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Wortmannin-Sensitive Pathway Is Required for Insulin-Stimulated Phosphorylation of Inhibitor B

Diabetes Section, Laboratory of Clinical Investigation (S.K.P., H.-J.H., M.B.), Laboratory of Cardiovascular Science (A.C., M.T.C.), and Research Resource Branch (M.J.), National Institute on Aging, NIH, Baltimore, Maryland 21224-6825

Address all correspondence and requests for reprints to: Michel Bernier, Ph.D., Diabetes Section, Laboratory of Clinical Investigation, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, Maryland 21224. E-mail: bernierm{at}vax.grc.nia.nih.gov

The aim of this study was to examine the signaling pathways by which insulin promotes activation of nuclear factor B (NFB) through the regulation of inhibitor B (IB). We show here that although insulin increased B-dependent reporter gene expression and augmented nuclear translocation of the p65/RelA subunit of NFB and its DNA binding, it was able to induce a time-dependent accumulation of phosphorylated and ubiquitinated IB without its proteolytic degradation. In contrast, cell stimulation with the cytokine TNF allowed activation of NFB through phosphorylation, ubiquitination, and subsequent degradation of IB. Immunofluorescence studies revealed the presence of a large pool of phosphorylated IB in the nucleus of unstimulated and insulin-treated cells. IB kinase and ß, central players in the phosphorylation of IB, were rapidly induced following exposure to TNF but not insulin. Furthermore, insulin-stimulated IB phosphorylation did not depend on activation of the Ras/ERK cascade. Expression of a dominant-negative mutant of Akt1 or class I PI3K inhibited the insulin stimulation of PI3K/Akt1 signaling without affecting phosphorylation of IB. Interestingly, the PI3K inhibitors wortmannin and LY294002 blocked insulin-stimulated class I PI3K-dependent events at much lower doses than that required to inhibit phosphorylation of IB. These data demonstrate that insulin regulates IB function through a distinct low-affinity wortmannin-sensitive pathway.

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