Gapex-5, a Rab31 guanine nucleotide exchange factor that regulates Glut4 trafficking in adipocytes.
Insulin stimulates glucose uptake by promoting translocation of the Glut4 glucose transporter from intracellular storage compartments to the plasma membrane. In the absence of insulin, Glut4 is retained intracellularly; the mechanism underlying this process remains uncertain. Using the TC10-interacting protein CIP4 as bait in a yeast two-hybrid screen, we cloned a RasGAP and VPS9 domain-containing protein, Gapex-5/RME-6. The VPS9 domain is a guanine nucleotide exchange factor for Rab31, a Rab5 subfamily GTPase implicated in trans-Golgi network (TGN)-to-endosome trafficking. Overexpression of Rab31 blocks insulin-stimulated Glut4 translocation, whereas knockdown of Rab31 potentiates insulin-stimulated Glut4 translocation and glucose uptake. Gapex-5 is predominantly cytosolic in untreated cells; its overexpression promotes intracellular retention of Glut4 in adipocytes. Insulin recruits the CIP4/Gapex-5 complex to the plasma membrane, thus reducing Rab31 activity and permitting Glut4 vesicles to translocate to the cell surface, where Glut4 docks and fuses to transport glucose into the cell.
Lodhi
Irfan J
IJ
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Chiang
Shian-Huey
SH
Chang
Louise
L
Vollenweider
Daniel
D
Watson
Robert T
RT
Inoue
Mayumi
M
Pessin
Jeffrey E
JE
Saltiel
Alan R
AR
D017667:Adipocytes / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D016415:Sequence Alignment; D020798:Two-Hybrid System Techniques; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
D051275:Glucose Transporter Type 4; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D008869:Microtubule-Associated Proteins; D015778:Minor Histocompatibility Antigens; C485787:Trip10 protein, mouse; D020696:rab5 GTP-Binding Proteins