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Morris F. White - One of the best experts on this subject based on the ideXlab platform.

  • Insulin Receptor Substrate 1 deficiency drives a proinflammatory phenotype in kras mutant lung adenocarcinoma
    Proceedings of the National Academy of Sciences of the United States of America, 2016
    Co-Authors: Heather E Metz, Julia Kargl, Stephanie E Busch, Kyounghee Kim, Brenda F Kurland, Shira Abberbock, Julie Randolphhabecker, Sue E Knoblaugh, Jay K Kolls, Morris F. White
    Abstract:

    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-1(fl/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.

  • Alterations in growth and apoptosis of Insulin Receptor Substrate-1-deficient β-cells
    American Journal of Physiology-endocrinology and Metabolism, 2005
    Co-Authors: Anita M Hennige, Morris F. White, Umut Ozcan, Terumasa Okada, Ulupi S. Jhala, Markus Schubert, Rohit N. Kulkarni
    Abstract:

    Insulin and IGF-I activate antiapoptotic pathways via Insulin Receptor Substrate (IRS) proteins in most mammalian cells, including β-cells. IRS-1 knockout (IRS-1KO) mice show growth retardation, hy...

  • dysregulation of Insulin Receptor Substrate 2 in β cells and brain causes obesity and diabetes
    Journal of Clinical Investigation, 2004
    Co-Authors: Xueying Lin, Jake A Kushner, Sunmin Park, Akiko Taguchi, Morris F. White
    Abstract:

    The molecular link between obesity and β cell failure that causes diabetes is difficult to establish. Here we show that a conditional knockout of Insulin Receptor Substrate 2 (Irs2) in mouse pancreas β cells and parts of the brain — including the hypothalamus —increased appetite, lean and fat body mass, linear growth, and Insulin resistance that progressed to diabetes. Diabetes resolved when the mice were between 6 and 10 months of age: functional β cells expressing Irs2 repopulated the pancreas, restoring sufficient β cell function to compensate for Insulin resistance in the obese mice. Thus, Irs2 signaling promotes regeneration of adult β cells and central control of nutrient homeostasis, which can prevent obesity and diabetes in mice.

  • Insulin Receptor Substrate proteins and diabetes
    Archives of Pharmacal Research, 2004
    Co-Authors: Morris F. White
    Abstract:

    The discovery of Insulin Receptor Substrate (IRS) proteins and their role to link cell surface Receptors to the intracellular signaling cascades is a key step to understanding Insulin and Insulin-like growth factor (IGF) action. Moreover, IRS-proteins coordinate signals from the Insulin and IGF Receptor tyrosine kinases with those generated by proinflammatory cytokines and nutrients. The IRS2-branch of the Insulin/IGF signaling cascade has an important role in both peripheral Insulin response and pancreatic β-cell growth and function. Dysregulation of IRS2 signaling in mice causes the failure of compensatory hyperInsulinemia during peripheral Insulin resistance. IRS protein signaling is down regulated by serine phosphorylation or protea-some-mediated degradation, which might be an important mechanism of Insulin resistance during acute injury and infection, or chronic stress associated with aging or obesity. Understanding the regulation and signaling by IRS1 and IRS2 in cell growth, metabolism and survival will reveal new strategies to prevent or cure diabetes and other metabolic diseases.

  • Interferon-α Engages the Insulin Receptor Substrate-1 to Associate with the Phosphatidylinositol 3′-Kinase
    Journal of Biological Chemistry, 1995
    Co-Authors: Shahab Uddin, Lynne Yenush, Michelle E. Sweet, Morris F. White, Leonidas C Platanias
    Abstract:

    Abstract Interferon-α (IFNα) induces rapid tyrosine phosphorylation of the Insulin Receptor Substrate-1 (IRS-1), a docking protein with multiple tyrosine phosphorylation sites that bind to the Src homology 2 (SH2) domains of various signaling proteins. During IFNα stimulation, the p85 regulatory subunit of the phosphatidylinositol 3′-kinase binds via its SH2 domains to tyrosine-phosphorylated IRS-1, and phosphatidylinositol 3′-kinase activity is detected in association with IRS-1. Thus, IFNα responses occur by activation of the IRS signaling system, which it shares with Insulin, Insulin-like growth factor-1, and interleukin-4.

