scholarly journals Modularity and hormone sensitivity of the Drosophila melanogaster insulin receptor/target of rapamycin interaction proteome

2011 ◽  
Vol 7 (1) ◽  
pp. 547 ◽  
Author(s):  
Timo Glatter ◽  
Ralf B Schittenhelm ◽  
Oliver Rinner ◽  
Katarzyna Roguska ◽  
Alexander Wepf ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Insulin Receptor ◽  
Target Of Rapamycin ◽  
Hormone Sensitivity

scholarly journals Activation of the Hexosamine Pathway Leads to Phosphorylation of Insulin Receptor Substrate-1 on Ser307 and Ser612 and Impairs the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Insulin Biosynthetic Pathway in RIN Pancreatic β-Cells

Endocrinology ◽  
2004 ◽  
Vol 145 (6) ◽  
pp. 2845-2857 ◽  
Author(s):  
Francesco Andreozzi ◽  
Cristina D’Alessandris ◽  
Massimo Federici ◽  
Emanuela Laratta ◽  
Silvia Del Guerra ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
High Glucose ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Insulin Biosynthesis ◽  
Phosphatidylinositol 3 Kinase ◽  
Β Cells ◽  
Hexosamine Pathway ◽  
Acid Stable ◽  
Kinase Pathway

Abstract Many adverse effects of glucose were attributed to its increased routing through the hexosamine pathway (HBP). There is evidence for an autocrine role of the insulin signaling in β-cell function. We tested the hypothesis that activation of the HBP induces defects in insulin biosynthesis by affecting the insulin-mediated protein translation signaling. Exposure of human pancreatic islets and RIN β-cells to glucosamine resulted in reduction in glucose- and insulin-stimulated insulin biosynthesis, which in RIN β-cells was associated with impairment in insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation at Tyr608 and Tyr628, which are essential for engaging phosphatidylinositol 3-kinase (PI 3-kinase). These changes were accompanied by impaired activation of PI 3-kinase, and activation of Akt/mammalian target of rapamycin/phosphorylated heat- and acid-stable protein-1/p70S6 kinase pathway. RIN β-cells exposed to high glucose exhibited increased c-Jun N-terminal kinase (JNK) and ERK1/2 activity, which was associated with increased IRS-1 phosphorylation at serine (Ser)307 and Ser612, respectively, that inhibits coupling of IRS-1 to the insulin receptor and is upstream of the inhibition of IRS-1 tyrosine phosphorylation. Azaserine reverted the stimulatory effects of high glucose on JNK and ERK1/2 activity and IRS-1 phosphorylation at Ser307 and Ser612. Glucosamine mimicked the stimulatory effects of high glucose on JNK and ERK1/2 activity and IRS-1 phosphorylation at Ser307 and Ser612. Inhibition of JNK and MAPK kinase-1 activity reverted the negative effects of glucosamine on insulin-mediated protein synthesis. These results suggest that activation of the HBP accounts, in part, for glucose-induced phosphorylation at Ser307 and Ser612 of IRS-1 mediated by JNK and ERK1/2, respectively. These changes result in impaired coupling of IRS-1 and PI 3-kinase, and activation of the Akt/mammalian target of rapamycin/phosphorylated heat- and acid-stable protein-1/p70S6 kinase pathway.

scholarly journals Tissue localization of Drosophila melanogaster insulin receptor transcripts during development.

1988 ◽  
Vol 8 (4) ◽  
pp. 1638-1647 ◽  
Author(s):  
R S Garofalo ◽  
O M Rosen
Keyword(s):  
Nervous System ◽  
Drosophila Melanogaster ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Protein Tyrosine Kinase ◽  
Kinase Activity ◽  
Ganglion Cells ◽  
Northern Analysis ◽  
Tyrosine Kinase Domain ◽  
Subunit Structure

