title: A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action.
abstract: Insulin stimulates glucose transport in muscle  and adipose tissue by translocation of glucose transporter 4 (GLUT4) to the plasma membrane. We previously reported that activation of the small GTPase RalA downstream of PI 3-kinase plays a critical role in this process by mobilizing the exocyst complex for GLUT4 vesicle targeting in adipocytes. Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. Knockdown of RGC proteins leads to increased RalA activity and glucose uptake in adipocytes. Insulin inhibits the GAP complex through Akt2-catalyzed phosphorylation of RGC2 in vitro and in vivo, while activated Akt relieves the inhibitory effect of RGC proteins on RalA activity. The RGC complex thus connects PI 3-kinase/Akt activity to the transport machineries responsible for GLUT4 translocation.
authors.affiliation: Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Chen
authors.forename: Dara
authors.initials: D
authors.lastname: Leto
authors.forename: Tingting
authors.initials: T
authors.lastname: Xiong
authors.forename: Genggeng
authors.initials: G
authors.lastname: Yu
authors.forename: Alan
authors.initials: A
authors.lastname: Cheng
authors.forename: Stuart
authors.initials: S
authors.lastname: Decker
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D020134:Catalytic Domain; D002522:Chlorocebus aethiops; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D005947:Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020725:ral GTP-Binding Proteins; C118120:Rala protein, mouse