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Role of protein tyrosine phosphatases in the modulation of insulin signaling and their implication in the pathogenesis of obesity-linked insulin resistance

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Abstract

Insulin resistance is a major disorder that links obesity to type 2 diabetes mellitus (T2D). It involves defects in the insulin actions owing to a reduced ability of insulin to trigger key signaling pathways in major metabolic tissues. The pathogenesis of insulin resistance involves several inhibitory molecules that interfere with the tyrosine phosphorylation of the insulin receptor and its downstream effectors. Among those, growing interest has been developed toward the protein tyrosine phosphatases (PTPs), a large family of enzymes that can inactivate crucial signaling effectors in the insulin signaling cascade by dephosphorylating their tyrosine residues. Herein we briefly review the role of several PTPs that have been shown to be implicated in the regulation of insulin action, and then focus on the Src homology 2 (SH2) domain-containing SHP1 and SHP2 enzymes, since recent reports have indicated major roles for these PTPs in the control of insulin action and glucose metabolism. Finally, the therapeutic potential of targeting PTPs for combating insulin resistance and alleviating T2D will be discussed.

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Abbreviations

aPKC:

Atypical protein kinase C

ABC:

ATP binding cassette transporter

ACD:

Acyl CoA dehydrogenases

ACO:

Acyl CoA oxidase

AGC:

Protein kinase A G, and C

Akt:

Protein kinase B

AP:

Adaptor protein

aPKC:

Atypical protein kinase C

AT2:

Angiotensin II subtype 2 receptor

Cbl:

Casitas B-lineage lymphoma

Cdk:

Cyclin-dependent kinase

CEA:

Carcinoembryonic antigen

CEACAM:

CEA-related adhesion molecules

CNS:

Central nervous system

COP1:

Caspase recruitment domain-containing protein 16

CPT:

Carnitine palmitoyl transferase

CVD:

Cardiovascular diseases

ER:

Endoplasmic reticulum

FA:

Fatty acids

FAS:

Fatty acid synthase

FFA/NEFA:

Free fatty acids/non-esterified FA

Fkhr/FoxO1:

Forkhead transcription factor

G6Pase:

Glucose-6-phosphatase

Gab:

Grb2-associated-binding protein

GLP:

Glucagon-like peptide

GLUT:

Glucose transporter

Grb2:

Growth factor receptor-bound protein 2

GSK3:

Glycogen synthase kinase 3

IGF:

Insulin growth factor

IL:

Interleukin

IR:

Insulin receptor

IRR:

Insulin receptor-related receptor

IRS:

Insulin-receptor substrate

JAK:

Janus kinase

KO:

Knockout

LAR:

Leukocyte common antigen-related (phosphatase)

LMW-PTP:

Low molecular weight PTP

MAPK/ERK:

Mitogen activated protein kinase/Extracellular signal-regulated kinase

MCK:

Muscle creatine kinase

MEK:

MAPK kinase

mRNA:

Messenger ribonucleic acid

mTORC:

Mammalian TOR complex

NAFLD:

Non-alcoholic fatty liver disease

NEFA:

Non-esterified fatty acids

NO:

Nitric oxide

p60dok :

60-kDa tyrosine phosphorylated protein

PAF:

RNA polymerase II associated factor

PDK:

PDH kinase or Phosphoinositide-dependent kinase

PGC-1:

PPARγ co-activator 1

PH:

Pleckstrin homology

PHLPP:

PH-domain leucine-rich repeat protein phosphatase

PI3K:

Phosphatidylinositol 3-kinase

PIP2:

Phosphotidylinositol-4,5-bisphosphate

PIP3:

Phosphotidylinositol-3,4,5-triphosphate

PKB:

Protein kinase B (also known as Akt)

PM:

Plasmic membrane

PP:

Protein phosphatase

PPAR:

Peroxisome proliferator-activated receptor

Prep:

PBX-regulating protein

PTB:

Phospho-tyrosine binding domain

PTEN:

Phosphatase with sequence homology to protein-tyrosine phosphatases and the cytoskeleton protein tensin

PTP:

Protein tyrosine phosphatase

Raf:

Proto-oncogene serine/threonine-protein kinase

Ras:

G-protein and/or a family of related proteins discovered from rat sarcoma

RPTP:

