FIGURE 11.2 Insulin-induced ROS production and PTP regulation via Nox4 in insulinsensitive cells. This figure illustrates the action of insulin to stimulate receptor tyrosine autophosphorylation which activates the receptor toward its cellular substrate (IRS) proteins. The receptor and IRS tyrosine phosphorylation require cellular PTP activity to return to a basal state. The insulin receptor is coupled to the Nox4 homolog of NADPH oxidase and stimulates the cellular generation of reactive oxygen species which, in turn, leads to oxidative inhibition of the thiol-dependent PTPs, including PTP1B, the major phosphatase for the insulin signaling cascade. The lower right portion illustrates the PTP reaction mechanism in which the reduced thiol side chain in the enzyme catalytic domain forms a phosphocysteine intermediate with the phosphotyrosine substrate. If the catalytic PTP thiol is oxidized, this reaction intermediate cannot form and the enzymatic reaction is blocked. See text for discussion and references.

homologs catalyzes the generation of ROS at the plasma membrane, we have recently provided evidence in the 3T3-L1 adipocyte system that Nox4, which is expressed in insulin-sensitive cell types, is a novel molecular target that may mediate this process (Figure 11.2).


This work was supported by National Institutes of Health grant RO1 DK43396 to Dr. Goldstein.


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12 Intracellular Signaling Pathways and Peroxisome Proliferator-Activated Receptors in Vascular Health in Hypertension and in Diabetes

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