The Drosophila melanogaster insulin receptor (Drosophila insulin receptor homolog [dIRH]) is similar to its mammalian counterpart in deduced amino acid sequence, subunit structure, and ligand-stimulated protein tyrosine kinase activity. The function of this receptor in D. melanogaster is not yet known. However, a role in development is suggested by the observations that levels of insulin-stimulated kinase activity and expression of dIRH mRNA are maximal during Drosophila midembryogenesis. In this study, a 2.9-kilobase (kb) cDNA clone corresponding to both the dIRH tyrosine kinase domain and some of the 3' untranslated sequence was used to determine the tissue distribution of dIRH mRNA during development. Two principal mRNAs of 11 and 8.6 kb hybridized with the dIRH cDNA in Northern (RNA) blot analysis. The abundance of the 8.6-kb mRNA increased transiently in early embryos, whereas the 11-kb species was most abundant during midembryogenesis. A similar pattern of expression was previously determined by Northern analysis, using a dIRH genomic clone (L. Petruzzelli, R. Herrera, R. Arenas-Garcia, R. Fernandez, M. J. Birnbaum, and O. M. Rosen, Proc. Natl. Acad. Sci. USA 83:4710-4714, 1986). In situ hybridization revealed dIRH transcripts in the ovaries of adult flies, in which the transcripts appeared to be synthesized by nurse cells for eventual storage as maternal RNA in the mature oocyte. Throughout embryogenesis, dIRH transcripts were ubiquitously expressed, although after midembryogenesis, higher levels were detected in the developing nervous system. Nervous system expression remained elevated throughout the larval stages and persisted in the adult, in which the cortex of the brain and ganglion cells were among the most prominently labeled tissues. In larvae, the imaginal disk cells exhibited comparatively high levels of dIRH mRNA expression. The broad distribution of dIRH mRNA in embryos and imaginal disks is compatible with a role for dIRH in anabolic processes required for cell growth. The apparently elevated expression of dIRH mRNA in nervous tissue during mid- and late embryogenesis coincides with a period of active neurite outgrowth and suggests that dIRH may be involved in this process.

scholarly journals Heparin-Binding EGF-Like Growth Factor (HB-EGF) Mediates 5-HT-Induced Insulin Resistance Through Activation of EGF Receptor-ERK1/2-mTOR Pathway

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 56-68 ◽  
Author(s):  
Qinkai Li ◽  
Toshio Hosaka ◽  
Yosuke Shikama ◽  
Yukiko Bando ◽  
Chisato Kosugi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Factor ◽  
Insulin Receptor ◽  
Egf Receptor ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Heparin Binding ◽  
Insulin Receptor Substrate 1 ◽  
Endothelin 1

Although an inverse correlation between insulin sensitivity and the level of Gq/11-coupled receptor agonists, such as endothelin-1, thrombin, and 5-hydroxytryptamine (5-HT), has been reported, its precise mechanism remains unclear. In this report, we provide evidence that 5-HT induced production of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and caused insulin resistance in 3T3-L1 adipocytes, primary adipocytes, and C2C12 myotubes. In 3T3-L1 adipocytes, 5-HT stimulated HB-EGF production by promoting metalloproteinase-dependent shedding of transmembrane protein pro-HB-EGF. HB-EGF then bound and tyrosine-phosphorylated EGF receptors, which activated the mammalian target of rapamycin pathway through ERK1/2 phosphorylation. Mammalian target of rapamycin activation caused serine phosphorylation of insulin receptor substrate-1, which attenuated insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and glucose uptake. Pharmacological inhibition of either Gq/11-coupled receptors or metalloproteinases, as well as either inhibition or knockdown of HB-EGF or Gαq/11, restored insulin signal transduction impaired by 5-HT. Inhibition of metalloproteinase activity also abolished HB-EGF production and subsequent EGF receptor activation by other Gq/11-coupled receptor agonists known to cause insulin resistance, such as endothelin-1 and thrombin. These results suggest that transactivation of the EGF receptor through HB-EGF processing plays a pivotal role in 5-HT-induced insulin resistance.

