Morris F White

Summary

Affiliation: Harvard University
Country: USA

Publications

  1. ncbi request reprint Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function
    Sunmin Park
    Howard Hughes Medical Institute, Division of Endocrinology, Department of Medicine, Children s Hospital Boston, MA 02215, USA
    J Biol Chem 281:1159-68. 2006
  2. ncbi request reprint Insulin signaling in health and disease
    Morris F White
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA
    Science 302:1710-1. 2003
  3. ncbi request reprint IRS proteins and the common path to diabetes
    Morris F White
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    Am J Physiol Endocrinol Metab 283:E413-22. 2002
  4. ncbi request reprint Insulin receptor substrate 2 is essential for maturation and survival of photoreceptor cells
    Xianjin Yi
    Howard Hughes Medical Institute, Children s Hospital Boston, Boston, Massachusetts 02115, USA
    J Neurosci 25:1240-8. 2005
  5. pmc Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes
    Xueying Lin
    Howard Hughes Medical Institute Children s Hospital, Division of Endocrinology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Clin Invest 114:908-16. 2004
  6. pmc Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents
    Katsutaro Morino
    Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06536 8012, USA
    J Clin Invest 115:3587-93. 2005
  7. pmc Serine phosphorylation sites on IRS2 activated by angiotensin II and protein kinase C to induce selective insulin resistance in endothelial cells
    Kyoungmin Park
    Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
    Mol Cell Biol 33:3227-41. 2013
  8. doi request reprint Foxo1 integrates insulin signaling with mitochondrial function in the liver
    Zhiyong Cheng
    Harvard Medical School, Boston, Massachusetts, USA
    Nat Med 15:1307-11. 2009
  9. pmc IRS2 signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action
    Marianna Sadagurski
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, Boston, MA 02062, USA
    Cell Metab 15:703-12. 2012
  10. pmc Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation
    Xiaocheng C Dong
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Karp Family Research Laboratories, 300 Longwood Avenue, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 8:65-76. 2008

Research Grants

Detail Information

Publications70

  1. ncbi request reprint Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function
    Sunmin Park
    Howard Hughes Medical Institute, Division of Endocrinology, Department of Medicine, Children s Hospital Boston, MA 02215, USA
    J Biol Chem 281:1159-68. 2006
    ....
  2. ncbi request reprint Insulin signaling in health and disease
    Morris F White
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA
    Science 302:1710-1. 2003
    ..Drugs that stimulate IRS2 (insulin receptor substrate protein 2) synthesis or signaling might be a good starting point. This knowledge will lead to rational strategies that prevent or cure diabetes...
  3. ncbi request reprint IRS proteins and the common path to diabetes
    Morris F White
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    Am J Physiol Endocrinol Metab 283:E413-22. 2002
    ....
  4. ncbi request reprint Insulin receptor substrate 2 is essential for maturation and survival of photoreceptor cells
    Xianjin Yi
    Howard Hughes Medical Institute, Children s Hospital Boston, Boston, Massachusetts 02115, USA
    J Neurosci 25:1240-8. 2005
    ....
  5. pmc Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes
    Xueying Lin
    Howard Hughes Medical Institute Children s Hospital, Division of Endocrinology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Clin Invest 114:908-16. 2004
    ..Thus, Irs2 signaling promotes regeneration of adult beta cells and central control of nutrient homeostasis, which can prevent obesity and diabetes in mice...
  6. pmc Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents
    Katsutaro Morino
    Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06536 8012, USA
    J Clin Invest 115:3587-93. 2005
    ....
  7. pmc Serine phosphorylation sites on IRS2 activated by angiotensin II and protein kinase C to induce selective insulin resistance in endothelial cells
    Kyoungmin Park
    Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
    Mol Cell Biol 33:3227-41. 2013
    ..Thus, AngII or PKCβ activation can phosphorylate Ser303 and Ser675 in IRS2 to inhibit insulin-induced p-Tyr911 and its anti-atherogenic actions (p-Akt/eNOS) in endothelial cells. ..
  8. doi request reprint Foxo1 integrates insulin signaling with mitochondrial function in the liver
    Zhiyong Cheng
    Harvard Medical School, Boston, Massachusetts, USA
    Nat Med 15:1307-11. 2009
    ..Thus, Foxo1 integrates insulin signaling with mitochondrial function, and inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome...
