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Molecular and Cellular Biology, March 2004, p. 1844-1854, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.1844-1854.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The NAD(P)H Oxidase Homolog Nox4 Modulates Insulin-Stimulated Generation of H2O2 and Plays an Integral Role in Insulin Signal Transduction

Kalyankar Mahadev,1 Hiroyuki Motoshima,1 Xiangdong Wu,1 Jean Marie Ruddy,1 Rebecca S. Arnold,2 Guangjie Cheng,2 J. David Lambeth,2 and Barry J. Goldstein1*

Dorrance H. Hamilton Research Laboratories, Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107,1 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 303222

Received 3 September 2003/ Returned for modification 8 October 2003/ Accepted 26 November 2003

Insulin stimulation of target cells elicits a burst of H2O2 that enhances tyrosine phosphorylation of the insulin receptor and its cellular substrate proteins as well as distal signaling events in the insulin action cascade. The molecular mechanism coupling the insulin receptor with the cellular oxidant-generating apparatus has not been elucidated. Using reverse transcription-PCR and Northern blot analyses, we found that Nox4, a homolog of gp91phox, the phagocytic NAD(P)H oxidase catalytic subunit, is prominently expressed in insulin-sensitive adipose cells. Adenovirus-mediated expression of Nox4 deletion constructs lacking NAD(P)H or FAD/NAD(P)H cofactor binding domains acted in a dominant-negative fashion in differentiated 3T3-L1 adipocytes and attenuated insulin-stimulated H2O2 generation, insulin receptor (IR) and IRS-1 tyrosine phosphorylation, activation of downstream serine kinases, and glucose uptake. Transfection of specific small interfering RNA oligonucleotides reduced Nox4 protein abundance and also inhibited the insulin signaling cascade. Overexpression of Nox4 also significantly reversed the inhibition of insulin-stimulated IR tyrosine phosphorylation induced by coexpression of PTP1B by inhibiting PTP1B catalytic activity. These data suggest that Nox4 provides a novel link between the IR and the generation of cellular reactive oxygen species that enhance insulin signal transduction, at least in part via the oxidative inhibition of cellular protein-tyrosine phosphatases (PTPases), including PTP1B, a PTPase that has been previously implicated in the regulation of insulin action.

* Corresponding author. Mailing address: Division of Endocrinology and Metabolic Diseases, Department of Medicine, Jefferson Medical College, Jefferson Alumni Hall, Suite 349, 1020 Locust St., Philadelphia, PA 19107-6799. Phone: (215) 503-1272. Fax: (215) 923-7932. E-mail: Barry.Goldstein{at}jefferson.edu.

Molecular and Cellular Biology, March 2004, p. 1844-1854, Vol. 24, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.5.1844-1854.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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