title: Activation of RalA is required for insulin-stimulated Glut4 trafficking to the plasma membrane via the exocyst and the motor protein Myo1c.
abstract: Insulin stimulates glucose transport in muscle and adipose tissue by producing translocation of the glucose transporter Glut4. The exocyst, an evolutionarily conserved vesicle tethering complex, is crucial for targeting Glut4 to the plasma membrane. Here we report that insulin regulates this process via the G protein RalA, which is present in Glut4 vesicles and interacts with the exocyst in adipocytes. Insulin stimulates the activity of RalA in a PI 3-kinase-dependent manner. Disruption of RalA function by dominant-negative mutants or siRNA-mediated knockdown attenuates insulin-stimulated glucose transport. RalA also interacts with Myo1c, a molecular motor implicated in Glut4 trafficking. This interaction is modulated by Calmodulin, which functions as the light chain for Myo1c during insulin-stimulated glucose uptake. Thus, RalA serves two functions in insulin action: as a cargo receptor for the Myo1c motor, and as a signal for the unification of the exocyst to target Glut4 vesicles to the plasma membrane.
authors.affiliation: Department of Molecular and Integrative Physiology, 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: Shian-Huey
authors.initials: SH
authors.lastname: Chiang
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D005089:Exocytosis / Q000187:drug effects* / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D024461:Myosin Type I; D009218:Myosins / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection
chemical_list: D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; C470422:Myo1c protein, mouse; D034741:RNA, Small Interfering; C490620:Ralbp1 protein, mouse; C495693:Slc2a4 protein, mouse; D024461:Myosin Type I; D009218:Myosins