Morris F. White, PhD

Boston Children's Hospital

Boston Children's Hospital
Phone: (617) 919-2846
Fax: (617) 730-0244

Morris F. White, PhD

Boston Children's Hospital

EDUCATIONAL TITLES

  • Professor, Pediatrics, Harvard Medical School
  • Associate Scientific Staff, Endocrinology, Boston Children's Hospital

Research Abstract

We investigate the molecular basis of insulin signal transduction to understand the pathophysiology of diabetes and related disorders, including obesity, infertility, and cardiovascular and retinal disease. Since diabetes is a complicated, multisystem disease, we use mice to integrate our molecular studies with physiology. Transgenic mice lacking the genes for Irs1 or Irs2 form the basis of many of our experimental models. These mice reveal a surprisingly close relation between the molecular regulation of insulin secretion and that of insulin action. We now understand that the IRS2-branch of the insulin/IGF signaling pathways controls pancreatic beta-cell growth, function and survival. Many of our current experiments focus upon way to exploit the IRS2 signaling cascade to restore beta-cell function and prevent or cure diabetes. Diabetes is serious, but only one of the consequences of insulin resistance, as dysregulated insulin signaling is associated with a cohort of systemic disorders妖yslipidemia, hypertension, cardiovascular disease, stroke, blindness, kidney disease female infertility, and neurodegeneration. Therefore, whether better management of inflammatory responses can attenuate insulin resistance and promote betacell function is an important area of investigation. Training opportunities are available to study insulin signaling cascades, and show how this system plays a role in peripheral and central tissues to regulate nutrient homeostasis.

