title: Signal transduction meets vesicle traffic: the software and hardware of GLUT4 translocation.
abstract: Skeletal muscle is the major tissue disposing of dietary glucose, a function regulated by insulin-elicited signals that impart mobilization of GLUT4 glucose transporters to the plasma membrane. This phenomenon, also central to adipocyte biology, has been the subject of intense and productive research for decades. We focus on muscle cell studies scrutinizing insulin signals and vesicle traffic in a spatiotemporal manner. Using the analogy of an integrated circuit to approach the intersection between signal transduction and vesicle mobilization, we identify signaling relays ("software") that engage structural/mechanical elements ("hardware") to enact the rapid mobilization and incorporation of GLUT4 into the cell surface. We emphasize how insulin signal transduction switches from tyrosine through lipid and serine phosphorylation down to activation of small G proteins of the Rab and Rho families, describe key negative regulation step of Rab GTPases through the GTPase-activating protein activity of the Akt substrate of 160 kDa (AS160), and focus on the mechanical effectors engaged by Rabs 8A and 10 (the molecular motor myosin Va), and the Rho GTPase Rac1 (actin filament branching and severing through Arp2/3 and cofilin). Finally, we illustrate how actin filaments interact with myosin 1c and α-Actinin4 to promote vesicle tethering as preamble to fusion with the membrane.
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; and Department of Biochemistry, The University of Toronto, Ontario, Canada amira@sickkids.ca.
authors.forename: Amira
authors.initials: A
authors.lastname: Klip
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; and Department of Biochemistry, The University of Toronto, Ontario, Canada.
authors.forename: Tim Ting
authors.initials: TT
authors.lastname: Chiu
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; and Department of Biochemistry, The University of Toronto, Ontario, Canada.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Foley
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D000185:Actinin / Q000235:genetics / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D022161:Transport Vesicles / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; C495692:SLC2A4 protein, human; C518767:TBC1D4 protein, human; D000185:Actinin; D051057:Proto-Oncogene Proteins c-akt; D009218:Myosins; D020691:rab GTP-Binding Proteins
keywords: GLUT4; Rab; Rac1; insulin; vesicle traffic