Hagit Eldar-finkelman - One of the best experts on this subject based on the ideXlab platform.

Gustav E. Lienhard - One of the best experts on this subject based on the ideXlab platform.

  • Association of Insulin Receptor Substrate 3 with SH2 domain-containing proteins in rat adipocytes.
    Biochemical and biophysical research communications, 1998
    Co-Authors: Stuart A. Ross, Gustav E. Lienhard, Brian E. Lavan
    Abstract:

    Abstract We have recently purified and cloned a new member of the Insulin Receptor Substrate family, designated Insulin Receptor Substrate 3 (IRS-3), from rat adipocytes. The amino acid sequence of IRS-3 shows multiple potential sites for tyrosine phosphorylation in motifs which engage specific SH2 domain-containing proteins. In order to determine which SH2 domain proteins complex with IRS-3, we have searched for coimmunoprecipitation from lysates of untreated and Insulin-stimulated adipocytes. Phosphatidylinositol 3-kinase and the tyrosine phosphatase SHP-2 complexed with the tyrosine phosphorylated form of IRS-3, whereas the phospholipase Cγ did not, and the adaptor Grb2 did so to a much lesser extent. These findings complete the survey of SH2 domain proteins associated with each of the four known members of the IRS family and provide the framework for further analysis of the role of IRS-3 in Insulin signaling.

  • Transforming potential of the Insulin Receptor Substrate 1.
    Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 1995
    Co-Authors: C D'ambrosio, Andrea Morrione, Renato Baserga, Gustav E. Lienhard, Keller, Eva Surmacz
    Abstract:

    Abstrad The role of the Insulin Receptor Substrate 1 (IRS-i) in cellular transformation was studied in R- cells, which are 3T3-like fibroblasts derived from mouse embryos with a targeted disruption of the Insulin-like growth fador I Receptor gene. These cells cannot be transformed by oncogenes that readily transform cells originating from wild-type littermate embryos (or other 3T3-Iike cells). In the present study, we demonstrate that in R- cells, the overexpression of the fundional IRS-i protein was sufficient to induce a mitogenic response to Insulin but did not promote transformation, as measured by colony formation in soft agar. The coexpression of IRS-i and the SV4O T antigen, however, induced transformation. Conversely, expression of an antisense IRS-i RNA reversed the transformed phenotype in wildtype cells carrying the T antigen. Since the type 1 Insulin-like growth fador Receptor, by itself, is fully transforming, we propose the hypothesis that the transforming competence of this Receptor is based on at least two signaling pathways, one of which is IRS-i dependent, whereas the other(s) can be substituted with the 5V40 T antigen.

  • Insulin signalling: the role of Insulin Receptor Substrate 1.
    Trends in cell biology, 1994
    Co-Authors: Susanne R. Keller, Gustav E. Lienhard
    Abstract:

    The Insulin Receptor is a ligand-activated tyrosine kinase that phosphorylates its major Substrate protein, Insulin Receptor Substrate 1 (IRS1), at multiple sites. Tyrosine-phosphorylated IRS1 then serves as a docking/effector protein for at least four Src homology 2 (SH2)-domain proteins involved in signal transduction. This initial step in signalling distinguishes the Insulin Receptor from other Receptor tyrosine kinases, which directly bind several SH2-domain proteins, and establishes IRS1 as a founding member of a group of proteins whose function is to link activated tyrosine kinases to SH2-domain proteins.