Publications

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  • Geetha T, Rege SD, Mathews SE, Meakin SO, White MF, Babu JR. Nerve growth factor receptor TrkA, a new receptor in insulin signaling pathway in PC12 cells. J Biol Chem 2013; 288:23807-13. PubMed
  • Park K, Li Q, Rask-Madsen C, Mima A, Mizutani K, Winnay J, Maeda Y, D'Aquino K, White MF, Feener EP, King GL. Serine phosphorylation sites on IRS2 activated by angiotensin II and protein kinase C to induce selective insulin resistance in endothelial cells. Mol Cell Biol 2013; 33:3227-41. PubMed
  • Ersoy BA, Tarun A, D'Aquino K, Hancer NJ, Ukomadu C, White MF, Michel T, Manning BD, Cohen DE. Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling. Sci Signal 2013; 6:ra64. PubMed
  • Zhou Y, Lee J, Reno CM, Sun C, Park SW, Chung J, Lee J, Fisher SJ, White MF, Biddinger SB, Ozcan U. Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction. Nat Med 2011; 17:356-65. PubMed
  • Wei D, Tao R, Zhang Y, White MF, Dong XC. Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1. Am J Physiol Endocrinol Metab 2011; 300:E312-20. PubMed
  • Long YC, Cheng Z, Copps KD, White MF. Insulin receptor substrates Irs1 and Irs2 coordinate skeletal muscle growth and metabolism via the Akt and AMPK pathways. Mol Cell Biol 2011; 31:430-41. PubMed
  • Cheng Z, White MF. Targeting Forkhead Box O1 from the Concept to Metabolic Diseases: Lessons from Mouse Models. Antioxid Redox Signal 2010. PubMed
  • Cheng Z, White MF. Foxo1 in hepatic lipid metabolism. Cell Cycle 2010; 9:219-20. PubMed
  • Cheng Z, Guo S, Copps K, Dong X, Kollipara R, Rodgers JT, Depinho RA, Puigserver P, White MF. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat Med 2009; 15:1307-11. PubMed
  • Dong XC,Copps KD,Guo S,Li Y,Kollipara R,DePinho RA,White MF. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab 2008; 8:65-76. PubMed
  • Overton IM, van Niekerk CA, Carter LG, Dawson A, Martin DM, Cameron S, McMahon SA, White MF, Hunter WN, Naismith JH, Barton GJ. TarO: a target optimisation system for structural biology. Nucleic Acids Res 2008; 36:W190-6. PubMed
  • Richard DJ, Bolderson E, Cubeddu L, Wadsworth RI, Savage K, Sharma GG, Nicolette ML, Tsvetanov S, McIlwraith MJ, Pandita RK, Takeda S, Hay RT, Gautier J, West SC, Paull TT, Pandita TK, White MF, Khanna KK. Single-stranded DNA-binding protein hSSB1 is critical for genomic stability. Nature 2008; 453:677-81. PubMed
  • Mason JO 3rd, White MF, Feist RM, Thomley ML, Albert MA, Persaud TO, Yunker JJ, Vail RS. Incidence of acute onset endophthalmitis following intravitreal bevacizumab (Avastin) injection. Retina 2008; 28:564-7. PubMed
  • Wu J, Tseng YD, Xu CF, Neubert TA, White MF, Hubbard SR. Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2. Nat Struct Mol Biol 2008; 15:251-8. PubMed
  • Li D, Yin X, Zmuda EJ, Wolford CC, Dong X, White MF, Hai T. The repression of IRS2 gene by ATF3, a stress-inducible gene, contributes to pancreatic beta-cell apoptosis. Diabetes 2007; 57:635-44. PubMed
  • Richards JD, Cubeddu L, Roberts J, Liu H, White MF. The archaeal XPB protein is a ssDNA-dependent ATPase with a novel partner. J Mol Biol 2008; 376:634-44. PubMed
  • Richards JD, Johnson KA, Liu H, McRobbie AM, McMahon S, Oke M, Carter L, Naismith JH, White MF. Structure of the DNA repair helicase hel308 reveals DNA binding and autoinhibitory domains. J Biol Chem 2007; 283:5118-26. PubMed
  • Tanabe K, Liu Z, Patel S, Doble BW, Li L, Cras-Meneur C, Martinez SC, Welling CM, White MF, Bernal-Mizrachi E, Woodgett JR, Permutt MA. Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance. PLoS Biol 2008; 6:e37. PubMed
  • Quaiser A, Constantinesco F, White MF, Forterre P, Elie C. The Mre11 protein interacts with both Rad50 and the HerA bipolar helicase and is recruited to DNA following gamma irradiation in the archaeon Sulfolobus acidocaldarius. BMC Mol Biol 2008; 9:25. PubMed
  • Taguchi A, White MF. Insulin-like signaling, nutrient homeostasis, and life span. Annu Rev Physiol 2007; 70:191-212. PubMed
  • Sadagurski M, Nofech-Mozes S, Weingarten G, White MF, Kadowaki T, Wertheimer E. Insulin receptor substrate 1 (IRS-1) plays a unique role in normal epidermal physiology. J Cell Physiol 2007; 213:519-27. PubMed
  • Giraud J, Haas M, Feener EP, Copps KD, Dong X, Dunn SL, White MF. Phosphorylation of Irs1 at SER-522 inhibits insulin signaling. Mol Endocrinol 2007; 21:2294-302. PubMed
  • Taguchi A, Wartschow LM, White MF. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 2007; 317:369-72. PubMed
  • Kim JJ, Kido Y, Scherer PE, White MF, Accili D. Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2. Am J Physiol Endocrinol Metab 2007; 292:E1694-701. PubMed
  • Nagle JA, Ma Z, Byrne MA, White MF, Shaw LM. Involvement of insulin receptor substrate 2 in mammary tumor metastasis. Mol Cell Biol 2004; 24:9726-35. PubMed
  • Lin X, Taguchi A, Park S, Kushner JA, Li F, Li Y, White MF. Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes. J Clin Invest 2004; 114:908-16. PubMed
  • Duan C, Yang H, White MF, Rui L. Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. Mol Cell Biol 2004; 24:7435-43. PubMed
  • Fujii N, Boppart MD, Dufresne SD, Crowley PF, Jozsi AC, Sakamoto K, Yu H, Aschenbach WG, Kim S, Miyazaki H, Rui L, White MF, Hirshman MF, Goodyear LJ. Overexpression or ablation of JNK in skeletal muscle has no effect on glycogen synthase activity. Am J Physiol Cell Physiol 2004; 287:C200-8. PubMed
  • Carlson CJ, White MF, Rondinone CM. Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation. Biochem Biophys Res Commun 2004; 316:533-9. PubMed
  • Lee YH, White MF. Insulin receptor substrate proteins and diabetes. Arch Pharm Res 2004; 27:361-70. PubMed
  • Giraud J, Leshan R, Lee YH, White MF. Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling. J Biol Chem 2003; 279:3447-54. PubMed
  • Kushner JA, Haj FG, Klaman LD, Dow MA, Kahn BB, Neel BG, White MF. Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice. Diabetes 2003; 53:61-6. PubMed
  • White MF. Insulin signaling in health and disease. Science 2003; 302:1710-1. PubMed
  • Salerno V, Napoli A, White MF, Rossi M, Ciaramella M. Transcriptional response to DNA damage in the archaeon Sulfolobus solfataricus. Nucleic Acids Res 2003; 31:6127-38. PubMed
  • Hennige AM, Burks DJ, Ozcan U, Kulkarni RN, Ye J, Park S, Schubert M, Fisher TL, Dow MA, Leshan R, Zakaria M, Mossa-Basha M, White MF. Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes. J Clin Invest 2003; 112:1521-32. PubMed
  • Valverde AM, Burks DJ, Fabregat I, Fisher TL, Carretero J, White MF, Benito M. Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes. Diabetes 2003; 52:2239-48. PubMed
  • Schubert M, Brazil DP, Burks DJ, Kushner JA, Ye J, Flint CL, Farhang-Fallah J, Dikkes P, Warot XM, Rio C, Corfas G, White MF. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci 2003; 23:7084-92. PubMed
  • Arribas M, Valverde AM, Burks D, Klein J, Farese RV, White MF, Benito M. Essential role of protein kinase C zeta in the impairment of insulin-induced glucose transport in IRS-2-deficient brown adipocytes. FEBS Lett 2003; 536:161-6. PubMed
  • Lee YH, Giraud J, Davis RJ, White MF. c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem 2002; 278:2896-902. PubMed
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