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Ma, Zhefu, Shannon L. Gibson, Maura A. Byrne, Junran Zhang, Morris F. White, and Leslie M. Shaw. "Suppression of Insulin Receptor Substrate 1 (IRS-1) Promotes Mammary Tumor Metastasis." Molecular and Cellular Biology 26, no. 24 (October 9, 2006): 9338–51. http://dx.doi.org/10.1128/mcb.01032-06.
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ABSTRACT The insulin receptor substrate (IRS) proteins are cytoplasmic adaptors that organize signaling complexes downstream of activated cell surface receptors. Here, we show that IRS-1 and IRS-2, despite significant homology, play critical yet distinct functions in breast cancer, and we identify specific signaling pathways that are influenced by IRS-1 using the polyoma virus middle-T (PyV-MT) transgenic mouse model of mammary carcinoma and Irs-1 null (Irs1 −/−) mice. The absence of Irs-1 expression enhanced metastatic spread significantly without a significant effect on primary tumor growth. Orthotopic transplant studies revealed that the increased metastatic potential of Irs1-deficient tumor cells is cell autonomous. Mammary tumors that developed in PyV-MT::Irs1 −/− mice exhibited elevated Irs-2 function and enhanced phosphatidylinositol 3-kinase/Akt/mTor activity, suggesting that one mechanism by which Irs-1 impedes metastasis is to suppress Irs-2-dependent signaling. In support of this mechanism, reduction of Irs-2 expression in Irs1 −/− tumor cells restored mTor signaling to wild-type levels. PyV-MT::Irs1 −/− tumors also exhibited a significant increase in vascular endothelial growth factor expression and microvessel density, which could facilitate their dissemination. The significance of our findings for human breast cancer is heightened by our observation that Irs-1 is inactivated in wild-type, metastatic mammary tumors by serine phosphorylation. Collectively, our findings reveal that inactivation of IRS-1 enhances breast cancer metastasis and support the novel hypothesis that IRS-1 has metastasis suppressor functions for breast cancer.
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Negara, Dewa Ngakan Ketut Putra, Tjokorda Gde Tirta Nindhia, Lusiana, I. Made Widiyarta, I. Made Astika, and Cokorda Istri Putri Kusuma Kencanawati. "The Effect of Impregnation Ratio on the Surface Characteristics of Gigantochloa Verticillata Bamboo-Activated Carbon." Materials Science Forum 1045 (September 6, 2021): 59–66. http://dx.doi.org/10.4028/www.scientific.net/msf.1045.59.
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The activation process is the final stage in the manufacturing of activated carbon that can be carried out physically or chemically. This paper focuses on characterizing the surface properties of activated carbons from Gigantochloa verticillata bamboo that are chemically activated at 750°C under different impregnation ratios (IRs) of 1:1, 2:1, and 3:1. The activated carbons produced were denoted as IR1-AC, IR2-AC, and IR3-AC for impregnation ratios of 1:1, 2:1, and 3:1, respectively. Characterizations include TGA, SEM, and adsorption isotherm tests. The results of the research show that variation of the impregnation ratio yielded fluctuated content of proximate elements and surface properties of activated carbons. The highest fixed carbon of 75.69% and the lowest ash of 13.10% were obtained by IR2-AC. The highest surface area of 511.10 m2/g and pore volume of 0.561 cc/g was obtained by IR3-AC and IR2-AC, respectively. The activated carbon pores are distributed in micropores and mesopores areas with average pore diameters of 1.245, 2.494, and 1.984 nm for IR1-AC, IR2-AC, and IR3-AC, respectively. The existence of the pores can be found on the surface morphology of activated carbons.
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Hirashima, Y., K. Tsuruzoe, S. Kodama, M. Igata, T. Toyonaga, K. Ueki, CR Kahn, and E. Araki. "Insulin down-regulates insulin receptor substrate-2 expression through the phosphatidylinositol 3-kinase/Akt pathway." Journal of Endocrinology 179, no. 2 (November 1, 2003): 253–66. http://dx.doi.org/10.1677/joe.0.1790253.
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Insulin receptor substrate (IRS)-1 and IRS-2 are the major substrates that mediate insulin action. Insulin itself regulates the expression of the IRS protein in the liver, but the underlying mechanisms of IRS-1 and IRS-2 regulation are not fully understood. Here we report that insulin suppressed the expression of both IRS-1 and IRS-2 proteins in Fao hepatoma cells. The decrease in IRS-1 protein occurred via proteasomal degradation without any change in IRS-1 mRNA, whereas the insulin-induced suppression of IRS-2 protein was associated with a parallel decrease in IRS-2 mRNA without changing IRS-2 mRNA half-life. The insulin-induced suppression of IRS-2 mRNA and protein was blocked by the phosphatidylinositol (PI) 3-kinase inhibitor, LY294002, but not by the MAP kinase-ERK kinase (MEK) inhibitor, PD098059. Inhibition of Akt by overexpression of dominant-negative Akt also caused complete attenuation of the insulin-induced decrease in IRS-2 protein and partial attenuation of its mRNA down-regulation. Some nuclear proteins bound to the insulin response element (IRE) sequence on the IRS-2 gene in an insulin-dependent manner in vitro, and the binding was also blocked by the PI 3-kinase inhibitor. Reporter gene assay showed that insulin suppressed the activity of both human and rat IRS-2 gene promoters through the IRE in a PI 3-kinase-dependent manner. Our results indicate that insulin regulates IRS-1 and IRS-2 through different mechanisms and that insulin represses IRS-2 gene expression via a PI 3-kinase/Akt pathway.
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Hadsell, Darryl L., Walter Olea, Nicole Lawrence, Jessy George, Daniel Torres, Takahashi Kadowaki, and Adrian V. Lee. "Decreased lactation capacity and altered milk composition in insulin receptor substrate null mice is associated with decreased maternal body mass and reduced insulin-dependent phosphorylation of mammary Akt." Journal of Endocrinology 194, no. 2 (August 2007): 327–36. http://dx.doi.org/10.1677/joe-07-0160.
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Expression of insulin receptor substrates (IRS)-1 and -2 within the mammary gland was found to be high at mid-lactation and dramatically decreased with mammary involution. This observation supports the hypothesis that these proteins are induced in the mammary gland with lactogenesis and involved in normal milk synthesis. To test this hypothesis, lactation capacity, along with indices of mammary secretory cell glucose metabolism and cell signaling were compared in normal mice and mice carrying targeted mutations in either the Irs1 or Irs2 genes. Mammary IRS-1 and IRS-2 protein levels were increased within 1 day of parturition and reached maximal levels by 5 days post partum. Dams carrying germline mutations of Irs1 or Irs2 displayed reduced lactation capacity as assessed by weight gain of pup litters. The reduction was more dramatic in Irs1−/− versus Irs2−/− dams. Maternal body weight was also reduced in Irs1−/− dams as well as in Irs1+/− Irs2+/− dams. The loss of IRS-1 had little impact on mammary gland expression of milk protein mRNAs, glucose transport, or on the abundance and subcellular localization of hexokinases I and II. The loss of IRS-1 was associated with a compensatory increase in insulin-induced IRS-2 phosphorylation; however, the loss of IRS-1 did also cause a reduction in insulin-dependent mammary gland-specific activation of Akt phosphorylation. These results support the conclusion that IRS-1 is important for insulin-dependent activation of Akt signaling within the lactating mammary gland, but that loss of this protein has only modest impact on normal milk synthesis, since related signaling proteins such as IRS-2 may act in compensatory fashion.
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Lempke, Landon B., Rachel S. Johnson, Rachel K. Le, Melissa N. Anderson, Julianne D. Schmidt, and Robert C. Lynall. "Head Impact Biomechanics in Youth Flag Football: A Prospective Cohort Study." American Journal of Sports Medicine 49, no. 10 (July 15, 2021): 2817–26. http://dx.doi.org/10.1177/03635465211026643.
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Background: Youth flag football participation has rapidly grown and is a potentially safer alternative to tackle football. However, limited research has quantitatively assessed youth flag football head impact biomechanics. Purpose: To describe head impact biomechanics outcomes in youth flag football and explore factors associated with head impact magnitudes. Study Design: Cross-sectional study; Level of evidence, 3. Methods: We monitored 52 player-seasons among 48 male flag football players (mean ± SD; age, 9.4 ± 1.1 years; height, 138.6 ± 9.5 cm; mass, 34.7 ± 9.2 kg) across 3 seasons using head impact sensors during practices and games. Sensors recorded head impact frequencies, peak linear ( g) and rotational (rad/s2) acceleration, and estimated impact location. Impact rates (IRs) were calculated as 1 impact per 10 player-exposures; IR ratios (IRRs) were used to compare season, event type, and age group IRs; and 95% CIs were calculated for IRs and IRRs. Weekly and seasonal cumulative head impact frequencies and magnitudes were calculated. Mixed-model regression models examined the association between player characteristics, event type, and seasons and peak linear and rotational accelerations. Results: A total of 429 head impacts from 604 exposures occurred across the study period (IR, 7.10; 95% CI, 4.81-10.50). Weekly and seasonal cumulative median head impact frequencies were 1.00 (range, 0-2.63) and 7.50 (range, 0-21.00), respectively. The most frequent estimated head impact locations were the skull base (n = 96; 22.4%), top of the head (n = 74; 17.2%), and back of the head (n = 66; 15.4%). The combined event type IRs differed among the 3 seasons (IRR range, 1.45-2.68). Games produced greater IRs (IRR, 1.24; 95% CI, 1.01-1.53) and peak linear acceleration (mean difference, 5.69 g; P = .008) than did practices. Older players demonstrated greater combined event–type IRs (IRR, 1.46; 95% CI, 1.12-1.90) and increased head impact magnitudes than did younger players, with every 1-year age increase associated with a 3.78 g and 602.81-rad/s2 increase in peak linear and rotational acceleration magnitude, respectively ( P≤ .005). Conclusion: Head IRs and magnitudes varied across seasons, thus highlighting multiple season and cohort data are valuable when providing estimates. Head IRs were relatively low across seasons, while linear and rotational acceleration magnitudes were relatively high.
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Esposito, Diana L., Yunhua Li, Cinzia Vanni, Sandra Mammarella, Serena Veschi, Fulvio Della Loggia, Renato Mariani-Costantini, Pasquale Battista, Michael J. Quon, and Alessandro Cama. "A Novel T608R Missense Mutation in Insulin Receptor Substrate-1 Identified in a Subject with Type 2 Diabetes Impairs Metabolic Insulin Signaling." Journal of Clinical Endocrinology & Metabolism 88, no. 4 (April 1, 2003): 1468–75. http://dx.doi.org/10.1210/jc.2002-020933.