  • the Insulin Receptor Substrate 1 associates with the sh2 containing phosphotyrosine phosphatase syp
    Journal of Biological Chemistry, 1993
    Co-Authors: Michelle R Kuhne, Gustav E. Lienhard, T Pawson, Gensheng Feng
    Abstract:

    The Insulin Receptor Substrate 1 (IRS1) is a protein that is rapidly phosphorylated on tyrosine by the activated Insulin Receptor. Syp is a recently discovered, broadly expressed phosphotyrosine (Tyr(P)) phosphatase that contains two Src homology 2 (SH2) domains. We have found that Insulin treatment of 3T3-L1 adipocytes leads to complex formation between IRS1 and Syp. Syp was detected in immunoadsorbates of IRS1 from extracts of Insulin-treated but not basal cells by both immunoblotting and Tyr(P) phosphatase activity. The association of Syp with IRS1 apparently occurs between the SH2 domains of Syp and Tyr(P)-containing sequences of IRS1, since a fusion protein containing only the SH2 domains of Syp bound the Tyr(P) form of IRS1. Unlike the Receptors for epidermal and platelet-derived growth factors, which in their activated state bind to the SH2 domains of Syp and elicit phosphorylation of Syp on tyrosine in intact cells, the Tyr(P) form of the Insulin Receptor did not bind to the SH2 domains of Syp, and no phosphorylation of Syp on tyrosine was detected in Insulin-treated 3T3-L1 adipocytes. In combination with other findings these results indicate that IRS1 functions as a docking protein for SH2 domain-containing proteins participating in signaling from the Insulin Receptor.

  • The Insulin-elicited 160 kDa phosphotyrosine protein in mouse adipocytes is an Insulin Receptor Substrate 1: Identification by cloning
    Biochimica et biophysica acta, 1993
    Co-Authors: Susanne R. Keller, Ruedi Aebersold, Charles W. Garner, Gustav E. Lienhard
    Abstract:

    Abstract Insulin elicits the tyrosine phosphorylation of one or more proteins of 160–185 kDa in many cell types. Peptide sequences, obtained from this protein purified from mouse 3T3-L1 adipocytes (pp160), were used as the basis for cloning its cDNA. pp160 is highly homologous to the Insulin Receptor Substrate 1, previously cloned from rat liver. Thus, this component of the Insulin signaling pathway is the same in adipocytes and in liver.

Renato Baserga - One of the best experts on this subject based on the ideXlab platform.

  • Growth inhibition by microRNAs that target the Insulin Receptor Substrate-1
    Cell cycle (Georgetown Tex.), 2009
    Co-Authors: Gaspare La Rocca, Bin Shi, Margherita Badin, Tiziana De Angelis, Laura Sepp-lorenzino, Renato Baserga
    Abstract:

    We have examined several microRNAs (miRs) indicated by the databases as targeting the signaling pathway of the type-1 Insulin-like growth factor Receptor (IGF-IR). Most of the miRs tested had multiple targets, as expected, leading to cell death. However, miR145 seemed to affect its tumor suppressor activity largely by downregulating the docking protein of the IGF-IR, the Insulin Receptor Substrate-1 (IRS-1). These results suggest that, despite the many targets provided by the databases, in some cases a single target can be predominant in determining the end results.

  • The role of Insulin Receptor Substrate-1 in the oncogenicity of simian virus 40 T antigen.
    Cell cycle (Georgetown Tex.), 2008
    Co-Authors: Jia Chen, Renato Baserga
    Abstract:

    The Simian Virus 40 large T antigen (Tag) and the Insulin Receptor Substrate-1 (IRS-1) interact with each other. Tag is a nuclear protein even in the absence of IRS-1, but IRS-1 is required for occupancy and activation by Tag of the ribosomal DNA (rDNA), cyclin D1 and c-myc promoters. Our results indicate that IRS-1 plays a significant role in Tag activation of cell cycle progression genes.

  • The role of Insulin Receptor Substrate-1 in transformation by v-src.
    Journal of cellular physiology, 2008
    Co-Authors: Hongzhi Sun, Renato Baserga
    Abstract:

    The Insulin Receptor Substrate-1 (IRS-1), a docking protein for both the Insulin (InR) and the Insulin-like growth factor-1 (IGF-IR) Receptors, sends a mitogenic, anti-differentiation and transforming signal. We now show that down-regulation of IRS-1 in cells transformed by v-src reverses the transformed phenotype (growth in serum-free medium and colony formation in soft agar). IRS-1 translocates to nuclei and is found in the cyclin D1 and rDNA promoters. Stat3, which is activated by src, requires both IRS-1 and src for promoter occupancy. IRS-1 (by itself or in combination with src) also markedly increases transcription from these two promoters. We also show that IRS-1 binds to src via its two PI3-K binding tyrosine residues, and that these two residues are required for transformation of mammary cancer cells expressing v-src. Taken together, these results indicate a significant role of IRS-1 in the activation of cell cycle progression genes and transformation of cells by v-src.

