Adenovirus Protein E4-ORF1 Activation of PI3 Kinase Reveals Differential Regulation of Downstream Effector Pathways in Adipocytes

Cell Rep. 2016 Dec 20;17(12):3305-3318. doi: 10.1016/j.celrep.2016.11.082.


Insulin activation of phosphatidylinositol 3-kinase (PI3K) regulates metabolism, including the translocation of the Glut4 glucose transporter to the plasma membrane and inactivation of the FoxO1 transcription factor. Adenoviral protein E4-ORF1 stimulates cellular glucose metabolism by mimicking growth-factor activation of PI3K. We have used E4-ORF1 as a tool to dissect PI3K-mediated signaling in adipocytes. E4-ORF1 activation of PI3K in adipocytes recapitulates insulin regulation of FoxO1 but not regulation of Glut4. This uncoupling of PI3K effects occurs despite E4-ORF1 activating PI3K and downstream signaling to levels achieved by insulin. Although E4-ORF1 does not fully recapitulate insulin's effects on Glut4, it enhances insulin-stimulated insertion of Glut4-containing vesicles to the plasma membrane independent of Rab10, a key regulator of Glut4 trafficking. E4-ORF1 also stimulates plasma membrane translocation of ubiquitously expressed Glut1 glucose transporter, an effect that is likely essential for E4-ORF1 to promote an anabolic metabolism in a broad range of cell types.

Keywords: E4ORF1; GLUT1; GLUT4; PI3-kinase; PI3K-AKT signaling; RAB10.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenovirus E4 Proteins / biosynthesis
  • Adenovirus E4 Proteins / genetics*
  • Adipocytes / metabolism
  • Animals
  • Cell Membrane / metabolism
  • Forkhead Box Protein O1 / genetics*
  • Gene Expression Regulation
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 4 / genetics*
  • Humans
  • Insulin / genetics
  • Insulin / metabolism*
  • Mice
  • Phosphatidylinositol 3-Kinases / genetics
  • Signal Transduction
  • Transfection
  • rab GTP-Binding Proteins / genetics


  • Adenovirus E4 Proteins
  • Forkhead Box Protein O1
  • Glucose Transporter Type 1
  • Glucose Transporter Type 4
  • Insulin
  • Slc2a1 protein, mouse
  • Phosphatidylinositol 3-Kinases
  • Rab10 protein, mouse
  • rab GTP-Binding Proteins