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Naturally occurring mutations in insulin receptor substrate-1 (IRS-1) have previously been implicated in impaired insulin action. We now report a novel mutation in IRS-1 with substitution of Arg for Thr608 that was identified in a patient with type 2 diabetes mellitus. We detected the T608R mutation in 1 of 136 chromosomes from diabetic patients and in 0 of 120 chromosomes from nondiabetic controls, suggesting that this is a rare IRS-1 variant. Conservation of Thr608 in human, monkey, rat, mouse, and chicken IRS-1 sequences is consistent with a crucial function for this residue. Moreover, Thr608 is located near the YMXM motif containing Tyr612 that is important for binding and activation of phosphoinositol 3-kinase (PI 3-kinase). To investigate whether the T608R mutation impairs insulin signaling, we transiently transfected NIH-3T3IR cells with hemagglutinin-tagged wild-type or T608R mutant IRS-1 constructs. Recombinant IRS-1 immunoprecipitated from transfected cells treated with or without insulin was subjected to immunoblotting for the p85 regulatory subunit of PI 3-kinase as well as a PI 3-kinase assay. As expected, in control cells transfected with wild-type IRS-1, insulin stimulation caused an increase in p85 coimmunoprecipitated with IRS-1 as well as a 10-fold increase in IRS-1-associated PI 3-kinase activity. Interestingly, when cells transfected with IRS1-T608R were stimulated with insulin, both the amount of p85 coimmunoprecipitated with IRS1-T608R as well as the associated PI 3-kinase activity were approximately 50% less than those observed with wild-type IRS-1. Moreover, in rat adipose cells, overexpression of IRS1-T608R resulted in significantly less translocation of GLUT4 to the cell surface than comparable overexpression of wild-type IRS-1. We conclude that a naturally occurring substitution of Arg for Thr608 in IRS-1 is a rare human mutation that may contribute to insulin resistance by impairing metabolic signaling through PI 3-kinase-dependent pathways.
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Delafontaine, P. "IRS-1 Variant." Arteriosclerosis, Thrombosis, and Vascular Biology 20, no. 2 (February 2000): 283–84. http://dx.doi.org/10.1161/01.atv.20.2.283.
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Brüning, J. C., J. Winnay, B. Cheatham, and C. R. Kahn. "Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells." Molecular and Cellular Biology 17, no. 3 (March 1997): 1513–21. http://dx.doi.org/10.1128/mcb.17.3.1513.
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Mice made insulin receptor substrate 1 (IRS-1) deficient by targeted gene knockout exhibit growth retardation and abnormal glucose metabolism due to resistance to the actions of insulin-like growth factor 1 (IGF-1) and insulin (E. Araki et al., Nature 372:186-190, 1994; H. Tamemoto et al., Nature 372:182-186, 1994). Embryonic fibroblasts and 3T3 cell lines derived from IRS-1-deficient embryos exhibit no IGF-1-stimulated IRS-1 phosphorylation or IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity but exhibit normal phosphorylation of IRS-2 and Shc and normal IRS-2-associated PI 3-kinase activity. IRS-1 deficiency results in a 70 to 80% reduction in IGF-1-stimulated cell growth and parallel decreases in IGF-1-stimulated S-phase entry, PI 3-kinase activity, and induction of the immediate-early genes c-fos and egr-1 but unaltered activation of the mitogen-activated protein kinases ERK 1 and ERK 2. Expression of IRS-1 in IRS-1-deficient cells by retroviral gene transduction restores IGF-1-stimulated mitogenesis, PI 3-kinase activation, and c-fos and egr-1 induction in proportion to the level of reconstitution. Increasing the level of IRS-2 in these cells by using a retrovirus reconstitutes IGF-1 activation of PI 3-kinase and immediate-early gene expression to the same degree as expression of IRS-1; however, IRS-2 overexpression has only a minor effect on IGF-1 stimulation of cell cycle progression. These results indicate that IRS-1 is not necessary for activation of ERK 1 and ERK 2 and that activation of ERK 1 and ERK 2 is not sufficient for IGF-1-stimulated activation of c-fos and egr-1. These data also provide evidence that IRS-1 and IRS-2 are not functionally interchangeable signaling intermediates for stimulation of mitogenesis despite their highly conserved structure and many common functions such as activating PI 3-kinase and early gene expression.
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Henry, Kevin A., Recinda L. Sherman, Kaila McDonald, Christopher J. Johnson, Ge Lin, Antoinette M. Stroup, and Francis P. Boscoe. "Associations of Census-Tract Poverty with Subsite-Specific Colorectal Cancer Incidence Rates and Stage of Disease at Diagnosis in the United States." Journal of Cancer Epidemiology 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/823484.
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Background. It remains unclear whether neighborhood poverty contributes to differences in subsite-specific colorectal cancer (CRC) incidence. We examined associations between census-tract poverty and CRC incidence and stage by anatomic subsite and race/ethnicity.Methods. CRC cases diagnosed between 2005 and 2009 from 15 states and Los Angeles County (N=278,097) were assigned to 1 of 4 groups based on census-tract poverty. Age-adjusted and stage-specific CRC incidence rates (IRs) and incidence rate ratios (IRRs) were calculated. Analyses were stratified by subsite (proximal, distal, and rectum), sex, race/ethnicity, and poverty.Results. Compared to the lowest poverty areas, CRC IRs were significantly higher in the most impoverished areas for men (IRR = 1.14 95% CI 1.12–1.17) and women (IRR = 1.06 95% CI 1.05–1.08). Rate differences between high and low poverty were strongest for distal colon (male IRR = 1.24 95% CI 1.20–1.28; female IRR = 1.14 95% CI 1.10–1.18) and weakest for proximal colon. These rate differences were significant for non-Hispanic whites and blacks and for Asian/Pacific Islander men. Inverse associations between poverty and IRs of all CRC and proximal colon were found for Hispanics. Late-to-early stage CRC IRRs increased monotonically with increasing poverty for all race/ethnicity groups.Conclusion. There are differences in subsite-specific CRC incidence by poverty, but associations were moderated by race/ethnicity.
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Kappel, Camila Ripoll, Nélson A. Kretzmann, and Mário Reis Álvares-da-Silva. "IRS1 Expression in Hepatic Tissue and Leukocytes in Chronic Hepatitis C Virus Infected Patients: A Comparative Study." International Journal of Hepatology 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/698905.
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Aims.To determine lymphocyte IRS (IRS1 cells) in HCV patients, correlating it to liver IRS (IRS 1liver) and HOMA-IR. This study tested the hypothesis that IRS1 cells expression can be used as insulin resistance (IR) marker in HCV-infected patients. IRS1 cells were not studied before in HCV infection.Materials and Methods.HCV chronically infected patients, naïve, nonobese, noncirrhotic, and nondiabetic were prospectively included and compared to controls (blood donors). Blood was taken, and leukocytes were separated. IRS1 was determined by real-time PCR. Liver tissue was obtained from transplant donors as controls.Results.41 HCV-positive patients were included, 26 males (60.5%); mean age of 45 (); 33 (80.5%) from genotype 1. 6 out of 12 controls were males (50%); mean age was 26.7 (). There was expression of IRS1 in leukocytes. The median IRS1 cells (HCV) were 0.061 (0.004 to 0.469); the median IRS 1liver (HCV) was 0.0003 (0.00002 to 0.0186)—lower than in controls (resp., and ). HOMA-IR had an inverse correlation with IRS 1liver (). There was no correlation between IRS1 liver and IRS1 cells ().Conclusions.There was expression of IRS1 in leukocytes. IRS1 cells and IRS1 liver were lower in HCV patients than in controls.
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Greene, Michael W., Mary S. Ruhoff, Richard A. Roth, Jeong-a. Kim, Michael J. Quon, and Jean A. Krause. "PKCδ-mediated IRS-1 Ser24 phosphorylation negatively regulates IRS-1 function." Biochemical and Biophysical Research Communications 349, no. 3 (October 2006): 976–86. http://dx.doi.org/10.1016/j.bbrc.2006.08.158.
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Miki, Hiroshi, Toshimasa Yamauchi, Ryo Suzuki, Kajuro Komeda, Atsuko Tsuchida, Naoto Kubota, Yasuo Terauchi, et al. "Essential Role of Insulin Receptor Substrate 1 (IRS-1) and IRS-2 in Adipocyte Differentiation." Molecular and Cellular Biology 21, no. 7 (April 1, 2001): 2521–32. http://dx.doi.org/10.1128/mcb.21.7.2521-2532.2001.
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ABSTRACT To investigate the role of insulin receptor substrate 1 (IRS-1) and IRS-2, the two ubiquitously expressed IRS proteins, in adipocyte differentiation, we established embryonic fibroblast cells with four different genotypes, i.e., wild-type, IRS-1 deficient (IRS-1−/−), IRS-2 deficient (IRS-2−/−), and IRS-1 IRS-2 double deficient (IRS-1−/−IRS-2−/−), from mouse embryos of the corresponding genotypes. The abilities of IRS-1−/− cells and IRS-2−/− cells to differentiate into adipocytes are approximately 60 and 15%, respectively, lower than that of wild-type cells, at day 8 after induction and, surprisingly, IRS-1−/− IRS-2−/− cells have no ability to differentiate into adipocytes. The expression of CCAAT/enhancer binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) is severely decreased in IRS-1−/−IRS-2−/− cells at both the mRNA and the protein level, and the mRNAs of lipoprotein lipase and adipocyte fatty acid binding protein are severely decreased in IRS-1−/−IRS-2−/− cells. Phosphatidylinositol 3-kinase (PI 3-kinase) activity that increases during adipocyte differentiation is almost completely abolished in IRS-1−/−IRS-2−/− cells. Treatment of wild-type cells with a PI 3-kinase inhibitor, LY294002, markedly decreases the expression of C/EBPα and PPARγ, a result which is associated with a complete block of adipocyte differentiation. Moreover, histologic analysis of IRS-1−/− IRS-2−/− double-knockout mice 8 h after birth reveals severe reduction in white adipose tissue mass. Our results suggest that IRS-1 and IRS-2 play a crucial role in the upregulation of the C/EBPα and PPARγ expression and adipocyte differentiation.
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Persi, P., M. Perrari-Toniolo, and L. Spinoglio. "Star formation in the southern complex region NGC 3576." Symposium - International Astronomical Union 122 (1987): 93–94. http://dx.doi.org/10.1017/s0074180900156050.
