
authors.forename: Yuma
authors.initials: Y
authors.lastname: Nihata
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hosooka
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Noguchi
authors.affiliation: Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Atsu
authors.initials: A
authors.lastname: Aiba
authors.affiliation: Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Japan. Electronic address: tkysato@b.s.osakafu-u.ac.jp.
authors.forename: Takaya
authors.initials: T
authors.lastname: Satoh
mesh_terms: D000818:Animals; D002460:Cell Line; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012508:Sarcolemma / Q000235:genetics / Q000378:metabolism*; D013049:Spectrin / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051275:Glucose Transporter Type 4; D020662:Guanine Nucleotide Exchange Factors; D007004:Hypoglycemic Agents; D007328:Insulin; D009479:Neuropeptides; C503982:PLEKHG4 protein, human; C582673:PLEKHG4 protein, mouse; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; C495694:Slc2a4 protein, rat; D013049:Spectrin; D019869:Phosphatidylinositol 3-Kinases; C494921:AKT2 protein, human; C494922:Akt2 protein, mouse; C494923:Akt2 protein, rat; D051057:Proto-Oncogene Proteins c-akt; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D005947:Glucose
keywords: Akt2; FLJ00068; GLUT4; Glucose uptake; Guanine nucleotide exchange factor; Insulin; Rac1; Skeletal muscle; Small GTPase