  9. pmc IRS2 signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action
    Marianna Sadagurski
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, Boston, MA 02062, USA
    Cell Metab 15:703-12. 2012
    ..Thus, Irs2 signaling in LepR-b neurons plays a crucial role in metabolic sensing and regulation. While not required for leptin action, Irs2 suppresses FoxO1 signaling in LepR-b neurons to promote energy balance and metabolism...
  10. pmc Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation
    Xiaocheng C Dong
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Karp Family Research Laboratories, 300 Longwood Avenue, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 8:65-76. 2008
    ....
  11. pmc Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth
    Xiaocheng Dong
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Clin Invest 116:101-14. 2006
    ..Thus, signals delivered by Irs1 or Irs2 regulate hepatic gene expression that coordinates glucose homeostasis and systemic growth...
  12. ncbi request reprint Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation
    Markus Schubert
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Neurosci 23:7084-92. 2003
    ..Thus, dysregulation of the Irs2 branch of the insulin-Igf-signaling cascade reveals a molecular link between diabetes and neurodegenerative disease...
  13. pmc The Irs1 branch of the insulin signaling cascade plays a dominant role in hepatic nutrient homeostasis
    Shaodong Guo
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, Karp Family Research Laboratories, Boston, MA 02115, USA
    Mol Cell Biol 29:5070-83. 2009
    ..Moreover, LKO1 mice -- but not LKO2 mice -- that were fed a high-fat diet developed postprandial hyperglycemia. We conclude that Irs1 is the principal mediator of hepatic insulin action that maintains glucose homeostasis...
  14. ncbi request reprint Alterations in growth and apoptosis of insulin receptor substrate-1-deficient beta-cells
    Anita M Hennige
    Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA
    Am J Physiol Endocrinol Metab 289:E337-46. 2005
    ....
  15. ncbi request reprint Overexpression or ablation of JNK in skeletal muscle has no effect on glycogen synthase activity
    Nobuharu Fujii
    Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA
    Am J Physiol Cell Physiol 287:C200-8. 2004
    ..JNK activation is unlikely to be the major mechanism by which contractile activity increases glycogen synthase activity in skeletal muscle...
  16. pmc Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes
    Anita M Hennige
    Howard Hughes Medical Institute, Joslin Diabetes Center, Boston, Massachusetts 02215, USA
    J Clin Invest 112:1521-32. 2003
    ..Thus, pharmacological approaches that promote Irs2 expression in beta cells, especially specific cAMP agonists, could be rational treatments for beta cell failure and diabetes...
  17. ncbi request reprint Brain IRS2 signaling coordinates life span and nutrient homeostasis
    Akiko Taguchi
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
    Science 317:369-72. 2007
    ..Thus, less Irs2 signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice...
  18. ncbi request reprint Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice
    Jake A Kushner
    Howard Hughes Medical Institute, Joslin Diabetes Center, and Division of Endocrinology, Children s Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA
    Diabetes 53:61-6. 2004
    ..Our studies demonstrate a novel role for Ptp1b in regulating beta-cell homeostasis and indicate that Ptp1b deficiency can partially compensate for lack of Irs2...
  19. ncbi request reprint Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling
    Jodel Giraud
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 279:3447-54. 2004
    ..Replacing Ser(302) with alanine reduced insulin/IGF-I-stimulated DNA synthesis. We conclude that Ser(302) phosphorylation integrates nutrient availability with insulin/IGF-I signaling to promote mitogenesis and cell growth...
  20. pmc Insulin-like growth factor 2 and the insulin receptor, but not insulin, regulate fetal hepatic glycogen synthesis
    Li Liang
    Department of Medicine Endocrine Division, Children s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Endocrinology 151:741-7. 2010
    ....
  21. pmc Insulin receptor substrates Irs1 and Irs2 coordinate skeletal muscle growth and metabolism via the Akt and AMPK pathways
    Yun Chau Long
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Center for Life Sciences, CLS 16020, 3 Blackfan Circle, Boston, MA 02115, USA
    Mol Cell Biol 31:430-41. 2011
    ..Thus, insulin-like signaling via Irs1/2 is essential to terminate skeletal muscle catabolic/fasting pathways in the presence of adequate nutrition...
  22. ncbi request reprint c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade
    Yong Hee Lee
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 278:2896-902. 2003
    ..These results support the hypothesis that JNK is a negative feedback regulator of insulin action by phosphorylating Ser(307) in Irs1...