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NGC 3576 (RCW 57) is a very bright optically visible nebula (~10' in size) located near the galactic plane at a distance of 3.6kpc. The region is associated with the HII region G291.28–0.71 (Retallack & Goss), and with a giant molecular cloud of M≃9×104 M⊙ (Cheung et al.1980) The source is reported in the IRAS Small Scale Structure Catalog. From the observed far-IR fluxes we derive a total luminosity of L(FIR)≃7×105 L⊙, suggesting that at least seven possible 07–09 stars could ionize the entire observed region. A cluster of five IR sources and extended 10μm emission were found by Frogel & Persson (1974). IRS 1 is a very compact object (<3'), while IRS 2–5 show diffuse infrared emission. In addition IRS 2, very close to IRS 1, is coincident with the radio emission peak. An H2O maser source and NH3 emission are present in the complex region.We present multidiaphragm photometry from 1 to 20μm of 1RS 1, IRS 3 and IRS 4 and CVF observations between 2-μm and 8–13μm of IRS 1, collected at the 1m and 3.6m ESO telescopes.
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Liu, X. J., A. Sorisky, L. Zhu, and T. Pawson. "Molecular cloning of an amphibian insulin receptor substrate 1-like cDNA and involvement of phosphatidylinositol 3-kinase in insulin-induced Xenopus oocyte maturation." Molecular and Cellular Biology 15, no. 7 (July 1995): 3563–70. http://dx.doi.org/10.1128/mcb.15.7.3563.
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An insulin receptor substrate 1 (IRS-1)-like cDNA was isolated from a Xenopus ovary cDNA library by low-stringency hybridization using rat IRS-1 cDNA as a probe. The deduced amino acid sequence encoded by this cDNA (termed XIRS-L) is 67% identical (77% similar) to that of rat IRS-1. Significantly, all the insulin-induced tyrosine phosphorylation sites identified in rat IRS-1, including those responsible for binding to the Src homology domains of phosphatidylinositol (PI) 3-kinase, Syp and Grb2, are conserved in XIRS-L. Both mRNA and protein corresponding to the cloned XIRS-L can be detected in immature Xenopus oocytes. Recombinant XIRS-L protein produced in insect cells or a bacterial glutathione S-transferase fusion protein containing the putative PI 3-kinase binding site can be phosphorylated in vitro by purified insulin receptor kinase (IRK) domain, and the IRK-catalyzed phosphorylation renders both proteins capable of binding PI 3-kinase in Xenopus oocyte lysates. Another glutathione S-transferase fusion protein containing the C terminus of XIRS-L and including several putative tyrosine phosphorylation sites is also phosphorylated by IRK in vitro, but it failed to bind PI 3-kinase. Insulin stimulation of immature Xenopus oocytes activates PI 3-kinase in vivo [as indicated by an elevation of PI(3,4)P2 and PI(3,4,5)P3] as well as oocyte maturation (as indicated by germinal vesicle breakdown). Pretreatment of these oocytes with wortmannin inhibited insulin-induced activation of PI 3-kinase in vivo. The same treatment also abolished insulin-induced, but not progesterone-induced, germinal vesicle breakdown. These results (i) identify an IRS-1-like molecule in immature Xenopus oocytes, suggesting that the use of IRS-1-like Scr homology 2 domain-docking proteins in signal transduction is conserved in vertebrates, and (ii) strongly implicate PI 3-kinase as an essential effector of insulin-induced oocyte maturation.
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Hartman, Matthew E., Montserrat Villela-Bach, Jie Chen, and Gregory G. Freund. "FRAP-Dependent Serine Phosphorylation of IRS-1 Inhibits IRS-1 Tyrosine Phosphorylation." Biochemical and Biophysical Research Communications 280, no. 3 (January 2001): 776–81. http://dx.doi.org/10.1006/bbrc.2000.4214.
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Solórzano, Chincoya, Sanchez-Flores, Estrada, Díaz-Velásquez, González-Rodríguez, Vaca-Paniagua, Dávila, and Arias. "De Novo Assembly Discovered Novel Structures in Genome of Plastids and Revealed Divergent Inverted Repeats in Mammillaria (Cactaceae, Caryophyllales)." Plants 8, no. 10 (October 1, 2019): 392. http://dx.doi.org/10.3390/plants8100392.
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The complete sequence of chloroplast genome (cpDNA) has been documented for single large columnar species of Cactaceae, lacking inverted repeats (IRs). We sequenced cpDNA for seven species of the short-globose cacti of Mammillaria and de novo assembly revealed three novel structures in land plants. These structures have a large single copy (LSC) that is 2.5 to 10 times larger than the small single copy (SSC), and two IRs that contain strong differences in length and gene composition. Structure 1 is distinguished by short IRs of <1 kb composed by rpl23-trnI-CAU-ycf2; with a total length of 110,189 bp and 113 genes. In structure 2, each IR is approximately 7.2 kb and is composed of 11 genes and one Intergenic Spacer-(psbK-trnQ)-trnQ-UUG-rps16-trnK-UUU-matK-trnK-UUU-psbA-trnH-GUG-rpl2-rpl23-trnI-CAU-ycf2; with a total size of 116,175 bp and 120 genes. Structure 3 has divergent IRs of approximately 14.1 kb, where IRA is composed of 20 genes: psbA-trnH-GUG-rpl23-trnI-CAU-ycf2-ndhB-rps7-rps12-trnV-GAC-rrn16-ycf68-trnI-GAU-trnA-AGC-rrn23-rrn4.5-rrn5-trnR-ACG-trnN-GUU-ndhF-rpl32; and IRB is identical to the IRA, but lacks rpl23. This structure has 131 genes and, by pseudogenization, it is shown to have the shortest cpDNA, of just 107,343 bp. Our findings show that Mammillaria bears an unusual structural diversity of cpDNA, which supports the elucidation of the evolutionary processes involved in cacti lineages.
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Valverde, Angela M., Cecilia Mur, Sebastián Pons, Alberto M. Alvarez, Morris F. White, C. Ronald Kahn, and Manuel Benito. "Association of Insulin Receptor Substrate 1 (IRS-1) Y895 with Grb-2 Mediates the Insulin Signaling Involved in IRS-1-Deficient Brown Adipocyte Mitogenesis." Molecular and Cellular Biology 21, no. 7 (April 1, 2001): 2269–80. http://dx.doi.org/10.1128/mcb.21.7.2269-2280.2001.
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ABSTRACT We have recently generated immortalized fetal brown adipocyte cell lines from insulin receptor substrate 1 (IRS-1) knockout mice and demonstrated an impairment in insulin-induced lipid synthesis as compared to wild-type cell lines. In this study, we investigated the consequences of IRS-1 deficiency on mitogenesis in response to insulin. The lack of IRS-1 resulted in the inability of insulin-stimulated IRS-1-deficient brown adipocytes to increase DNA synthesis and enter into S/G2/M phases of the cell cycle. These cells showed a severe impairment in activating mitogen-activated protein kinase kinase (MEK1/2) and p42-p44 mitogen-activated protein kinase (MAPK) upon insulin stimulation. IRS-1-deficient cells also lacked tyrosine phosphorylation of SHC and showed no SHC–Grb-2 association in response to insulin. The mitogenic response to insulin could be partially restored by enhancing IRS-2 tyrosine phosphorylation and its association with Grb-2 by inhibition of phosphatidylinositol 3-kinase activity through a feedback mechanism. Reconstitution of IRS-1-deficient brown adipocytes with wild-type IRS-1 restored insulin-induced IRS-1 and SHC tyrosine phosphorylation and IRS-1–Grb-2, IRS-1–SHC, and SHC–Grb-2 associations, leading to the activation of MAPK and enhancement of DNA synthesis. Reconstitution of IRS-1-deficient brown adipocytes with the IRS-1 mutant Tyr895Phe, which lacks IRS-1–Grb-2 binding, restored SHC–IRS-1 association and SHC–Grb-2 association. However, the lack of IRS-1–Grb-2 association impaired MAPK activation and DNA synthesis in insulin-stimulated mutant cells. These data provide strong evidence for an essential role of IRS-1 and its direct association with Grb-2 in the insulin signaling pathway leading to MAPK activation and mitogenesis in brown adipocytes.
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Tsuruzoe, Kaku, Renee Emkey, Kristina M. Kriauciunas, Kohjiro Ueki, and C. Ronald Kahn. "Insulin Receptor Substrate 3 (IRS-3) and IRS-4 Impair IRS-1- and IRS-2-Mediated Signaling." Molecular and Cellular Biology 21, no. 1 (January 1, 2001): 26–38. http://dx.doi.org/10.1128/mcb.21.1.26-38.2001.
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ABSTRACT To investigate the roles of insulin receptor substrate 3 (IRS-3) and IRS-4 in the insulin-like growth factor 1 (IGF-1) signaling cascade, we introduced these proteins into 3T3 embryonic fibroblast cell lines prepared from wild-type (WT) and IRS-1 knockout (KO) mice by using a retroviral system. Following transduction of IRS-3 or IRS-4, the cells showed a significant decrease in IRS-2 mRNA and protein levels without any change in the IRS-1 protein level. In these cell lines, IGF-1 caused the rapid tyrosine phosphorylation of all four IRS proteins. However, IRS-3- or IRS-4-expressing cells also showed a marked decrease in IRS-1 and IRS-2 phosphorylation compared to the host cells. This decrease was accounted for in part by a decrease in the level of IRS-2 protein but occurred with no significant change in the IRS-1 protein level. IRS-3- or IRS-4-overexpressing cells showed an increase in basal phosphatidylinositol 3-kinase activity and basal Akt phosphorylation, while the IGF-1-stimulated levels correlated well with total tyrosine phosphorylation level of all IRS proteins in each cell line. IRS-3 expression in WT cells also caused an increase in IGF-1-induced mitogen-activated protein kinase phosphorylation and egr-1 expression (∼1.8- and ∼2.4-fold with respect to WT). In the IRS-1 KO cells, the impaired mitogenic response to IGF-1 was reconstituted with IRS-1 to supranormal levels and was returned to almost normal by IRS-2 or IRS-3 but was not improved by overexpression of IRS-4. These data suggest that IRS-3 and IRS-4 may act as negative regulators of the IGF-1 signaling pathway by suppressing the function of other IRS proteins at several steps.
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de Blaquière, Gail E., Felicity E. B. May, and Bruce R. Westley. "Increased expression of both insulin receptor substrates 1 and 2 confers increased sensitivity to IGF-1 stimulated cell migration." Endocrine-Related Cancer 16, no. 2 (June 2009): 635–47. http://dx.doi.org/10.1677/erc-08-0216.
