title: Identification of P-Rex1 as a novel Rac1-guanine nucleotide exchange factor (GEF) that promotes actin remodeling and GLUT4 protein trafficking in adipocytes.
abstract: Phosphoinositide 3-kinase (PI3K) signaling promotes the translocation of the glucose transporter, GLUT4, to the plasma membrane in insulin-sensitive tissues to facilitate glucose uptake. In adipocytes, insulin-stimulated reorganization of the actin cytoskeleton has been proposed to play a role in promoting GLUT4 translocation and glucose uptake, in a PI3K-dependent manner. However, the PI3K effectors that promote GLUT4 translocation via regulation of the actin cytoskeleton in adipocytes remain to be fully elucidated. Here we demonstrate that the PI3K-dependent Rac exchange factor, P-Rex1, enhances membrane ruffling in 3T3-L1 adipocytes and promotes GLUT4 trafficking to the plasma membrane at submaximal insulin concentrations. P-Rex1-facilitated GLUT4 trafficking requires a functional actin network and membrane ruffle formation and occurs in a PI3K- and Rac1-dependent manner. In contrast, expression of other Rho GTPases, such as Cdc42 or Rho, did not affect insulin-stimulated P-Rex1-mediated GLUT4 trafficking. P-Rex1 siRNA knockdown or expression of a P-Rex1 dominant negative mutant reduced but did not completely inhibit glucose uptake in response to insulin. Collectively, these studies identify a novel RacGEF in adipocytes as P-Rex1 that, at physiological insulin concentrations, functions as an insulin-dependent regulator of the actin cytoskeleton that contributes to GLUT4 trafficking to the plasma membrane.
authors: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors: Demis
authors: D
authors: Balamatsias
authors: Anne M
authors: AM
authors: Kong
authors: Joanne E
authors: JE
authors: Waters
authors: Absorn
authors: A
authors: Sriratana
authors: Rajendra
authors: R
authors: Gurung
authors: Charles G
authors: CG
authors: Bailey
authors: John E J
authors: JE
authors: Rasko
authors: Tony
authors: T
authors: Tiganis
authors: S Lance
authors: SL
authors: Macaulay
authors: Christina A
authors: CA
authors: Mitchell
mesh_terms: D041721:3T3-L1 Cells; D000199:Actins / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D051275:Glucose Transporter Type 4; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; C511197:PREX1 protein, mouse; D034741:RNA, Small Interfering; D020830:rac1 GTP-Binding Protein