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

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

Author information

1
Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
2
Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
3
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.
4
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.

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.

KEYWORDS:

E4ORF1; GLUT1; GLUT4; PI3-kinase; PI3K-AKT signaling; RAB10

PMID:
28009298
PMCID:
PMC5193245
DOI:
10.1016/j.celrep.2016.11.082
[Indexed for MEDLINE]
Free PMC Article

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