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Insulin-like growth factors (IGFs) are thought to promote tumour progression and metastasis in part by stimulating cell migration. Insulin receptor substrate-1 (IRS-1) and IRS-2 are multisite docking proteins positioned immediately downstream from the type I IGF and insulin receptors. IRS-2 but not IRS-1 has been reported to be involved in the migratory response of breast cancer cells to IGFs. The purpose of this investigation was to determine if IRS-1 is involved in, and to assess the contributions of IRS-1 and IRS-2 to, the migratory response of breast cancer cells to IGFs. The expression of IRS-1 and IRS-2 varied considerably between ten breast cancer cell lines. Oestrogen increases expression of the type I IGF receptor, IRS-1 and IRS-2 in MCF-7 and ZR-75 cells. Oestrogens may control the sensitivity of breast cancer cells to IGFs by regulating the expression of components of the IGF signal transduction pathway. The migratory response to a range of IGF-1 concentrations was measured in MCF-7 and MDA-MB-231 breast cancer cells in which IRS-1 and IRS-2 levels were modulated using a doxycycline-inducible expression system. Induction of both IRS-1 and IRS-2 expression increased the sensitivity of the migratory response to IGF-1 but did not increase the magnitude of the response stimulated at higher concentrations of IGF-1. Knockdown of IRS-1, IRS-2 and the type I IGF receptor in MCF-7 and MDA-MB-2231 cells decreased sensitivity to IGF-1. We conclude that both IRS-1 and IRS-2 control the migratory response of breast cancer cells to IGF-1 and may, therefore, be key molecules in determining breast cancer spread.
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Liang, Fang Ting, Richard H. Jacobson, Reinhard K. Straubinger, Amy Grooters, and Mario T. Philipp. "Characterization of a Borrelia burgdorferi VlsE Invariable Region Useful in Canine Lyme Disease Serodiagnosis by Enzyme-Linked Immunosorbent Assay." Journal of Clinical Microbiology 38, no. 11 (2000): 4160–66. http://dx.doi.org/10.1128/jcm.38.11.4160-4166.2000.
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Sera collected from dogs experimentally infected withBorrelia burgdorferi by tick inoculation were analyzed for an antibody response to each of the six invariable regions (IRs; i.e., IR1 to IR6) of VlsE, the variable surface antigen of B. burgdorferi. Six synthetic peptides (C1 to C6), which reproduced the six IR sequences were used as peptide-based, enzyme-linked immunosorbent assay (ELISA) antigens. Two IRs, IR2 and IR6, were found to be immunodominant. Studies with serially collected serum samples from experimentally infected dogs revealed that the antibody response to IR6 appears earlier and is stronger than that to IR2. Thus, the IR6 sequence alone appeared to be sufficient for serodiagnosis. When C6 alone was used as antigen, the peptide-based ELISA was positive in 7 of 23 dogs (30%) as early as 3 weeks postinfection. All dogs (n = 33) became strongly positive 1 or 2 weeks later, and this response persisted for the entire study, which lasted for 69 weeks. Of 55 sera submitted by veterinarians from dogs suspected of having Lyme disease, 19 were also positive by the C6 ELISA, compared to 20 positives detected by immunoblot analysis using cultured B. burgdorferi lysates as antigen. The sensitivity of using C2 and C6 together for detecting specific antibody in both experimentally infected and clinically diagnosed dogs was not better than sensitivity with C6 alone, confirming that C6 suffices as a diagnostic probe. Moreover, the C6 ELISA yielded 100% specificity with serum samples collected from 70 healthy dogs, 14 dogs with infections other than B. burgdorferi, and 15 animals vaccinated with either outer surface protein A, whole-spirochete vaccines, or the common puppy-vaccines. Therefore, this C6 ELISA was both sensitive and specific for the serodiagnosis of canine Lyme disease and could be used with vaccinated dogs.
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Akarsu, Ersin, Can Demirel, Sibel Oguzkan Balci, Zeynel A. Sayiner, İbrahim Yilmaz, Murat Korkmaz, Ayten Eraydin, and Suzan Tabur. "Effects of Exercise, Metformin, Pioglitazone and Exenatide Treatment on Inflammation Induced Insulin Resistance and Ubiquitin Proteasome System in Diabetes and Obesity." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A438. http://dx.doi.org/10.1210/jendso/bvab048.893.
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Abstract Purpose: The aim of this study is; To examine the destruction of insulin receptor substrate-1 (IRS-1) molecule, which is one of the mechanisms that cause insulin resistance in diabetes and obesity, and its effect to reduce this destruction. For this purpose, the effects of exercise, metformin, exenatide and pioglitazone treatments on IRS-1 ubiquitination in pancreas, muscle and adipose tissue were investigated in an obese and diabetic animal model. Method: Obese rat model was used in this study. This model is characterised by obesity, diabetes and insulin resistance. This study investigated the molecular mechanisms of IRS-1 breakdown in diabetes. IRS1, SOCS1, SOC3 expressions were evaluated in the liver, muscle and adipose tissue of this model. At the same time, immunohistochemical analyses were performed in terms of IRS1, SOCS1 and SOCS3 in the same tissues. Results: Gene expression and Immunohistochemical analysis results were evaluated, the increase in IRS1 was noticeable in rats treated with exenatide, especially in the liver tissue despite the greater decrease in SOCS1 (P> 0.05). It was determined that other drugs in this study and used in the treatment of diabetes may also affect this mechanism to different degrees. Conclusion: Our findings showed that some drugs used in the treatment of diabetes may alter the SOCS effect and / or proteasomal degradation of the IRS-1 protein. This effect was particularly pronounced in liver tissue. However, more comprehensive studies are required to show the contribution of ubiquitination in the destruction of IRS-1 and which drugs are effective on this mechanism. Acknowledgement: This study was supported by the Scientific And Tecnological Research Council Of Turkey (TÜBİTAK) Project No: 217S089
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Zhande, Rachel, John J. Mitchell, Jiong Wu, and Xiao Jian Sun. "Molecular Mechanism of Insulin-Induced Degradation of Insulin Receptor Substrate 1." Molecular and Cellular Biology 22, no. 4 (February 15, 2002): 1016–26. http://dx.doi.org/10.1128/mcb.22.4.1016-1026.2002.
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ABSTRACT Insulin receptor substrate 1 (IRS-1) plays an important role in the insulin signaling cascade. In vitro and in vivo studies from many investigators have suggested that lowering of IRS-1 cellular levels may be a mechanism of disordered insulin action (so-called insulin resistance). We previously reported that the protein levels of IRS-1 were selectively regulated by a proteasome degradation pathway in CHO/IR/IRS-1 cells and 3T3-L1 adipocytes during prolonged insulin exposure, whereas IRS-2 was unaffected. We have now studied the signaling events that are involved in activation of the IRS-1 proteasome degradation pathway. Additionally, we have addressed structural elements in IRS-1 versus IRS-2 that are required for its specific proteasome degradation. Using ts20 cells, which express a temperature-sensitive mutant of ubiquitin-activating enzyme E1, ubiquitination of IRS-1 was shown to be a prerequisite for insulin-induced IRS-1 proteasome degradation. Using IRS-1/IRS-2 chimeric proteins, the N-terminal region of IRS-1 including the PH and PTB domains was identified as essential for targeting IRS-1 to the ubiquitin-proteasome degradation pathway. Activation of phosphatidylinositol 3-kinase is necessary but not sufficient for activating and sustaining the IRS-1 ubiquitin-proteasome degradation pathway. In contrast, activation of mTOR is not required for IRS-1 degradation in CHO/IR cells. Thus, our data provide insight into the molecular mechanism of insulin-induced activation of the IRS-1 ubiquitin-proteasome degradation pathway.
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Davis, Wendy A., Aron Chakera, Edward Gregg, Daniel McAullay, and Timothy M. E. Davis. "Temporal Trends in Renal Replacement Therapy in Community-Based People with or without Type 2 Diabetes: The Fremantle Diabetes Study." Journal of Clinical Medicine 11, no. 3 (January 28, 2022): 695. http://dx.doi.org/10.3390/jcm11030695.
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Background: Although rates of cardiovascular disease complicating type 2 diabetes are declining, equivalent data for renal replacement therapy (RRT) are conflicting. The aim of this study was to characterize temporal changes in RRT incidence rates (IRs) in Australians with or without type 2 diabetes. Methods: Participants with type 2 diabetes from the Fremantle Diabetes Study Phases I (FDS1; n = 1291 recruited 1993–1996) and II (FDS2; n = 1509 recruited 2008–2011) were age-, sex- and postcode-matched 1:4 to people without diabetes and followed for first hospitalization for/with RRT. Five-year IRs, IR ratios (IRRs) for those with versus without diabetes in FDS1 and FDS2, and IR differences (IRDs), were calculated. Results: The 13,995 participants had a mean age of 64.8 years and 50.4% were males. For the type 2 diabetes cohorts, the 5-year RRT IR was nearly threefold higher in FDS2 versus FDS1 (IRR (95% CI): 2.85 (1.01–9.87)). Sixteen more participants with type 2 diabetes/10,000 person-years received RRT in FDS2 than FDS1 compared with an IRD of 2/10,000 person-years in those without diabetes. Type 2 diabetes increased RRT risk at least 5-fold. This increased risk was greater in Aboriginal participants who were relatively young when RRT was initiated and more prone to rapid progression to RRT. Multivariable analysis using the combined FDS type 2 diabetes cohorts confirmed albuminuria as a strong independent RRT risk factor. Conclusions: The incidence of RRT is increasing substantially in Australians with type 2 diabetes, especially in Aboriginals who progress to RRT more rapidly at a younger age than non-Aboriginals.
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Usui, Isao, Takeshi Imamura, Jie Huang, Hiroaki Satoh, Sudha K. Shenoy, Robert J. Lefkowitz, Christopher J. Hupfeld, and Jerrold M. Olefsky. "β-Arrestin-1 Competitively Inhibits Insulin-Induced Ubiquitination and Degradation of Insulin Receptor Substrate 1." Molecular and Cellular Biology 24, no. 20 (October 15, 2004): 8929–37. http://dx.doi.org/10.1128/mcb.24.20.8929-8937.2004.