  23. pmc Pdx1 restores beta cell function in Irs2 knockout mice
    Jake A Kushner
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Clin Invest 109:1193-201. 2002
    ..Our results suggest that dysregulation of Pdx1 might represent a common link between ordinary type 2 diabetes and MODY...
  24. pmc Targeted disruption of ROCK1 causes insulin resistance in vivo
    Dae Ho Lee
    Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 284:11776-80. 2009
    ..Thus, our results identify ROCK1 as a novel regulator of glucose homeostasis and insulin sensitivity in vivo, which could lead to new treatment approaches for obesity and type 2 diabetes...
  25. ncbi request reprint Phosphorylation of Irs1 at SER-522 inhibits insulin signaling
    Jodel Giraud
    Howard Hughes Medical Institute, Children s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA
    Mol Endocrinol 21:2294-302. 2007
    ..Together, these results suggest the phosphatidylinositol 3-kinase-->Akt cascade can inhibit insulin signaling through the phosphorylation of S522(Irs1)...
  26. doi request reprint Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction
    Yingjiang Zhou
    Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA
    Nat Med 17:356-65. 2011
    ....
  27. pmc Involvement of insulin receptor substrate 2 in mammary tumor metastasis
    Julie A Nagle
    Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
    Mol Cell Biol 24:9726-35. 2004
    ..In contrast, IRS-1(-/-) tumor cells, which express only IRS-2, were highly invasive and were resistant to apoptotic stimuli. Collectively, our findings reveal an important contribution of IRS-2 to breast cancer metastasis...
  28. pmc Irs1 serine 307 promotes insulin sensitivity in mice
    KYLE D COPPS
    Children s Hospital Boston, Harvard Medical School, MA 02115, USA
    Cell Metab 11:84-92. 2010
    ..Thus, contrary to the results of cell-based experiments, Ser307 in mice is a positive regulatory site that moderates the severity of insulin resistance by maintaining proximal insulin signaling...
  29. ncbi request reprint The reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling
    Shaodong Guo
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, Karp Family Research Laboratories, Room 04210, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Mol Endocrinol 20:3389-99. 2006
    ..The dynamic relation between Irs2 and FoxO expression, compared with the subordinate role of Irs1, can explain the dominant role of Irs2 in metabolic regulation...
  30. pmc Insulin receptor substrate-2 in beta-cells decreases diabetes in nonobese diabetic mice
    Lisa D Norquay
    Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA
    Endocrinology 150:4531-40. 2009
    ..In conclusion, increased Irs2 attenuated the progression of beta-cell destruction, promoted beta-cell mitogenesis, and reduced diabetes incidence in NOD(Irs2) mice...
  31. pmc Inhibition of insulin signaling in endothelial cells by protein kinase C-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase (PI3K)
    Yasuhiro Maeno
    Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 287:4518-30. 2012
    ..Thus, PKC and angiotensin-induced phosphorylation of Thr-86 of p85/PI3K may partially inhibit the activation of PI3K/eNOS by multiple cytokines and contribute to endothelial dysfunction in metabolic disorders...
  32. pmc IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease
    Marianna Sadagurski
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Boston, Massachusetts 02115, USA
    J Clin Invest 121:4070-81. 2011
    ..Since we found the expression of Irs2 to be normal in grade II HD patients, our results suggest that decreasing IRS2 signaling could be part of a therapeutic approach to slow the progression of HD...
  33. ncbi request reprint Regulating insulin signaling and beta-cell function through IRS proteins
    Morris F White
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, Karp Family Research Laboratories, Room 4210, 300 Longwood Avenue, Boston, MA 02115, USA
    Can J Physiol Pharmacol 84:725-37. 2006
    ..Understanding the molecular basis of insulin resistance can prevent these disorders and their inevitable progression to type 2 diabetes...
  34. ncbi request reprint Signaling pathways: the benefits of good communication
    Tracey L Fisher
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Curr Biol 14:R1005-7. 2004
    ..This crosstalk reveals how hyperactivated mTOR may suppress metastasis locally, while causing systemic insulin resistance that can progress to diabetes...
  35. ncbi request reprint Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors: therapeutic implications
    Qing Chang
    Department of Pathology, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Cancer Res 62:6035-8. 2002
    ..These studies suggest that constitutive IRS-1 activation is a common phenomenon in tumors and that activated IRS-1 may present an attractive therapeutic target...