Mammalian Target of Rapamycin Is Activated in Association with Myometrial Proliferation during Pregnancy

Endocrinology ◽  
2009 ◽  
Vol 150 (10) ◽  
pp. 4672-4680 ◽  
Author(s):  
Shabana Jaffer ◽  
Oksana Shynlova ◽  
Stephen Lye
Keyword(s):  
Insulin Receptor ◽  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Mtor Signaling Pathway ◽  
Insulin Receptor Substrate 1 ◽  
Ovx Rats

Abstract The adaptive growth of the uterus during gestation involves gradual changes in cellular phenotypes from the early proliferative to the intermediate synthetic phase of cellular hypertrophy, ending in the final contractile/labour phenotype. The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth and proliferation in many tissues. We hypothesized that mTOR was a mediator of hormone-initiated myometrial hyperplasia during gestation. The protein expression and phosphorylation levels of mTOR, its upstream regulators [insulin receptor substrate-1, phosphoinositide-3-kinase (PI3K), Akt], and downstream effectors [S6-kinase-1 (S6K1) and eI4FE-binding protein 1 (4EBP1)] were analyzed throughout normal pregnancy in rats. In addition, we used an ovariectomized (OVX) rat model to analyze the modulation of the mTOR pathway and proliferative activity of the uterine myocytes by estradiol alone and in combination with the mTOR-specific inhibitor rapamycin. Our results demonstrate that insulin receptor substrate-1 protein levels and the phosphorylated (activated) forms of PI3K, mTOR, and S6K1 were significantly up-regulated in the rat myometrium during the proliferative phase of pregnancy. Treatment of the OVX rats with estradiol caused a transient increase in IGF-I followed by an up-regulation of the PI3K/mTOR pathway, which became apparent by a cascade of phosphorylation reactions (P-P85, P-Akt, P-mTOR, P-S6K1, and P-4EBP1). Rapamycin blocked activation of P-mTOR, P-S6K1, and P-4EBP1 proteins and significantly reduced the number of proliferating cells in the myometrium of OVX rats. Our in vivo data demonstrate that estradiol was able to activate the PI3K/mTOR signaling pathway in uterine myocytes and suggest that this activation is responsible for the induction of myometrial hyperplasia during early gestation.

scholarly journals Drosophila poly suggests a novel role for the Elongator complex in insulin receptor–target of rapamycin signalling

Open Biology ◽  
2012 ◽  
Vol 2 (1) ◽  
pp. 110031 ◽  
Author(s):  
Ekin Bolukbasi ◽  
Sharron Vass ◽  
Neville Cobbe ◽  
Bryce Nelson ◽  
Victor Simossis ◽  
...  
Keyword(s):  
Cell Growth ◽  
Insulin Receptor ◽  
Insulin Signalling ◽  
Essential Gene ◽  
Target Of Rapamycin ◽  
Environmental Cues ◽  
Insulin Stimulation ◽  
Protein Ratio ◽  
Elongator Complex ◽  
Microarray Expression

Multi-cellular organisms need to successfully link cell growth and metabolism to environmental cues during development. Insulin receptor–target of rapamycin (InR–TOR) signalling is a highly conserved pathway that mediates this link. Herein, we describe poly , an essential gene in Drosophila that mediates InR–TOR signalling. Loss of poly results in lethality at the third instar larval stage, but only after a stage of extreme larval longevity. Analysis in Drosophila demonstrates that Poly and InR interact and that poly mutants show an overall decrease in InR–TOR signalling, as evidenced by decreased phosphorylation of Akt, S6K and 4E-BP. Metabolism is altered in poly mutants, as revealed by microarray expression analysis and a decreased triglyceride : protein ratio in mutant animals. Intriguingly, the cellular distribution of Poly is dependent on insulin stimulation in both Drosophila and human cells, moving to the nucleus with insulin treatment, consistent with a role in InR–TOR signalling. Together, these data reveal that Poly is a novel, conserved (from flies to humans) mediator of InR signalling that promotes an increase in cell growth and metabolism. Furthermore, homology to small subunits of Elongator demonstrates a novel, unexpected role for this complex in insulin signalling.

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