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ABSTRACT β-Arrestin-1 is an adaptor protein that mediates agonist-dependent internalization and desensitization of G-protein-coupled receptors (GPCRs) and also participates in the process of heterologous desensitization between receptor tyrosine kinases and GPCR signaling. In the present study, we determined whether β-arrestin-1 is involved in insulin-induced insulin receptor substrate 1 (IRS-1) degradation. Overexpression of wild-type (WT) β-arrestin-1 attenuated insulin-induced degradation of IRS-1, leading to increased insulin signaling downstream of IRS-1. When endogenous β-arrestin-1 was knocked down by transfection of β-arrestin-1 small interfering RNA, insulin-induced IRS-1 degradation was enhanced. Insulin stimulated the association of IRS-1 and Mdm2, an E3 ubiquitin ligase, and this association was inhibited to overexpression of WT β-arrestin-1, which led by decreased ubiquitin content of IRS-1, suggesting that both β-arrestin-1 and IRS-1 competitively bind to Mdm2. In summary, we have found the following: (i) β-arrestin-1 can alter insulin signaling by inhibiting insulin-induced proteasomal degradation of IRS-1; (ii) β-arrestin-1 decreases the rate of ubiquitination of IRS-1 by competitively binding to endogenous Mdm2, an E3 ligase that can ubiquitinate IRS-1; (iii) dephosphorylation of S412 on β-arrestin and the amino terminus of β-arrestin-1 are required for this effect of β-arrestin on IRS-1 degradation; and (iv) inhibition of β-arrestin-1 leads to enhanced IRS-1 degradation and accentuated cellular insulin resistance.
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Tseng, Yu-Hua, Kristina M. Kriauciunas, Efi Kokkotou, and C. Ronald Kahn. "Differential Roles of Insulin Receptor Substrates in Brown Adipocyte Differentiation." Molecular and Cellular Biology 24, no. 5 (March 1, 2004): 1918–29. http://dx.doi.org/10.1128/mcb.24.5.1918-1929.2004.
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ABSTRACT Insulin promotes adipocyte differentiation via a complex signaling network involving multiple insulin receptor substrates (IRSs). In cultured brown preadipocytes, expression of IRS-1 and IRS-2 mRNAs and proteins was at relatively high levels before and after differentiation into mature fat cells, while IRS-3 transcript was not detectable in preadipocytes but increased during the course of differentiation, and IRS-4 mRNA was barely detected in both states. To determine more precisely the roles of various IRS proteins in adipogenesis, we established and characterized brown preadipocyte cell lines from wild-type and IRS knockout (KO) animals. While wild-type, IRS-2 KO, and IRS-4 KO cells fully differentiated into mature adipocytes, IRS-3 KO cells showed a moderate defect in differentiation and IRS-1 KO cells exhibited a severe defect in the process. Cells lacking both IRS-1 and IRS-3 completely failed to differentiate. Expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha, fatty acid synthase, glucose transporter 4, and the transcription factor signal transducer and activator of transcription 5, as well as the brown-fat-specific markers PPARγ coactivator 1 alpha and uncoupling protein 1, mirrored the differentiation pattern. Reconstitution of the IRS-1 KO cells with IRS-1 and IRS-4, but not IRS-2 or IRS-3, compensated for the lack of differentiation in IRS-1 KO cells. A chimeric molecule containing the N terminus of IRS-1 and the C terminus of IRS-2, but not one with the N terminus of IRS-2 and the C terminus of IRS-1, also rescued differentiation. Expression of Wnt 10a, a molecule known to inhibit adipogenesis, was dramatically increased in the IRS-1 KO cells, and this could be reduced by overexpression of IRS-1 or IRS-4, which was correlated with restoration of differentiation. These data indicate that both IRS-1 and -3 play important roles in the differentiation of brown adipocytes and that the N terminus of IRS-1 is more important for this function of the molecule. Although IRS-4 is not essential for the process, overexpression of IRS-4 can compensate for the deficiency in differentiation in IRS-1 KO cells.
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Myers, M. G., Y. Zhang, G. A. Aldaz, T. Grammer, E. M. Glasheen, L. Yenush, L. M. Wang, et al. "YMXM motifs and signaling by an insulin receptor substrate 1 molecule without tyrosine phosphorylation sites." Molecular and Cellular Biology 16, no. 8 (August 1996): 4147–55. http://dx.doi.org/10.1128/mcb.16.8.4147.
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Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) by the activated receptors for insulin, IGF-1, and various cytokines creates binding sites for signaling proteins with Src homology 2 domains (SH2 proteins). Determining the role of specific SH2 proteins during insulin signaling has been difficult because IRS-1 possesses as many as 18 potential tyrosine phosphorylation sites, several of which contain redundant motifs. Using 32D cells, which contain no endogenous IRS proteins, we compared the signaling ability of an IRS-1 molecule in which 18 potential tyrosine phosphorylation sites were replaced by phenylalanine (IRS-1(F18)) with two derivative molecules which retained three YMXM motifs (IRS-1(3YMXM)) or the two COOH-terminal SHP2-Fyn binding sites (IRS-1(YCT)). During insulin stimulation, IRS-1(F18) failed to undergo tyrosine phosphorylation or mediate activation of the phosphotidylinositol (PI) 3'-kinase or p70(s6k); IRS-1(YCT) was tyrosine phosphorylated but also failed to mediate these signaling events. Neither IRS-1(3YMXM) nor IRS-1(YCT) mediated activation of mitogen-activated protein kinases. IRS-1(F18) and IRS-1(YCT) partially mediated similar levels of insulin-stimulated mitogenesis at high insulin concentrations, however, suggesting that IRS-1 contains phosphotyrosine-independent elements which effect mitogenic signals, and that the sites in IRS-l(YCT) do not augment this signal. IRS-1(3YMXM) mediated the maximal mitogenic response to insulin, although the response to insulin was more sensitive with wild-type IRS-1. By contrast, the association of IRS-1(3YMXM) with PI 3'-kinase was more sensitive to insulin than the association with IRS-1. Thus, the binding of SH2 proteins (such as PI 3'-kinase) by YMXM motifs in IRS-1 is an important element in the mitogenic response, but other elements are essential for full mitogenic sensitivity.
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Roy, Jeane Rebecca, Coimbatore Sadagopan Janaki, Selvaraj Jayaraman, Vijayalakshmi Periyasamy, Thotakura Balaji, Madhavan Vijayamalathi, and Vishnu Priya Veeraraghavan. "Effect of Carica papaya on IRS-1/Akt Signaling Mechanisms in High-Fat-Diet–Streptozotocin-Induced Type 2 Diabetic Experimental Rats: A Mechanistic Approach." Nutrients 14, no. 19 (October 8, 2022): 4181. http://dx.doi.org/10.3390/nu14194181.
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Despite rigorous endeavors, existing attempts to handle type 2 diabetes (T2DM) are still a long way off, as a substantial number of patients do not meet therapeutic targets. Insulin resistance in skeletal muscle is discerned as a forerunner in the pathogenesis of T2DM and can be detected years before its progress. Studies have revealed the antidiabetic properties of Carica papaya (C. papaya), but its molecular mechanism on insulin receptor substrate-1 (IRS-1)/Akt signaling mechanisms is not yet known. The present study aimed to evaluate the role of C. papaya on IRS1 and Akt in high-fat-diet–streptozotocin-induced type 2 diabetic rats and also to analyze the bioactive compounds of C. papaya against IRS-1 and Akt via in silico analysis. Ethanolic extract of the leaves of C. papaya (600 mg/kg of body weight) was given daily for 45 days postinduction of T2DM up to the end of the study. Gluconeogenic enzymes, glycolytic enzymes, gene expression, and immunohistochemical analysis of IRS-1 and Akt in skeletal muscle were evaluated. C. papaya treatment regulated the levels of gluconeogenic and glycolytic enzymes and the levels of IRS-1 and Akt in skeletal muscle of type 2 diabetic animals. In silico studies showed that trans-ferulic acid had the greatest hit rate against the protein targets IRS-1 and Akt. C. papaya restored the normoglycemic effect in diabetic skeletal muscle by accelerating the expression of IRS-1 and Akt.
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Rousseau, P., C. Loot, C. Turlan, S. Nolivos, and M. Chandler. "Bias between the Left and Right Inverted Repeats during IS911 Targeted Insertion." Journal of Bacteriology 190, no. 18 (June 27, 2008): 6111–18. http://dx.doi.org/10.1128/jb.00452-08.
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ABSTRACT IS911 is a bacterial insertion sequence composed of two consecutive overlapping open reading frames (ORFs [orfA and orfB]) encoding the transposase (OrfAB) as well as a regulatory protein (OrfA). These ORFs are bordered by terminal left and right inverted repeats (IRL and IRR, respectively) with several differences in nucleotide sequence. IS911 transposition is asymmetric: each end is cleaved on one strand to generate a free 3′-OH, which is then used as the nucleophile in attacking the opposite insertion sequence (IS) end to generate a free IS circle. This will be inserted into a new target site. We show here that the ends exhibit functional differences which, in vivo, may favor the use of one compared to the other during transposition. Electromobility shift assays showed that a truncated form of the transposase [OrfAB(1-149)] exhibits higher affinity for IRR than for IRL. While there was no detectable difference in IR activities during the early steps of transposition, IRR was more efficient during the final insertion steps. We show here that the differential activities between the two IRs correlate with the different affinities of OrfAB(1-149) for the IRs during assembly of the nucleoprotein complexes leading to transposition. We conclude that the two inverted repeats are not equivalent during IS911 transposition and that this asymmetry may intervene to determine the ordered assembly of the different protein-DNA complexes involved in the reaction.
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Myers, M. G., L. M. Wang, X. J. Sun, Y. Zhang, L. Yenush, J. Schlessinger, J. H. Pierce, and M. F. White. "Role of IRS-1-GRB-2 complexes in insulin signaling." Molecular and Cellular Biology 14, no. 6 (June 1994): 3577–87. http://dx.doi.org/10.1128/mcb.14.6.3577-3587.1994.
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GRB-2 is a small SH2- and SH3 domain-containing adapter protein that associates with the mammalian SOS homolog to regulate p21ras during growth factor signaling. During insulin stimulation, GRB-2 binds to the phosphorylated Y895VNI motif of IRS-1. Substitution of Tyr-895 with phenylalanine (IRS-1F-895) prevented the IRS-1-GRB-2 association in vivo and in vitro. The myeloid progenitor cell line, 32-D, is insensitive to insulin because it contains few insulin receptors and no IRS-1. Coexpression of IRS-1 or IRS-1F-895 with the insulin receptor was required for insulin-stimulated mitogenesis in 32-D cells, while expression of the insulin receptor alone was sufficient to mediate insulin-stimulated tyrosine phosphorylation of Shc and activation of p21ras and mitogen-activated protein (MAP) kinase. The Shc-GRB-2 complex formed during insulin stimulation is a possible mediator of p21ras and MAP kinase activation in IRS-1-deficient 32-D cells. Interestingly, IRS-1, but not IRS-1F-895, enhanced the stimulation of MAP kinase by insulin in 32-D cells expressing insulin receptors. Thus, IRS-1 contributes to the stimulation of MAP kinase by insulin, probably through formation of the IRS-1-GRB-2 complex at Tyr-895. Our results suggest that the Shc-GRB-2 complex and the activation of p21ras-dependent signaling pathways, including MAP kinase, are insufficient for insulin-stimulated mitogenesis and that the essential function(s) of IRS-1 in proliferative signaling is largely unrelated to IRS-1-GRB-2 complex formation.