  36. ncbi request reprint Insulin signaling after exercise in insulin receptor substrate-2-deficient mice
    Kirsten F Howlett
    Research Division, Joslin Diabetes Center and Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA
    Diabetes 51:479-83. 2002
    ..IRS-2 signaling can partially account for the increase in insulin-stimulated phosphotyrosine-associated PI 3-kinase activity after exercise...
  37. doi request reprint Metformin and insulin meet in a most atypical way
    Morris F White
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 9:485-7. 2009
    ....
  38. ncbi request reprint Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle
    Chunli Yu
    Department of Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA
    J Biol Chem 277:50230-6. 2002
    ..This in turn leads to decreased IRS-1 tyrosine phosphorylation and decreased activation of IRS-1-associated PI3-kinase activity resulting in decreased insulin-stimulated glucose transport activity...
  39. doi request reprint Insulin signaling meets mitochondria in metabolism
    Zhiyong Cheng
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, Boston, MA, USA
    Trends Endocrinol Metab 21:589-98. 2010
    ..However, chronic exposure to high ROS levels could alter mitochondrial function and thereby cause insulin resistance...
  40. ncbi request reprint SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2
    Liangyou Rui
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 277:42394-8. 2002
    ..Thus, SOCS-mediated degradation of IRS proteins, presumably via the elongin BC ubiquitin-ligase, might be a general mechanism of inflammation-induced insulin resistance, providing a target for therapy...
  41. ncbi request reprint Interleukin-4-mediated protection of primary B cells from apoptosis through Stat6-dependent up-regulation of Bcl-xL
    Andrea L Wurster
    Department of Immunology and Infectious Diseases, School of Public Health, Harvard Medical School, Boston, MA 02115, USA
    J Biol Chem 277:27169-75. 2002
    ..These results suggest that the anti-apoptotic activity of IL-4 in B cells is mediated through the activation of Stat6 and subsequent transcription of Bcl-xL...
  42. ncbi request reprint Insulin-like signaling, nutrient homeostasis, and life span
    Akiko Taguchi
    Howard Hughes Medical Institute, Division of Endocrinology, Children s Hospital Boston, Harvard Medical School, Karp Family Research Laboratories, Boston, MA 02115, USA
    Annu Rev Physiol 70:191-212. 2008
    ..We discuss the possibility that the brain is the site where reduced insulin-like signaling can consistently extend mammalian life span-just as reduced insulin-like signaling extends the life span of lower metazoans...
  43. doi request reprint Integrating metabolism and longevity through insulin and IGF1 signaling
    Marianna Sadagurski
    Department of Endocrinology, Children s Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA
    Endocrinol Metab Clin North Am 42:127-48. 2013
    ..Genetic manipulations of insulin/IGF1 signaling components are revealing neuronal circuits that might resolve the central regulation of systemic metabolism from organism longevity...
  44. pmc Stat6 and IRS-2 cooperate in interleukin 4 (IL-4)-induced proliferation and differentiation but are dispensable for IL-4-dependent rescue from apoptosis
    Andrea L Wurster
    Department of Immunology and Infectious Diseases, Harvard School of Public Health Harvard Medical School, Boston, Massachusetts 02115, USA
    Mol Cell Biol 22:117-26. 2002
    ....
  45. ncbi request reprint Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action
    Vincent Aguirre
    Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 277:1531-7. 2002
    ..These results suggest that inhibition of PTB domain function in IRS-1 by phosphorylation of Ser(307) (Ser(312) in human IRS-1) might be a general mechanism to regulate insulin signaling...
  46. doi request reprint Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling
    Baran A Ersoy
    Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Sci Signal 6:ra64. 2013
    ..These findings reveal a phospholipid-dependent mechanism that suppresses insulin signaling downstream of its receptor. ..
  47. pmc Inhibition of TNF-α improves the bladder dysfunction that is associated with type 2 diabetes
    Zongwei Wang
    Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Diabetes 61:2134-45. 2012
    ....
  48. pmc Targeting Forkhead box O1 from the concept to metabolic diseases: lessons from mouse models
    Zhiyong Cheng
    Division of Endocrinology, Howard Hughes Medical Institute, Harvard Medical School, Children s Hospital Boston, Boston, Massachusetts 02115, USA
    Antioxid Redox Signal 14:649-61. 2011
    ..In this article, we review the role of FOXO1 in the regulation of metabolism and energy expenditure based on recent findings from mouse models, and discuss the therapeutic value of targeting FOXO1 in metabolic diseases...
