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Endocrinology Vol. 138, No. 10 4131-4137
Copyright © 1997 by The Endocrine Society

ARTICLES

Signal Transducer and Activator of Transcription-3 Serine Phosphorylation by Insulin Is Mediated by a Ras/Raf/MEK-Dependent Pathway1

Brian P. Ceresa2, Curt M. Horvath and Jeffrey E. Pessin

Department of Physiology and Biophysics, University of Iowa (B.P.C., J.E.P.), Iowa City, Iowa 52242; and the Department of Molecular and Cellular Biology, Rockefeller University (C.M.H.), New York, New York 10021

Address all correspondence and requests for reprints to: Dr. Jeffrey E. Pessin, Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242-1109. E-mail: Jeffrey-Pessin{at}UIOWA.EDU

We recently reported that insulin stimulation results in the serine phosphorylation of STAT3 (signal transducer and activator of transcription-3). In the present study, we identified serine 727 as the site of insulin-stimulated STAT3 serine phosphorylation. This phosphorylation event occurs independent of tyrosine phosphorylation. Furthermore, interleukin-6-induced tyrosine phosphorylation can occur independent of serine phosphorylation, demonstrating that these two phosphorylation pathways are mechanistically unrelated. Selective activation of the JNK and p38 family of mitogen-activated protein (MAP) kinases by anisomycin treatment did not result in the phosphorylation of STAT3. In contrast, activation of the ERK MAP kinase pathway with both insulin and osmotic shock resulted in the serine phosphorylation of STAT3. In addition, expression of a dominant-interfering Ras mutant (N17Ras) or treatment with the specific MEK inhibitor (PD98059) prevented the insulin stimulation of STAT3 serine phosphorylation. Blockade of ERK activation by expression of the MAP kinase phosphatase (MKP-1) had no effect on insulin-stimulated STAT3 serine phosphorylation. Together, these data demonstrate that the insulin-stimulated serine phosphorylation of STAT3 occurs by a MEK-dependent pathway that is independent of ERK activation.




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