Receptor-like PTP

RTK:

Receptor tyrosine kinases

S6K1:

S6 kinase 1

SCD:

Stearoyl-CoA desaturase

SH:

Src homology

Shc:

SH2-domain containing proteins

SHP:

2-SH2-domain containing protein tyrosine phosphatase

SNARE:

Soluble NSF attachment protein receptor

SOS:

Son-of-sevenless exchange protein

SREBP:

Sterol response element binding protein

STAT:

Signal transducer and activator of transcription

STP:

Serine/threonine phosphatase

T2D:

Type 2 diabetes

TAO:

Thousand and one amino acid kinase

TC-PTP:

T-cell PTP

TF:

Transcription factors

TNF:

Tumor necrosis factor

TOR:

Target of rapamycin

WHO:

World Health Organization

Wnt:

Wingless and int-1

References

  1. Waxman A. WHO global strategy on diet, physical activity and health. Food Nutr Bull. 2004;25(3):292–302.

    PubMed  Google Scholar 

  2. O’Sullivan JB, Mahan CM. Blood sugar levels, glycosuria, and body weight related to development of diabetes mellitus. The Oxford epidemiologic study 17 years later. JAMA. 1965;194(6):587–92.

    PubMed  Google Scholar 

  3. Wilson PW, McGee DL, Kannel WB. Obesity, very low density lipoproteins, and glucose intolerance over fourteen years: the Framingham study. Am J Epidemiol. 1981;114(5):697–704.

    CAS  PubMed  Google Scholar 

  4. Weyer C et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab. 2001;86(5):1930–5.

    CAS  PubMed  Google Scholar 

  5. McKenney RL, Short DK. Tipping the balance: the pathophysiology of obesity and type 2 diabetes mellitus. Surg Clin N Am. 2011;91(6):1139–48. vii.

    PubMed  Google Scholar 

  6. McCarthy MI. Genomics, type 2 diabetes, and obesity. N Engl J Med. 2010;363(24):2339–50.

    CAS  PubMed  Google Scholar 

  7. Smyth S, Heron A. Diabetes and obesity: the twin epidemics. Nat Med. 2006;12(1):75–80.

    CAS  PubMed  Google Scholar 

  8. DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14(3):173–94.

    CAS  PubMed  Google Scholar 

  9. Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148(5):852–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Goossens GH. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav. 2008;94(2):206–18.

    CAS  PubMed  Google Scholar 

  11. Qatanani M, Lazar MA. Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes Dev. 2007;21(12):1443–55.

    CAS  PubMed  Google Scholar 

  12. Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev. 2007;87(2):507–20.

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106(4):473–81.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Opie LH, Walfish PG. Plasma free fatty acid concentrations in obesity. N Engl J Med. 1963;268:757–60.

    CAS  PubMed  Google Scholar 

  15. Bjorntorp P, Bergman H, Varnauskas E. Plasma free fatty acid turnover rate in obesity. Acta Med Scand. 1969;185(4):351–6.

    CAS  PubMed  Google Scholar 

  16. Karpe F, Dickmann JR, Frayn KN. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes. 2011;60(10):2441–9.

    CAS  PubMed  Google Scholar 

  17. Boden G. Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes. 2011;18(2):139–43.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Randle PJ et al. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1(7285):785–9.

    CAS  PubMed  Google Scholar 

  19. Pan DA et al. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes. 1997;46(6):983–8.

    CAS  PubMed  Google Scholar 

  20. Roden M et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996;97(12):2859–65.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Boden G et al. FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. Am J Physiol Endocrinol Metab. 2002;283(1):E12–9.

    CAS  PubMed  Google Scholar 

  22. Lam TK et al. Mechanisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab. 2003;284(5):E863–73.

    CAS  PubMed  Google Scholar 

  23. Wu N et al. Taurine prevents free fatty acid-induced hepatic insulin resistance in association with inhibiting JNK1 activation and improving insulin signaling in vivo. Diabetes Res Clin Pract. 2010;90(3):288–96.

    CAS  PubMed  Google Scholar 

  24. Morita S, et al. Effect of exposure to non-esterified fatty acid on progressive deterioration of insulin secretion in patients with Type 2 diabetes: a long-term follow-up study. Diabet Med. 2012;29(8):980–5.