  49. ncbi request reprint Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice
    Tohru Uchida
    Division of Diabetes and Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7 5 1 Kusunoki cho, Chuo Ku, Kobe 650 0017, Japan
    Nat Med 11:175-82. 2005
    ..Thus, p27(Kip1) contributes to beta-cell failure during the development of type 2 diabetes in Irs2(-/-) and Lepr(-/-) mice and represents a potential new target for the treatment of this condition...
  50. pmc The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth
    Tadahiro Kitamura
    Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, USA
    J Clin Invest 110:1839-47. 2002
    ..We propose that insulin/IGFs regulate beta cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts...
  51. ncbi request reprint Plasma insulin levels predict the development of atherosclerosis when IRS2 deficiency is combined with severe hypercholesterolemia in apolipoprotein E-null mice
    Herminia Gonzalez-Navarro
    Vascular Biology Laboratory, Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia IBV CSIC, Valencia, Spain
    Front Biosci 12:2291-8. 2007
    ..Future studies are necessary to determine whether IRS2 dysfunction may promote atherosclerosis in normoglycemic, pre-diabetic patients with clinical manifestations of hyperinsulinemia and insulin resistance...
  52. pmc Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth
    Jake A Kushner
    Division of Endocrinology, Children s Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA
    Mol Cell Biol 25:3752-62. 2005
    ..Thus, cyclins D2 and D1 were essential for beta-cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in beta cells could prevent or cure diabetes...
  53. ncbi request reprint Attenuation of accumulation of neointimal lipid by pioglitazone in mice genetically deficient in insulin receptor substrate-2 and apolipoprotein E
    Maria H Clough
    Department of Pathology, 89 Beaumont Avenue, College of Medicine, University of Vermont, Burlington, VT 05405, USA
    J Histochem Cytochem 53:603-10. 2005
    ..018. Accordingly, genetically induced intensification of insulin resistance increases atheroma formation. Furthermore, attenuation of insulin resistance by treatment with pioglitazone decreases accumulation of lipid in the neointima...
  54. ncbi request reprint Specificity of interleukin-2 receptor gamma chain superfamily cytokines is mediated by insulin receptor substrate-dependent pathway
    Hui Xiao
    Department of Pharmacology and Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 4965, USA
    J Biol Chem 277:8091-8. 2002
    ..These data suggest that IRS-dependent signaling pathways work by recruiting different signaling molecules to determine specificity of IL-2R gamma superfamily cytokines...
  55. ncbi request reprint Phosphatase and tensin homolog regulation of islet growth and glucose homeostasis
    Jake A Kushner
    Division of Endocrinology, Children s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 280:39388-93. 2005
    ..Thus, steps to enhance phosphatidylinositol 3-kinase signaling can promote beta-cell growth, function, and survival without the Irs2 branch of the insulin/insulin-like growth factor signaling cascade...
  56. ncbi request reprint Essential role of protein kinase C zeta in the impairment of insulin-induced glucose transport in IRS-2-deficient brown adipocytes
    Monica Arribas
    Departamento de Bioquímica y Biología Molecular Instituto de Bioquímica, Centro Mixto CSIC UCM, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
    FEBS Lett 536:161-6. 2003
    ..Our results support the essential role played by PKC zeta in the insulin resistance and impaired glucose uptake observed in IRS-2-deficient brown adipocytes...
  57. ncbi request reprint Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes
    Angela M Valverde
    Instituto de Bioquímica Departamento de Bioquímica y Biología Molecular II, Centro Mixto CSIC UCM, Facultad de Farmacia, Universidad Complutense, Madrid, Spain
    Diabetes 52:2239-48. 2003
    ..Suppression of gluconeogenic gene expression in IRS-2-deficient primary hepatocytes was also restored by infection with dominant negative Delta 256Foxo1...
  58. ncbi request reprint Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2
    Jane J Kim
    Deparment of Pediatrics, University of California, San Diego, California, USA
    Am J Physiol Endocrinol Metab 292:E1694-701. 2007
    ..The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of beta-cell dysfunction in type 2 diabetes should positively affect both aspects of beta-cell physiology...
  59. ncbi request reprint The repression of IRS2 gene by ATF3, a stress-inducible gene, contributes to pancreatic beta-cell apoptosis
    Dan Li
    Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, Ohio State University, Columbus, OH 43210, USA
    Diabetes 57:635-44. 2008
    ..We tested the hypothesis that activating transcription factor 3 (ATF3), a stress-inducible proapoptotic gene, downregulates the expression of IRS2 in beta-cells...