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Myers, M. G., L. M. Wang, X. J. Sun, Y. Zhang, L. Yenush, J. Schlessinger, J. H. Pierce, and M. F. White. "Role of IRS-1-GRB-2 complexes in insulin signaling." Molecular and Cellular Biology 14, no. 6 (June 1994): 3577–87. http://dx.doi.org/10.1128/mcb.14.6.3577.
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GRB-2 is a small SH2- and SH3 domain-containing adapter protein that associates with the mammalian SOS homolog to regulate p21ras during growth factor signaling. During insulin stimulation, GRB-2 binds to the phosphorylated Y895VNI motif of IRS-1. Substitution of Tyr-895 with phenylalanine (IRS-1F-895) prevented the IRS-1-GRB-2 association in vivo and in vitro. The myeloid progenitor cell line, 32-D, is insensitive to insulin because it contains few insulin receptors and no IRS-1. Coexpression of IRS-1 or IRS-1F-895 with the insulin receptor was required for insulin-stimulated mitogenesis in 32-D cells, while expression of the insulin receptor alone was sufficient to mediate insulin-stimulated tyrosine phosphorylation of Shc and activation of p21ras and mitogen-activated protein (MAP) kinase. The Shc-GRB-2 complex formed during insulin stimulation is a possible mediator of p21ras and MAP kinase activation in IRS-1-deficient 32-D cells. Interestingly, IRS-1, but not IRS-1F-895, enhanced the stimulation of MAP kinase by insulin in 32-D cells expressing insulin receptors. Thus, IRS-1 contributes to the stimulation of MAP kinase by insulin, probably through formation of the IRS-1-GRB-2 complex at Tyr-895. Our results suggest that the Shc-GRB-2 complex and the activation of p21ras-dependent signaling pathways, including MAP kinase, are insufficient for insulin-stimulated mitogenesis and that the essential function(s) of IRS-1 in proliferative signaling is largely unrelated to IRS-1-GRB-2 complex formation.
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Myers, Martin G., Xian Jian Sun, and Morris F. White. "The IRS-1 signaling system." Trends in Biochemical Sciences 19, no. 7 (July 1994): 289–93. http://dx.doi.org/10.1016/0968-0004(94)90007-8.
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Reiss, Krzysztof, Luis Del Valle, Adam Lassak, and Joanna Trojanek. "Nuclear IRS-1 and cancer." Journal of Cellular Physiology 227, no. 8 (April 23, 2012): 2992–3000. http://dx.doi.org/10.1002/jcp.24019.
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White, Morris F. "The IRS-1 signaling system." Current Opinion in Genetics & Development 4, no. 1 (February 1994): 47–54. http://dx.doi.org/10.1016/0959-437x(94)90090-6.
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Shirakami, A., T. Toyonaga, K. Tsuruzoe, T. Shirotani, K. Matsumoto, K. Yoshizato, J. Kawashima, et al. "Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes." Journal of Endocrinology 174, no. 2 (August 1, 2002): 309–19. http://dx.doi.org/10.1677/joe.0.1740309.
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Insulin receptor substrate 1 (IRS-1) gene polymorphisms have been identified in type 2 diabetic patients; however, it is unclear how such polymorphisms contribute to the development of diabetes. Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. GTG injection resulted in approximately 30% weight gain in IRS-1(+/-) and wild type (WT) mice, compared with saline-injected controls. There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. The islets of obese IRS-1(+/-) were 1.4-fold larger than those of obese WT. The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity.
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Lee, Adrian V., Jennifer L. Gooch, Steffi Oesterreich, Rebecca L. Guler, and Douglas Yee. "Insulin-Like Growth Factor I-Induced Degradation of Insulin Receptor Substrate 1 Is Mediated by the 26S Proteasome and Blocked by Phosphatidylinositol 3′-Kinase Inhibition." Molecular and Cellular Biology 20, no. 5 (March 1, 2000): 1489–96. http://dx.doi.org/10.1128/mcb.20.5.1489-1496.2000.
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ABSTRACT Insulin receptor substrate 1 (IRS-1) is a critical adapter protein involved in both insulin and insulin-like growth factor (IGF) signaling. Due to the fact that alteration of IRS-1 levels can affect the sensitivity and response to both insulin and IGF-I, we examined the ability of each of these ligands to affect IRS-1 expression. IGF-I (10 nM) stimulation of MCF-7 breast cancer cells caused a transient tyrosine phosphorylation of IRS-1 that was maximal at 15 min and decreased thereafter. The decrease in tyrosine phosphorylation of IRS-1 was paralleled by an apparent decrease in IRS-1 levels. The IGF-mediated decrease in IRS-1 expression was posttranscriptional and due to a decrease in the half-life of the IRS-1 protein. Insulin (10 nM) caused tyrosine phosphorylation of IRS-1 but not degradation, whereas high concentrations of insulin (10 μM) resulted in degradation of IRS-1. IGF-I (10 nM) stimulation resulted in transient IRS-1 phosphorylation and extracellular signal-related kinase (ERK) activation. In contrast, insulin (10 nM) caused sustained IRS-1 phosphorylation and ERK activation. Inhibition of 26S proteasome activity by the use of lactacystin or MG132 completely blocked IGF-mediated degradation of IRS-1. Furthermore, coimmunoprecipitation experiments showed an association between ubiquitin and IRS-1 that was increased by treatment of cells with IGF-I. Finally, IGF-mediated degradation of IRS-1 was blocked by inhibition of phosphatidylinositol 3′-kinase activity but was not affected by inhibition of ERK, suggesting that this may represent a direct negative-feedback mechanism resulting from downstream IRS-1 signaling. We conclude that IGF-I can cause ligand-mediated degradation of IRS-1 via the ubiquitin-mediated 26S proteasome and a phosphatidylinositol 3′-kinase-dependent mechanism and that control of degradation may have profound effects on downstream activation of signaling pathways.
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Kriauciunas, Kristina M., Martin G. Myers, and C. Ronald Kahn. "Cellular Compartmentalization in Insulin Action: Altered Signaling by a Lipid-Modified IRS-1." Molecular and Cellular Biology 20, no. 18 (September 15, 2000): 6849–59. http://dx.doi.org/10.1128/mcb.20.18.6849-6859.2000.
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ABSTRACT While most receptor tyrosine kinases signal by recruiting SH2 proteins directly to phosphorylation sites on their plasma membrane receptor, the insulin receptor phosphorylates intermediary IRS proteins that are distributed between the cytoplasm and a state of loose association with intracellular membranes. To determine the importance of this distribution to IRS-1-mediated signaling, we constructed a prenylated, constitutively membrane-bound IRS-1 by adding the COOH-terminal 9 amino acids from p21 ras , including the CAAX motif, to IRS-1 (IRS-CAAX) and analyzed its function in 32D cells expressing the insulin receptor. IRS-CAAX migrated more slowly on sodium dodecyl sulfate-polyacrylamide gel electrophoresis than did IRS-1 and demonstrated increased levels of serine/threonine phosphorylation. Insulin-stimulated tyrosyl phosphorylation of IRS-CAAX was slightly decreased, while IRS-CAAX-mediated phosphatidylinositol 3′-kinase (PI3′-kinase) binding and activation were decreased by approximately 75% compared to those for wild-type IRS-1. Similarly, expression of IRS-CAAX desensitized insulin-stimulated [3H]thymidine incorporation into DNA by about an order of magnitude compared to IRS-1. By contrast, IRS-CAAX-expressing cells demonstrated increased signaling by mitogen-activated protein kinase, Akt, and p70S6 kinase in response to insulin. Hence, tight association with the membrane increased IRS-1 serine phosphorylation and reduced coupling between the insulin receptor, PI3′-kinase, and proliferative signaling while enhancing other signaling pathways. Thus, the correct distribution of IRS-1 between the cytoplasm and membrane compartments is critical to the normal balance in the network of insulin signaling.
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Hitomi, Hirofumi, Puja K. Mehta, Yoshihiro Taniyama, Bernard Lassègue, Bonnie Seidel-Rogol, Alejandra San Martin, and Kathy K. Griendling. "Vascular smooth muscle insulin resistance, but not hypertrophic signaling, is independent of angiotensin II-induced IRS-1 phosphorylation by JNK." American Journal of Physiology-Cell Physiology 301, no. 6 (December 2011): C1415—C1422. http://dx.doi.org/10.1152/ajpcell.00017.2011.
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Angiotensin II (ANG II) has been implicated in the pathogenesis of diabetic micro- and macrovascular disease. In vascular smooth muscle cells (VSMCs), ANG II phosphorylates and degrades insulin receptor substrate-1 (IRS-1). While the pathway responsible for IRS-1 degradation in this system is unknown, c-Jun NH2-terminal kinase (JNK) has been linked with serine phosphorylation of IRS-1 and insulin resistance. We investigated the role of JNK in ANG II-induced IRS-1 phosphorylation, degradation, Akt activation, glucose uptake, and hypertrophic signaling, focusing on three IRS-1 phosphorylation sites: Ser302, Ser307, and Ser632. Maximal IRS-1 phosphorylation on Ser632 occurred at 5 min, on Ser307 at 30 min, and on Ser302 at 60 min. The JNK inhibitor SP600125 reduced ANG II-induced IRS-1 Ser307 phosphorylation (by 80%), IRS-1 Ser302 phosphorylation (by 70%), and IRS-1 Ser632 phosphorylation (by 50%). However, JNK inhibition had no effect on ANG II-mediated IRS-1 degradation, nor did it reverse the ANG II-induced decrease in Akt phosphorylation or glucose uptake. Transfection of VSMCs with mutants S307A, S302A, or S632A of IRS-1 did not block ANG II-mediated IRS-1 degradation. In contrast, JNK inhibition attenuated insulin-induced upregulation of collagen and smooth muscle α-actin in ANG II-pretreated cells. We conclude that phosphorylation of Ser307, Ser302, and Ser632 of IRS-1 is not involved in ANG II-mediated IRS-1 degradation, and that JNK alone does not mediate ANG II-stimulated IRS-1 degradation, but rather is responsible for the hypertrophic effects of insulin on smooth muscle.