  • The role of the Insulin Receptor Substrate-1 in the differentiation of rat hippocampal neuronal cells.
    Oncogene, 2001
    Co-Authors: Andrea Morrione, Magali Navarro, Gaetano Romano, Michael Dews, Krzysztof Reiss, Barbara Valentinis, Barbara Belletti, Renato Baserga
    Abstract:

    The role of the Insulin Receptor Substrate-1 in the differentiation of rat hippocampal neuronal cells

  • Transforming potential of the Insulin Receptor Substrate 1.
    Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 1995
    Co-Authors: C D'ambrosio, Andrea Morrione, Renato Baserga, Gustav E. Lienhard, Keller, Eva Surmacz
    Abstract:

    Abstrad The role of the Insulin Receptor Substrate 1 (IRS-i) in cellular transformation was studied in R- cells, which are 3T3-like fibroblasts derived from mouse embryos with a targeted disruption of the Insulin-like growth fador I Receptor gene. These cells cannot be transformed by oncogenes that readily transform cells originating from wild-type littermate embryos (or other 3T3-Iike cells). In the present study, we demonstrate that in R- cells, the overexpression of the fundional IRS-i protein was sufficient to induce a mitogenic response to Insulin but did not promote transformation, as measured by colony formation in soft agar. The coexpression of IRS-i and the SV4O T antigen, however, induced transformation. Conversely, expression of an antisense IRS-i RNA reversed the transformed phenotype in wildtype cells carrying the T antigen. Since the type 1 Insulin-like growth fador Receptor, by itself, is fully transforming, we propose the hypothesis that the transforming competence of this Receptor is based on at least two signaling pathways, one of which is IRS-i dependent, whereas the other(s) can be substituted with the 5V40 T antigen.

Rohit N. Kulkarni - One of the best experts on this subject based on the ideXlab platform.

  • Alterations in growth and apoptosis of Insulin Receptor Substrate-1-deficient β-cells
    American Journal of Physiology-endocrinology and Metabolism, 2005
    Co-Authors: Anita M Hennige, Morris F. White, Umut Ozcan, Terumasa Okada, Ulupi S. Jhala, Markus Schubert, Rohit N. Kulkarni
    Abstract:

    Insulin and IGF-I activate antiapoptotic pathways via Insulin Receptor Substrate (IRS) proteins in most mammalian cells, including β-cells. IRS-1 knockout (IRS-1KO) mice show growth retardation, hy...

  • upregulation of Insulin Receptor Substrate 2 in pancreatic β cells prevents diabetes
    Journal of Clinical Investigation, 2003
    Co-Authors: Anita M Hennige, Umut Ozcan, Rohit N. Kulkarni, Deborah J Burks, Jing Ye, Sunmin Park, M Schubert, Tracey L Fisher, Rebecca L Leshan, M A Zakaria
    Abstract:

    The Insulin Receptor Substrate-2 (Irs2) branch of the Insulin/IGF signaling system coordinates peripheral Insulin action and pancreatic β cell function, so mice lacking Irs2 display similarities to humans with type 2 diabetes. Here we show that β cell–specific expression of Irs2 at a low or a high level delivered a graded physiologic response that promoted β cell growth, survival, and Insulin secretion that prevented diabetes in Irs2–/– mice, obese mice, and streptozotocin-treated mice; and that upon transplantation, the transgenic islets cured diabetes more effectively than WT islets. Thus, pharmacological approaches that promote Irs2 expression in β cells, especially specific cAMP agonists, could be rational treatments for β cell failure and diabetes.

