This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sawka-Verhelle, D. Articles by Van Obberghen, E. Search for Related Content PubMed PubMed Citation Articles by Sawka-Verhelle, D. Articles by Van Obberghen, E.

Stat 5B, Activated by Insulin in a Jak-Independent Fashion, Plays a Role in Glucokinase Gene Transcription¹

Institut National de la Santé et de la Recherche Médicale U145 (D.S.-V., S.T.-D., E.V.O.), IFR 50, Avenue de Valombrose, 06107 Nice Cédex 2 France; and Centre National de la Recherche Scientifique UPR 1524 (J.-F.D., J.G.), 92190 Meudon, France

Address all correspondence and requests for reprints to: E. Van Obberghen, INSERM U145, Faculté de Médecine, avenue de Valombrose, 06107 Nice Cédex 2, France. E-mail: vanobbeg{at}unice.fr

Stat proteins are SH2 domain-containing transcription factors that are activated by various cytokines and growth factors. In a previous work, we have identified Stat 5B as a substrate of the insulin receptor based on yeast two-hybrid and mammalian cell transfection studies. In the present study, we have approached the biological relevance of the interaction between the insulin receptor and the transcription factor Stat 5B. Firstly, we show that both insulin and insulin-like growth factor I lead to tyrosine phosphorylation of Stat 5B, and this promotes binding of the transcription factor to the ß-casein promoter containing a Stat 5 binding site. Further, we demonstrate that insulin stimulates the transcriptional activity of Stat 5B. Activation of Stat 5B by insulin appears to be Jak2-independent, whereas Jak2 is required for GH-induced Stat 5B activation. Hence the pathway by which Stat 5B is activated by insulin is different from that used by GH. In addition, by using Jak1- and Tyk2-deficient cells we exclude the involvement of both Jak1 and Tyk2 in Stat 5B activation by insulin. Taken together, our results strengthen the notion that insulin receptor can directly activate Stat 5B. More importantly, we have identified a Stat 5 binding site in the human hepatic glucokinase promoter, and we show that insulin leads to a Stat 5B-dependent increase in transcription of a reporter gene carrying this promoter. These observations favor the idea that Stat 5B plays a role in mediating the expression of the glucokinase gene induced by insulin. As a whole, our results provide evidence for the occurrence of a newly identified circuit in insulin signaling in which the cell surface receptor is directly linked to nuclear events through a transcription factor. Further, we have revealed an insulin target gene whose expression is, at least in part, dependent on Stat 5B activation and/or binding.

This article has been cited by other articles:

				D. L. Kleinberg, T. L. Wood, P. A. Furth, and A. V. Lee Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions Endocr. Rev., February 1, 2009; 30(1): 51 - 74. [Abstract] [Full Text] [PDF]

				A. J Weinhaus, L. E Stout, N. V Bhagroo, T C. Brelje, and R. L Sorenson Regulation of glucokinase in pancreatic islets by prolactin: a mechanism for increasing glucose-stimulated insulin secretion during pregnancy J. Endocrinol., June 1, 2007; 193(3): 367 - 381. [Abstract] [Full Text] [PDF]

				M Egea, I Meton, and I V Baanante Sp1 and Sp3 regulate glucokinase gene transcription in the liver of gilthead sea bream (Sparus aurata) J. Mol. Endocrinol., April 1, 2007; 38(4): 481 - 492. [Abstract] [Full Text] [PDF]

				D. Sawka-Verhelle, L. Escoubet-Lozach, A. L. Fong, K. D. Hester, S. Herzig, P. Lebrun, and C. K. Glass PE-1/METS, an Antiproliferative Ets Repressor Factor, Is Induced by CREB-1/CREM-1 during Macrophage Differentiation J. Biol. Chem., April 23, 2004; 279(17): 17772 - 17784. [Abstract] [Full Text] [PDF]

				K. Almind, R. N. Kulkarni, S. M. Lannon, and C. R. Kahn Identification of Interactive Loci Linked to Insulin and Leptin in Mice With Genetic Insulin Resistance Diabetes, June 1, 2003; 52(6): 1535 - 1543. [Abstract] [Full Text] [PDF]

				M. N. Le, R. A. Kohanski, L.-H. Wang, and H. B. Sadowski Dual Mechanism of Signal Transducer and Activator of Transcription 5 Activation by the Insulin Receptor Mol. Endocrinol., December 1, 2002; 16(12): 2764 - 2779. [Abstract] [Full Text] [PDF]

				P. Ribaux, A. Gjinovci, H. B. Sadowski, and P. B. Iynedjian Discrimination between Signaling Pathways in Regulation of Specific Gene Expression by Insulin and Growth Hormone in Hepatocytes Endocrinology, October 1, 2002; 143(10): 3766 - 3772. [Abstract] [Full Text] [PDF]

				B. Emanuelli, P. Peraldi, C. Filloux, C. Chavey, K. Freidinger, D. J. Hilton, G. S. Hotamisligil, and E. Van Obberghen SOCS-3 Inhibits Insulin Signaling and Is Up-regulated in Response to Tumor Necrosis Factor-alpha in the Adipose Tissue of Obese Mice J. Biol. Chem., December 14, 2001; 276(51): 47944 - 47949. [Abstract] [Full Text] [PDF]

				C. L. Sadowski, T.-S. Choi, M. Le, T. T. Wheeler, L.-H. Wang, and H. B. Sadowski Insulin Induction of SOCS-2 and SOCS-3 mRNA Expression in C2C12 Skeletal Muscle Cells Is Mediated by Stat5* J. Biol. Chem., June 1, 2001; 276(23): 20703 - 20710. [Abstract] [Full Text] [PDF]

				N. A. Patel, C. E. Chalfant, J. E. Watson, J. R. Wyatt, N. M. Dean, D. C. Eichler, and D. R. Cooper Insulin Regulates Alternative Splicing of Protein Kinase C beta II through a Phosphatidylinositol 3-Kinase-dependent Pathway Involving the Nuclear Serine/Arginine-rich Splicing Factor, SRp40, in Skeletal Muscle Cells J. Biol. Chem., June 15, 2001; 276(25): 22648 - 22654. [Abstract] [Full Text] [PDF]