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Trinidad, Miguel Angel. "High-velocity Wind from IRS 1 in the NGC 2071IR." Proceedings of the International Astronomical Union 10, S305 (December 2014): 301–4. http://dx.doi.org/10.1017/s1743921315004949.
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AbstractWe present the results of 1.3 and 3.6 cm radio continuum emission toward the NGC 2071IR star-forming region, carried out with the VLA in its A configuration. We detect continuum emission toward the infrared sources IRS 1 and IRS 3 at both wavelengths. In particular, IRS 1 breaks up into three continuum peaks (IRS 1E, 1C, and 1W), aligned in the east-west direction, being IRS 1 the central source. The morphology of the condensation IRS 1W is very interesting, which has an elongated structure and shows a significant curvature towards the north. We suggest that this morphology could be explained as the impact of a high-velocity wind or jetlike outflow from IRS 1 on a close companion or other obstruction, which also explains the strong water maser emission observed toward IRS 1W.
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Simmons, J. G., Y. Ling, H. Wilkins, C. R. Fuller, A. J. D'Ercole, James Fagin, and P. K. Lund. "Cell-specific effects of insulin receptor substrate-1 deficiency on normal and IGF-I-mediated colon growth." American Journal of Physiology-Gastrointestinal and Liver Physiology 293, no. 5 (November 2007): G995—G1003. http://dx.doi.org/10.1152/ajpgi.00537.2006.
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Insulin-like growth factor I (IGF-I) potently stimulates intestinal growth. Insulin receptor substrate-1 (IRS-1) mediates proliferative and antiapoptotic actions of IGF-I in cell lines, but its in vivo relevance in intestine is not defined. This study tested the hypothesis that there is cell type-specific dependence on IRS-1 as a mediator of IGF-I action. Length, mass, crypt cell proliferation, and apoptosis were measured in small intestine and colon of IRS-1-null mice and wild-type (WT) littermates and in colon of IRS-1-null or WT mice expressing IGF-I transgenes. Expression of IGF-I receptor and signaling intermediates was examined in intestine of WT and IRS-1-null mice, cultured intestinal epithelial cells, and myofibroblasts. Absolute IRS-1 deficiency reduced mucosal mass in jejunum and colon, but effects were more pronounced in colon. Muscularis mass was decreased in both segments. In IGF-I transgenics, IRS-1 deficiency significantly attenuated IGF-I-stimulated growth of colonic mucosa and abolished antiapoptotic but not mitogenic effects of IGF-I transgene on crypt cells. IGF-I-induced muscularis growth was unaffected by IRS-1 deficiency. In intestinal epithelial cells, IRS-1 was expressed at higher levels than IRS-2 and was preferentially activated by IGF-I. In contrast, IGF-I activated both IRS-1 and IRS-2 in intestinal myofibroblasts and IRS-2 activation was upregulated in IRS-1-null myofibroblasts. We conclude that the intestinal epithelium but not the muscularis requires IRS-1 for normal trophic actions of IGF-I and that IRS-1 is required for antiapoptotic but not mitogenic effects of IGF-I in the intestinal crypts in vivo.
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GREENE, Michael W., Nick MORRICE, Robert S. GAROFALO, and Richard A. ROTH. "Modulation of human insulin receptor substrate-1 tyrosine phosphorylation by protein kinase Cdelta." Biochemical Journal 378, no. 1 (February 15, 2004): 105–16. http://dx.doi.org/10.1042/bj20031493.
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Non-esterified fatty acid (free fatty acid)-induced activation of the novel PKC (protein kinase C) isoenzymes PKCδ and PKCθ correlates with insulin resistance, including decreased insulin-stimulated IRS-1 (insulin receptor substrate-1) tyrosine phosphorylation and phosphoinositide 3-kinase activation, although the mechanism(s) for this resistance is not known. In the present study, we have explored the possibility of a novel PKC, PKCδ, to modulate directly the ability of the insulin receptor kinase to tyrosine-phosphorylate IRS-1. We have found that expression of either constitutively active PKCδ or wild-type PKCδ followed by phorbol ester activation both inhibit insulin-stimulated IRS-1 tyrosine phosphorylation in vivo. Activated PKCδ was also found to inhibit the IRS-1 tyrosine phosphorylation in vitro by purified insulin receptor using recombinant full-length human IRS-1 and a partial IRS-1–glutathione S-transferase-fusion protein as substrates. This inhibition in vitro was not observed with a non-IRS-1 substrate, indicating that it was not the result of a general decrease in the intrinsic kinase activity of the receptor. Consistent with the hypothesis that PKCδ acts directly on IRS-1, we show that IRS-1 can be phosphorylated by PKCδ on at least 18 sites. The importance of three of the PKCδ phosphorylation sites in IRS-1 was shown in vitro by a 75–80% decrease in the incorporation of phosphate into an IRS-1 triple mutant in which Ser-307, Ser-323 and Ser-574 were replaced by Ala. More importantly, the mutation of these three sites completely abrogated the inhibitory effect of PKCδ on IRS-1 tyrosine phosphorylation in vitro. These results indicate that PKCδ modulates the ability of the insulin receptor to tyrosine-phosphorylate IRS-1 by direct phosphorylation of the IRS-1 molecule.
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Lee, Sihoon, Edward G. Lynn, Jeong-a. Kim, and Michael J. Quon. "Protein Kinase C-ζ Phosphorylates Insulin Receptor Substrate-1, -3, and -4 But Not -2: Isoform Specific Determinants of Specificity in Insulin Signaling." Endocrinology 149, no. 5 (January 17, 2008): 2451–58. http://dx.doi.org/10.1210/en.2007-1595.
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Protein kinase C-ζ, a downstream effector of phosphatidylinositol 3-kinase (PI3K), phosphorylates insulin receptor substrate (IRS)-1 on serine residues impairing activation of PI3K in response to insulin. Because IRS-1 is upstream from PI3K, this represents a negative feedback mechanism that may contribute to signal specificity in insulin action. To determine whether similar feedback pathways exist for other IRS isoforms, we evaluated IRS-2, -3, and -4 as substrates for PKC-ζ. In an in vitro kinase assay, purified recombinant PKC-ζ phosphorylated IRS-1, -3 and -4 but not IRS-2. Similar results were obtained with an immune-complex kinase assay demonstrating that wild-type, but not kinase-deficient mutant PKC-ζ, phosphorylated IRS-1, -3, and -4 but not IRS-2. We evaluated functional consequences of serine phosphorylation of IRS isoforms by PKC-ζ in NIH-3T3IR cells cotransfected with epitope-tagged IRS proteins and either PKC-ζ or empty vector control. Insulin-stimulated IRS tyrosine phosphorylation was impaired by overepxression of PKC-ζ for IRS-1, -3, and -4 but not IRS-2. Significant insulin-stimulated increases in PI3K activity was coimmunoprecipitated with all IRS isoforms. In cells overexpressing PKC-ζ there was marked inhibition of insulin-stimulated PI3K activity associated with IRS-1, -3 and -4 but not IRS-2. That is, PI3K activity associated with IRS-2 in response to insulin was similar in control cells and cells overexpressing PKC-ζ. We conclude that IRS-3 and -4 are novel substrates for PKC-ζ that may participate in a negative feedback pathway for insulin signaling similar to IRS-1. The inability of PKC-ζ to phosphorylate IRS-2 may help determine specific functional roles for IRS-2.
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Yamauchi, T., K. Tobe, H. Tamemoto, K. Ueki, Y. Kaburagi, R. Yamamoto-Honda, Y. Takahashi, et al. "Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice." Molecular and Cellular Biology 16, no. 6 (June 1996): 3074–84. http://dx.doi.org/10.1128/mcb.16.6.3074.
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We and others recently generated mice with a targeted disruption of the insulin receptor substrate 1 (IRS-1) gene and demonstrated that they exhibited growth retardation and had resistance to the glucose-lowering effect of insulin. Insulin initiates its biological effects by activating at least two major signalling pathways, one involving phosphatidylinositol 3-kinase (PI3-kinase) and the other involving a ras/mitogen-activated protein kinase (MAP kinase) cascade. In this study, we investigated the roles of IRS-1 and IRS-2 in the biological action in the physiological target organs of insulin by comparing the effects of insulin in wild-type and IRS-1-deficient mice. In muscles from IRS-1-deficient mice, the responses to insulin-induced PI3-kinase activation, glucose transport, p70 S6 kinase and MAP kinase activation, mRNA translation, and protein synthesis were significantly impaired compared with those in wild-type mice. Insulin-induced protein synthesis was both wortmannin sensitive and insensitive in wild-type and IRS-1 deficient mice. However, in another target organ, the liver, the responses to insulin-induced PI3-kinase and MAP kinase activation were not significantly reduced. The amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) was roughly equal to that of IRS-1 (in wild-type mice) in the liver, whereas it only 20 to 30% of that of IRS-1 in the muscles. In conclusion, (i) IRS-1 plays central roles in two major biological actions of insulin in muscles, glucose transport and protein synthesis; (ii) the insulin resistance of IRS-1-deficient mice is mainly due to resistance in the muscles; and (iii) the degree of compensation for IRS-1 deficiency appears to be correlated with the amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) relative to that of IRS-1 (in wild-type mice).
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Metz, Heather E., Julia Kargl, Stephanie E. Busch, Kyoung-Hee Kim, Brenda F. Kurland, Shira R. Abberbock, Julie Randolph-Habecker, et al. "Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma." Proceedings of the National Academy of Sciences 113, no. 31 (July 20, 2016): 8795–800. http://dx.doi.org/10.1073/pnas.1601989113.
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Insulin receptor substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many pathways activated in lung cancer. It has been assumed that IRS-1 promotes tumor growth through its ability to activate PI3K signaling downstream of the insulin-like growth factor receptor. Surprisingly, tumors with reduced IRS-1 staining in a human lung adenocarcinoma tissue microarray displayed a significant survival disadvantage, especially within the Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant subgroup. Accordingly, adenoviral Cre recombinase (AdCre)-treated LSL-Kras/Irs-1fl/fl (Kras/Irs-1−/−) mice displayed increased tumor burden and mortality compared with controls. Mechanistically, IRS-1 deficiency promotes Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling via the IL-22 receptor, resulting in enhanced tumor-promoting inflammation. Treatment of Kras/Irs-1+/+ and Kras/Irs-1−/− mice with JAK inhibitors significantly reduced tumor burden, most notably in the IRS-1-deficient group.