    Google Scholar 

  25. Koyama K et al. Tissue triglycerides, insulin resistance, and insulin production: implications for hyperinsulinemia of obesity. Am J Physiol. 1997;273(4 Pt 1):E708–13.

    CAS  PubMed  Google Scholar 

  26. Oprescu AI et al. Free fatty acid-induced reduction in glucose-stimulated insulin secretion: evidence for a role of oxidative stress in vitro and in vivo. Diabetes. 2007;56(12):2927–37.

    CAS  PubMed  Google Scholar 

  27. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116(7):1793–801.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Tremblay F et al. Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. Proc Natl Acad Sci U S A. 2007;104(35):14056–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Klip A, Paquet MR. Glucose transport and glucose transporters in muscle and their metabolic regulation. Diabetes Care. 1990;13(3):228–43.

    CAS  PubMed  Google Scholar 

  30. Heuson JC, Coune A, Heimann R. Cell proliferation induced by insulin in organ culture of rat mammary carcinoma. Exp Cell Res. 1967;45(2):351–60.

    CAS  PubMed  Google Scholar 

  31. Wang W et al. Mediator MED23 links insulin signaling to the adipogenesis transcription cascade. Dev Cell. 2009;16(5):764–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Pause A et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature. 1994;371(6500):762–7.

    CAS  PubMed  Google Scholar 

  33. Fulzele K et al. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell. 2010;142(2):309–19.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799–806.

    CAS  PubMed  Google Scholar 

  35. Buchanan KD, Mawhinney WA. Insulin control of glucagon release from insulin-deficient rat islets. Diabetes. 1973;22(11):801–3.

    CAS  PubMed  Google Scholar 

  36. Koch L et al. Central insulin action regulates peripheral glucose and fat metabolism in mice. J Clin Invest. 2008;118(6):2132–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Konner AC et al. Role for insulin signaling in catecholaminergic neurons in control of energy homeostasis. Cell Metab. 2011;13(6):720–8.

    PubMed  Google Scholar 

  38. Bruning JC et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289(5487):2122–5.

    CAS  PubMed  Google Scholar 

  39. Fisher SJ et al. Insulin signaling in the central nervous system is critical for the normal sympathoadrenal response to hypoglycemia. Diabetes. 2005;54(5):1447–51.

    CAS  PubMed  Google Scholar 

  40. Hill JW et al. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab. 2010;11(4):286–97.

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Konner AC et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 2007;5(6):438–49.

    PubMed  Google Scholar 

  42. Lee JC, Downing SE. Effects of insulin on cardiac muscle contraction and responsiveness to norepinephrine. Am J Physiol. 1976;230(5):1360–5.

    CAS  PubMed  Google Scholar 

  43. Maier S et al. Stimulation of L-type Ca2+ current in human atrial myocytes by insulin. Cardiovasc Res. 1999;44(2):390–7.

    CAS  PubMed  Google Scholar 

  44. Gupta AK, Clark RV, Kirchner KA. Effects of insulin on renal sodium excretion. Hypertension. 1992;19(1 Suppl):I78–82.

    CAS  PubMed  Google Scholar 

  45. Alvestrand A et al. Insulin-mediated potassium uptake is normal in uremic and healthy subjects. Am J Physiol. 1984;246(2 Pt 1):E174–80.

    CAS  PubMed  Google Scholar 

  46. Breen DM, Giacca A. Effects of insulin on the vasculature. Curr Vasc Pharmacol. 2011;9(3):321–32.

    CAS  PubMed  Google Scholar 

  47. Rubinsztein DC, Marino G, Kroemer G. Autophagy and aging. Cell. 2011;146(5):682–95.

    CAS  PubMed  Google Scholar 

  48. Muller D et al. Identification of insulin signaling elements in human beta-cells: autocrine regulation of insulin gene expression. Diabetes. 2006;55(10):2835–42.

    CAS  PubMed  Google Scholar 

  49. Kulkarni RN et al. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell. 1999;96(3):329–39.

    CAS  PubMed  Google Scholar 

  50. Lim GE et al. Insulin regulates glucagon-like peptide-1 secretion from the enteroendocrine L cell. Endocrinology. 2009;150(2):580–91.