  • Upregulation of Insulin Receptor Substrate-2 in pancreatic β cells prevents diabetes
    The Journal of clinical investigation, 2003
    Co-Authors: Anita M Hennige, Umut Ozcan, Markus Schubert, Rohit N. Kulkarni, Deborah J Burks, Sunmin Park, Tracey L Fisher, Matt A. Dow, Rebecca L Leshan
    Abstract:

    The Insulin Receptor Substrate-2 (Irs2) branch of the Insulin/IGF signaling system coordinates peripheral Insulin action and pancreatic beta cell function, so mice lacking Irs2 display similarities to humans with type 2 diabetes. Here we show that beta cell-specific expression of Irs2 at a low or a high level delivered a graded physiologic response that promoted beta cell growth, survival, and Insulin secretion that prevented diabetes in Irs2-/- mice, obese mice, and streptozotocin-treated mice; and that upon transplantation, the transgenic islets cured diabetes more effectively than WT islets. Thus, pharmacological approaches that promote Irs2 expression in beta cells, especially specific cAMP agonists, could be rational treatments for beta cell failure and diabetes.

  • impact of genetic background on development of hyperInsulinemia and diabetes in Insulin Receptor Insulin Receptor Substrate 1 double heterozygous mice
    Diabetes, 2003
    Co-Authors: Rohit N. Kulkarni, Terumasa Okada, K Ueki, Jonathon N Winnay, Katrine Almind, Joseph H Goren, Ronald C Kahn
    Abstract:

    Type 2 diabetes is a complex disease in which genetic and environmental factors interact to produce alterations in Insulin action and Insulin secretion, leading to hyperglycemia. To evaluate the influence of genetic background on development of diabetes in a genetically susceptible host, we generated mice that are double heterozygous (DH) for knockout of the Insulin Receptor and Insulin Receptor Substrate-1 on three genetic backgrounds (C57BL/6 [B6], 129Sv, and DBA). Although DH mice on all backgrounds showed Insulin resistance, their phenotypes were dramatically different. B6 DH mice exhibited marked hyperInsulinemia and massive islet hyperplasia and developed early hyperglycemia, with 85% overtly diabetic by 6 months. By contrast, 129Sv DH mice showed mild hyperInsulinemia and minimal islet hyperplasia, and

  • roles of Insulin Receptor Substrate 1 phosphatidylinositol 3 kinase and release of intracellular ca2 stores in Insulin stimulated Insulin secretion in β cells
    Journal of Biological Chemistry, 2000
    Co-Authors: Craig A Aspinwall, Rohit N. Kulkarni, Ronald C Kahn, Weijun Qian, Michael G Roper, Robert T Kennedy
    Abstract:

    Abstract The signaling pathway by which Insulin stimulates Insulin secretion and increases in intracellular free Ca2+ concentration ([Ca2+]i) in isolated mouse pancreatic β-cells and clonal β-cells was investigated. Application of Insulin to single β-cells resulted in increases in [Ca2+]i that were of lower magnitude, slower onset, and longer lifetime than that observed with stimulation with tolbutamide. Furthermore, the increases in [Ca2+]i originated from interior regions of the cell rather than from the plasma membrane as with depolarizing stimuli. The Insulin-induced [Ca2+]i changes and Insulin secretion at single β-cells were abolished by treatment with 100 nm wortmannin or 1 μm thapsigargin; however, they were unaffected by 10 μm U73122, 20 μmnifedipine, or removal of Ca2+ from the medium. Insulin-stimulated Insulin secretion was also abolished by treatment with 2 μm bisindolylmaleimide I, but [Ca2+]i changes were unaffected. In an Insulin Receptor Substrate-1 gene disrupted β-cell tumor line, Insulin did not evoke either [Ca2+]i changes or Insulin secretion. The data suggest that autocrine-activated increases in [Ca2+]i are due to release of intracellular Ca2+ stores, especially the endoplasmic reticulum, mediated by Insulin Receptor Substrate-1 and phosphatidylinositol 3-kinase. Autocrine activation of Insulin secretion is mediated by the increase in [Ca2+]i and activation of protein kinase C.