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Uchida, Tohru, Martin G. Myers, and Morris F. White. "IRS-4 Mediates Protein Kinase B Signaling during Insulin Stimulation without Promoting Antiapoptosis." Molecular and Cellular Biology 20, no. 1 (January 1, 2000): 126–38. http://dx.doi.org/10.1128/mcb.20.1.126-138.2000.
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ABSTRACT Insulin receptor substrate (IRS) proteins are tyrosine phosphorylated and mediate multiple signals during activation of the receptors for insulin, insulin-like growth factor 1 (IGF-1), and various cytokines. In order to distinguish common and unique functions of IRS-1, IRS-2, and IRS-4, we expressed them individually in 32D myeloid progenitor cells containing the human insulin receptor (32DIR). Insulin promoted the association of Grb-2 with IRS-1 and IRS-4, whereas IRS-2 weakly bound Grb-2; consequently, IRS-1 and IRS-4 enhanced insulin-stimulated mitogen-activated protein kinase activity. During insulin stimulation, IRS-1 and IRS-2 strongly bound p85α/β, which activated phosphatidylinositol (PI) 3-kinase, protein kinase B (PKB)/Akt, and p70s6k, and promoted the phosphorylation of BAD. IRS-4 also promoted the activation of PKB/Akt and BAD phosphorylation during insulin stimulation; however, it weakly bound or activated p85-associated PI 3-kinase and failed to mediate the activation of p70s6k. Insulin strongly inhibited apoptosis of interleukin-3 (IL-3)-deprived 32DIR cells expressing IRS-1 or IRS-2 but failed to inhibit apoptosis of cells expressing IRS-4. Consequently, 32DIR cells expressing IRS-4 proliferated slowly during insulin stimulation. Thus, the activation of PKB/Akt and BAD phosphorylation might not be sufficient to inhibit the apoptosis of IL-3-deprived 32DIR cells unless p85-associated PI 3-kinase or p70s6k are strongly activated.
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YAMAUCHI, TOSHIMASA, HIDEHARU NISHIMAKI, AKIHIRO FURUSAKA, TERUJI TANAKA, SHIN-ICHI HAYASHI, HIROYUKI TAMEMOTO, SIMEON TAYLAR, KAZUYUKI TOBE, TAKASHI KADOWAKI, and MASAKI NISHIYAMA. "Anti-IRS-1 Monoclonal Antibody, 6G5, Cross-reacts to IRS-2." Hybridoma 15, no. 4 (August 1996): 307–9. http://dx.doi.org/10.1089/hyb.1996.15.307.
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Xiang, Xiaoqin, Mingsheng Yuan, Ying Song, Neil Ruderman, Rong Wen, and Zhijun Luo. "14-3-3 Facilitates Insulin-Stimulated Intracellular Trafficking of Insulin Receptor Substrate 1." Molecular Endocrinology 16, no. 3 (March 1, 2002): 552–62. http://dx.doi.org/10.1210/mend.16.3.0790.
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Abstract The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. These findings strongly suggest that 14-3-3 participates in the intracellular trafficking of IRS-1 by promoting the displacement of serine-phosphorylated IRS-1 from particular structures. They also suggest that 14-3-3 proteins could play an integral role in the process of insulin desensitization.
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TU, Yizeng, Liang LIANG, Stuart J. FRANK, and Chuanyue WU. "Src homology 3 domain-dependent interaction of Nck-2 with insulin receptor substrate-1." Biochemical Journal 354, no. 2 (February 22, 2001): 315–22. http://dx.doi.org/10.1042/bj3540315.
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Insulin receptor substrate-1 (IRS-1) is a multi-domain protein that mediates signal transduction from receptors for insulin and other growth factors to a variety of downstream molecules through both tyrosine-phosphorylation-dependent and -independent interactions. While the tyrosine-phosphorylation-dependent interactions mediated by IRS-1 have been well characterized, the molecular basis underlying the tyrosine-phosphorylation-independent IRS-1 interactions is largely unknown. We previously detected, in an in vitro binding assay, interactions of Nck-2 Src homology (SH) 3 domains with IRS-1. We show here that IRS-1 associates with Nck-2 in vivo. Additionally, we have investigated the molecular basis underlying the IRS-1–Nck-2 complex formation. We have found that (i) mutations at the highly conserved tryptophan within the Nck-2 SH3 domains markedly reduced the association with IRS-1, (ii) interactions mediated by multiple SH3 domains enhance the complex formation of Nck-2 with IRS-1, (iii) deletion of either the phosphotyrosine-binding/Shc and IRS-1 NPXY-binding (PTB/SAIN) domains or the Pre-C-terminal domain of IRS-1, but not the pleckstrin homology (PH) domain, reduced the Nck-2 binding, (iv) PTB/SAIN domains or the Pre-C-terminal domain alone is capable of interacting with Nck-2, and (v) the IRS-1–Nck-2 interaction occurs in the absence of other proteins and therefore is direct. These results establish that IRS-1 is a bona fide target of the Nck-2 SH3 domains and reveal that IRS-1 forms a complex with Nck-2 via direct interactions mediated by multiple domains from both binding partners.
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Fasshauer, Mathias, Johannes Klein, Kristina M. Kriauciunas, Kohjiro Ueki, Manuel Benito, and C. Ronald Kahn. "Essential Role of Insulin Receptor Substrate 1 in Differentiation of Brown Adipocytes." Molecular and Cellular Biology 21, no. 1 (January 1, 2001): 319–29. http://dx.doi.org/10.1128/mcb.21.1.319-329.2001.
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ABSTRACT The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. These proteins participate in insulin and insulin-like growth factor 1 signaling, as well as the actions of some cytokines, growth hormone, and prolactin. To more precisely define the specific role of IRS-1 in adipocyte biology, we established brown adipocyte cell lines from wild-type and IRS-1 knockout (KO) animals. Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and lipid accumulation (10 to 40%) compared to wild-type cells (90 to 100%). Furthermore, IRS-1 KO cells showed decreased expression of adipogenic marker proteins, such as peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), fatty acid synthase, uncoupling protein-1, and glucose transporter 4. The differentiation deficit in the KO cells could be reversed almost completely by retrovirus-mediated reexpression of IRS-1, PPARγ, or C/EBPα but not the thiazolidinedione troglitazone. Phosphatidylinositol 3-kinase (PI 3-kinase) assays performed at various stages of the differentiation process revealed a strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associated PI 3-kinase in the wild-type cells, whereas the IRS-1 KO cells showed impaired phosphotyrosine-associated PI 3-kinase activation, all of which was associated with IRS-2. Akt phosphorylation was reduced in parallel with the total PI 3-kinase activity. Inhibition of PI 3-kinase with LY294002 blocked differentiation of wild-type cells. Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. Furthermore, this signaling molecule appears to exert its unique role in the differentiation process via activation of PI 3-kinase and its downstream target, Akt, and is upstream of the effects of PPARγ and C/EBPα.
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Chen, D., D. J. Van Horn, M. F. White, and J. M. Backer. "Insulin receptor substrate 1 rescues insulin action in CHO cells expressing mutant insulin receptors that lack a juxtamembrane NPXY motif." Molecular and Cellular Biology 15, no. 9 (September 1995): 4711–17. http://dx.doi.org/10.1128/mcb.15.9.4711.
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Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (IRS-1) and Shc by the activated insulin receptor (IR). Phosphorylation of both proteins is nearly abolished by an alanine substitution at Tyr-960 (A960) in the beta-subunit of the receptor. However, overexpression of IRS-1 in CHO cells expressing the mutant receptor (A960 cells) restored sufficient tyrosine phosphorylation of IRS-1 to rescue IRS-1/Grb-2 binding and phosphatidylinositol 3' kinase activation during insulin stimulation. Shc tyrosine phosphorylation and its binding to Grb-2 were impaired in the A960 cells and were unaffected by overexpression of IRS-1. Although overexpression of IRS-1 increased IRS-1 binding to Grb-2, ERK-1/ERK-2 activation was not rescued. These data suggest that signaling molecules other than IRS-1, perhaps including Shc, are critical for insulin stimulation of p21ras. Interestingly, overexpression of IRS-1 in the A960 cells restored insulin-stimulated mitogenesis and partially restored insulin stimulation of glycogen synthesis. Thus, IRS-1 tyrosine phosphorylation is sufficient to increase the mitogenic response to insulin, whereas insulin stimulation of glycogen synthesis appears to involve other factors. Moreover, IRS-1 phosphorylation is either not sufficient or not involved in insulin stimulation of ERK.
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Liu, Yan-Fang, Avia Herschkovitz, Sigalit Boura-Halfon, Denise Ronen, Keren Paz, Derek LeRoith, and Yehiel Zick. "Serine Phosphorylation Proximal to Its Phosphotyrosine Binding Domain Inhibits Insulin Receptor Substrate 1 Function and Promotes Insulin Resistance." Molecular and Cellular Biology 24, no. 21 (November 1, 2004): 9668–81. http://dx.doi.org/10.1128/mcb.24.21.9668-9681.2004.
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ABSTRACT Ser/Thr phosphorylation of insulin receptor substrate (IRS) proteins negatively modulates insulin signaling. Therefore, the identification of serine sites whose phosphorylation inhibit IRS protein functions is of physiological importance. Here we mutated seven Ser sites located proximal to the phosphotyrosine binding domain of insulin receptor substrate 1 (IRS-1) (S265, S302, S325, S336, S358, S407, and S408) into Ala. When overexpressed in rat hepatoma Fao or CHO cells, the mutated IRS-1 protein in which the seven Ser sites were mutated to Ala (IRS-17A), unlike wild-type IRS-1 (IRS-1WT), maintained its Tyr-phosphorylated active conformation after prolonged insulin treatment or when the cells were challenged with inducers of insulin resistance prior to acute insulin treatment. This was due to the ability of IRS-17A to remain complexed with the insulin receptor (IR), unlike IRS-1WT, which underwent Ser phosphorylation, resulting in its dissociation from IR. Studies of truncated forms of IRS-1 revealed that the region between amino acids 365 to 430 is a main insulin-stimulated Ser phosphorylation domain. Indeed, IRS-1 mutated only at S408, which undergoes phosphorylation in vivo, partially maintained the properties of IRS-17A and conferred protection against selected inducers of insulin resistance. These findings suggest that S408 and additional Ser sites among the seven mutated Ser sites are targets for IRS-1 kinases that play a key negative regulatory role in IRS-1 function and insulin action. These sites presumably serve as points of convergence, where physiological feedback control mechanisms, which are triggered by insulin-stimulated IRS kinases, overlap with IRS kinases triggered by inducers of insulin resistance to terminate insulin signaling.