title: Adenovirus Protein E4-ORF1 Activation of PI3 Kinase Reveals Differential Regulation of Downstream Effector Pathways in Adipocytes.
abstract: 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.
authors.affiliation: Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Chaudhary
authors.affiliation: Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Gonzalez
authors.affiliation: Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Geng
authors.affiliation: Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY 10065, USA; Lung Cancer Program, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Nasser K
authors.initials: NK
authors.lastname: Altorki
authors.affiliation: Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY 10065, USA; Lung Cancer Program, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: temcgraw@med.cornell.edu.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: McGraw
mesh_terms: D017504:Adenovirus E4 Proteins / Q000096:biosynthesis / Q000235:genetics*; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D000071161:Forkhead Box Protein O1 / Q000235:genetics*; D005786:Gene Expression Regulation; D051272:Glucose Transporter Type 1 / Q000235:genetics; D051275:Glucose Transporter Type 4 / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000235:genetics
chemical_list: D017504:Adenovirus E4 Proteins; D000071161:Forkhead Box Protein O1; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; C495678:Slc2a1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C520736:Rab10 protein, mouse; D020691:rab GTP-Binding Proteins
keywords: E4ORF1; GLUT1; GLUT4; PI3-kinase; PI3K-AKT signaling; RAB10