Gapex-5, a Rab31 Guanine Nucleotide Exchange Factor that Regulates Glut4 Trafficking in Adipocytes

Irfan J. Lodhi, Shian Huey Chiang, Louise Chang, Daniel Vollenweider, Robert T. Watson, Mayumi Inoue, Jeffrey E. Pessin, Alan R. Saltiel

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)59-72
Number of pages14
JournalCell metabolism
Volume5
Issue number1
DOIs
StatePublished - Jan 2007
Externally publishedYes

Keywords

  • CELLBIO
  • HUMDISEASE

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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