Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction

Coffer, PJ; vanPuijenbroek, A; Burgering, B. M. T.; Klopdejonge, M; Koenderman, Leo; Jl, Bos; Kruijer, W.

doi:10.1038/sj.onc.1201429

Cited by 89 publications

(84 citation statements)

References 49 publications

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“…UV light induces ligand-independent activation of various receptors, receptor tyrosine kinases, and protein tyrosine kinases at the inner side of the plasma membrane (36)(37)(38)(39)(40). Recently, UV light was found to cause epidermal and plateletderived growth factor receptor autophosphorylation by inhibiting dephosphorylation of these receptors, presumably by targeting membrane-associated protein tyrosine phosphatases (41).…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of interferon γ-activated STAT1 by UV light

Aragane¹,

Kulms²,

Luger³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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STAT1 is a cytoplasmic transcription factor that is phosphorylated by Janus kinases (Jak) in response to interferon-␥ (IFN␥). Phosphorylated STAT1 translocates to the nucleus, where it turns on specific sets of IFN␥-inducible genes. Here, we show that UV light interferes with tyrosine phosphorylation of STAT1, thereby hindering IFN␥ from exerting its biological effects. This effect is not due to a down-regulation of the IFN␥ receptor because phosphorylation of upstream-located Jak1 and Jak2 was not suppressed by UV light. In contrast, UV light had no effect on the phosphorylation of STAT3, which is activated by the proinf lammatory cytokine interleukin 6. The UV light effect on STAT1 phosphorylation could be antagonized by vanadate, indicating at least partial involvement of a protein tyrosine phosphatase. Therefore, this study indicates a mechanism by which UV light can inhibit gene activation and suggests STAT1 as a new extranuclear UV target closely located to the membrane.

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Section: Discussionmentioning

confidence: 99%

Down-regulation of interferon γ-activated STAT1 by UV light

Aragane¹,

Kulms²,

Luger³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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“…Ligand-independent phosphorylation of receptor tyrosine kinases, induced by UV irradiation, is known to represent a rapid, membrane-associated event (Sachsenmaier et al, 1994;Coffer et al, 1995;Huang et al, 1996;Rosette and Karin, 1996). Here we show that also the receptor for KGF, which plays a fundamental role in regulating keratinocyte growth and differentiation, is rapidly phosphorylated by exposure to physiological doses of UVB with timing and efficiency similar to that induced by binding of the ligand to the receptor.…”

Section: Discussionmentioning

confidence: 99%

“…The earliest step in response to UV irradiation and subsequent ROS generation involves ligand-independent phosphorylation of growth factor receptors such as epidermal growth factor receptor (EGFR) (Sachsenmaier et al, 1994;Coffer et al, 1995;Huang et al, 1996;Peus et al, 1998Peus et al, , 1999, signal transduction (Sachsenmaier et al, 1994;Rosette and Karin, 1996) and rapid expression of early growth response genes (Egr-1) (Huang and Adamson, 1995).…”

Section: Introductionmentioning

confidence: 99%

UVB-induced activation and internalization of keratinocyte growth factor receptor

et al. 2003

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Ultraviolet irradiation of mammalian cells induces several events that include activation of growth factor receptors and triggering of signal transduction pathway. Most of the UV responses are mediated by the production of reactive oxygen species (ROS) and can be blocked by antioxidants. In this study, we analysed the effect of UVB irradiation at physiologic doses and that of the prooxidant agent cumene hydroperoxide (CUH) on the activation of the receptor for keratinocyte growth factor (KGF), a key mediator of epithelial growth and differentiation. Exposure to both UVB (30-150 mJ/cm 2 ) and CUH (200 lm of NIH3T3 KGFR (KGF receptors) transfectants caused a rapid tyrosine phosphorylation and activation of KGFR similar to that induced by KGF, and internalization of the activated receptor. The KGFR expression appeared unmodified by the treatments. Ultrastructural observations of both UVB-and CUHtreated cells showed a normal morphology of the plasma membranes and intracellular organelles. The antioxidant N-acetylcysteine inhibited UVB-induced receptor phosphorylation. The generation of an intracellular oxidative stress was detected as a decrease of catalase activity and of vitamin E, and reduced glutathione levels, whereas superoxide dismutase activity was not significantly modified. A peroxidation of polyunsaturated fatty acids of cell membranes was observed after both treatments, associated with the intracellular oxidative stress. Similar biochemical events were observed on NIH3T3 untransfected control cells, suggesting that KGFR activation follows intracellular generation of ROS and is not associated with a scavenging effect. Taken together our results demonstrate that exposure to UVB and to oxidant stimuli induces a rapid intracellular production of ROS, which in turn are capable of triggering KGFR activation and internalization, similar to those induced by KGF.

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“…Earlier studies have shown that STAT3 could be phosphorylated by insulin in vitro (14,15). However, the biological effect of the activation remains unknown, probably due to the lack of an animal model resulting from embryonic lethality in generalized STAT3 ablation.…”

mentioning

confidence: 99%

STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3β

Moh

Zhang

et al. 2008

Diabetes

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OBJECTIVE-Glucose homeostasis is achieved by triggering regulation of glycogen synthesis genes in response to insulin when mammals feed, but the underlying molecular mechanism remains largely unknown. The aim of our study was to examine the role of the signal transducers and activators of transcription 3 (STAT3) in insulin signaling.RESEARCH DESIGN AND METHODS-We generated a strain of mice carrying a targeted disruption of Stat3 gene in the liver (L-Stat3 Ϫ/Ϫ mice). Hepatocytes of the L-Stat3 Ϫ/Ϫ mice were isolated to establish cell lines for mechanistic studies. Nuclear translocation and DNA-protein interaction of STAT3 was analyzed with immunofluorescent and chromatin immunoprecipitation methods, respectively. Levels of glucose, insulin, leptin, and glucagon were profiled, and putative downstream molecules of STAT3 were examined in the presence of various stimuli in L-Stat3 Ϫ/Ϫ and control mice. RESULTS-STAT3was found to sensitize the insulin signaling through suppression of GSK-3␤, a negative regulator of insulin signaling pathway. During feeding, both mRNA and protein levels of GSK-3␤ decreased in Stat3 f/ϩ mice, which reflected the need of hepatocytes for insulin to induce glycogen synthesis. In contrast, the L-Stat3 Ϫ/Ϫ mice lost this control and showed a monophasic increase in the GSK-3␤ level in response to insulin. Administration of GSK-3␤ inhibitors lithium chloride and L803-mts restored glucose homeostasis and rescued the glucose intolerance and impaired insulin response in L-Stat3 Ϫ/Ϫ mice.CONCLUSIONS-These data indicate that STAT3 sensitizes insulin signaling by negatively regulating GSK-3␤. Inactivation of STAT3 in the liver contributes significantly to the pathogenesis of insulin resistance.

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Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction

Cited by 89 publications

References 49 publications

Down-regulation of interferon γ-activated STAT1 by UV light

Down-regulation of interferon γ-activated STAT1 by UV light

UVB-induced activation and internalization of keratinocyte growth factor receptor

STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3β

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