  60. doi request reprint Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2
    Jinhua Wu
    Structural Biology Program, Kimmel Center for Biology and Medicine of the Skirball Institute, and Department of Pharmacology, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA
    Nat Struct Mol Biol 15:251-8. 2008
    ..Although Tyr628 was phosphorylated by the insulin receptor, its catalytic turnover was poor, resulting in kinase inhibition. Our studies indicate that the KRLB region functions to limit tyrosine phosphorylation of IRS2...
  61. ncbi request reprint IRS-2 mediates the antiapoptotic effect of insulin in neonatal hepatocytes
    Angela M Valverde
    Instituto de Bioquímica Departamento de Bioquímica y Biología Molecular II, Centro Mixto CSIC UCM, Facultad de Farmacia, Universidad Complutense, Madrid, Spain
    Hepatology 40:1285-94. 2004
    ..Epidermal growth factor, via PIP3/Akt/Foxo1 phosphorylation, was able to rescue IRS-2(-/-) hepatocytes from serum withdrawal-induced apoptosis, modulating pro- and anti-apoptotic gene expression and downregulating caspase-3 activity...
  62. pmc Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance
    Chaojun Duan
    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109 0622, USA
    Mol Cell Biol 24:7435-43. 2004
    ..Our data suggest that SH2-B is a physiological enhancer of insulin receptor activation and is required for maintaining normal insulin sensitivity and glucose homeostasis during aging...
  63. ncbi request reprint Insulin receptor substrate 1 (IRS-1) plays a unique role in normal epidermal physiology
    Marianna Sadagurski
    Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
    J Cell Physiol 213:519-27. 2007
    ..Furthermore, we suggest that IRS-1 and IRS-2 have distinct roles in skin physiology...
  64. ncbi request reprint Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation
    Christian J Carlson
    Insulin Signaling, Metabolic Diseases Division, Global Pharmaceutical Research Division, Abbott Laboratories, Abbott Park, IL 60064, USA
    Biochem Biophys Res Commun 316:533-9. 2004
    ..Finally, we demonstrated that serine 307 phosphorylated IRS-1 is detected primarily in the cytosolic fraction...
  65. ncbi request reprint Insulin receptor substrate proteins and diabetes
    Yong Hee Lee
    Institute for Tumor Research, Chungbuk National University, Cheongju, Chungbuk 361 763, Korea
    Arch Pharm Res 27:361-70. 2004
    ..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...
  66. pmc Suppression of insulin receptor substrate 1 (IRS-1) promotes mammary tumor metastasis
    Zhefu Ma
    Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Mol Cell Biol 26:9338-51. 2006
    ..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...
  67. pmc Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor
    Shouhong Xuan
    Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, New York, USA
    J Clin Invest 110:1011-9. 2002
    ..These observations reveal a requirement of IGF1R-mediated signaling for insulin secretion...
  68. pmc Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance
    Katsuya Tanabe
    Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St Louis, Missouri, United States of America
    PLoS Biol 6:e37. 2008
    ..These results thus form the rationale for developing agents to inhibit this enzyme in obese insulin-resistant individuals to preserve beta-cells and prevent diabetes onset...
  69. ncbi request reprint Insulin receptor substrate 2 plays diverse cell-specific roles in the regulation of glucose transport
    Marianna Sadagurski
    Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
    J Biol Chem 280:14536-44. 2005
    ..These observations suggest that IRS-2 functions as a negative or positive regulator of glucose transport in a cell-specific manner. Our results also show that IRS-2 function depends on its cell-specific association with PI 3-kinase...
  70. ncbi request reprint RIP-Cre revisited, evidence for impairments of pancreatic beta-cell function
    Ji Yeon Lee
    Laboratory of Genetics and Physiology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Biol Chem 281:2649-53. 2006
    ..In addition, we review the use of RIP-Cre mice and discuss possible molecular underpinnings and ramifications of our findings...

Research Grants2

  1. Gordon Conference: Second Messengers and Phosphorylation
    Morris White; Fiscal Year: 2002
    ..To emphasize this goal, four poster presentations that complement the theme of the meeting will be selected for brief oral presentations during the major sessions. ..
  2. REGULATION AND FUNCTION OF IRS-PROTEINS
    Morris White; Fiscal Year: 2004
    ..This work might highlight IRS-proteins as ideal targets for inhibition of tumor growth. ..