    CAS  PubMed  Google Scholar 

  51. Kovacina KS, Roth RA. Characterization of the endogenous insulin receptor-related receptor in neuroblastomas. J Biol Chem. 1995;270(4):1881–7.

    CAS  PubMed  Google Scholar 

  52. Butler AA, LeRoith D. Minireview: tissue-specific versus generalized gene targeting of the igf1 and igf1r genes and their roles in insulin-like growth factor physiology. Endocrinology. 2001;142(5):1685–8.

    CAS  PubMed  Google Scholar 

  53. Patti ME, Kahn CR. The insulin receptor–a critical link in glucose homeostasis and insulin action. J Basic Clin Physiol Pharmacol. 1998;9(2–4):89–109.

    CAS  PubMed  Google Scholar 

  54. De Meyts P, Whittaker J. Structural biology of insulin and IGF1 receptors: implications for drug design. Nat Rev Drug Discov. 2002;1(10):769–83.

    PubMed  Google Scholar 

  55. Lizcano JM, Alessi DR. The insulin signalling pathway. Curr Biol. 2002;12(7):R236–8.

    CAS  PubMed  Google Scholar 

  56. Zhang-Sun G et al. A 60-kilodalton protein in rat hepatoma cells overexpressing insulin receptor was tyrosine phosphorylated and associated with Syp, phophatidylinositol 3-kinase, and Grb2 in an insulin-dependent manner. Endocrinology. 1996;137(7):2649–58.

    CAS  PubMed  Google Scholar 

  57. Moodie SA, Alleman-Sposeto J, Gustafson TA. Identification of the APS protein as a novel insulin receptor substrate. J Biol Chem. 1999;274(16):11186–93.

    CAS  PubMed  Google Scholar 

  58. Pronk GJ et al. Insulin-induced phosphorylation of the 46- and 52-kDa Shc proteins. J Biol Chem. 1993;268(8):5748–53.

    CAS  PubMed  Google Scholar 

  59. Huang C et al. Differential contribution of insulin receptor substrates 1 versus 2 to insulin signaling and glucose uptake in l6 myotubes. J Biol Chem. 2005;280(19):19426–35.

    CAS  PubMed  Google Scholar 

  60. Previs SF et al. Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo. J Biol Chem. 2000;275(50):38990–4.

    CAS  PubMed  Google Scholar 

  61. Kido Y et al. Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Invest. 2000;105(2):199–205.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Rhodes CJ, White MF. Molecular insights into insulin action and secretion. Eur J Clin Invest. 2002;32 Suppl 3:3–13.

    CAS  PubMed  Google Scholar 

  63. Sadagurski M et al. Insulin receptor substrate 2 plays diverse cell-specific roles in the regulation of glucose transport. J Biol Chem. 2005;280(15):14536–44.

    CAS  PubMed  Google Scholar 

  64. Withers DJ et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 1998;391(6670):900–4.

    CAS  PubMed  Google Scholar 

  65. Yamauchi T et al. Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. Mol Cell Biol. 1996;16(6):3074–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Tamemoto H et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature. 1994;372(6502):182–6.

    CAS  PubMed  Google Scholar 

  67. Araki E et al. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994;372(6502):186–90.

    CAS  PubMed  Google Scholar 

  68. Kubota N et al. Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding. Cell Metab. 2008;8(1):49–64.

    CAS  PubMed  Google Scholar 

  69. Tsuruzoe K et al. Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. Mol Cell Biol. 2001;21(1):26–38.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. White MF. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem. 1998;182(1–2):3–11.

    CAS  PubMed  Google Scholar 

  71. Backer JM et al. Insulin stimulation of phosphatidylinositol 3-kinase activity maps to insulin receptor regions required for endogenous substrate phosphorylation. J Biol Chem. 1992;267(2):1367–74.

    CAS  PubMed  Google Scholar 

  72. Lietzke SE et al. Structural basis of 3-phosphoinositide recognition by pleckstrin homology domains. Mol Cell. 2000;6(2):385–94.

    CAS  PubMed  Google Scholar 

  73. Peterson RT, Schreiber SL. Kinase phosphorylation: keeping it all in the family. Curr Biol. 1999;9(14):R521–4.

    CAS  PubMed  Google Scholar 

  74. Mackay DJ, Hall A. Rho GTPases. J Biol Chem. 1998;273(33):20685–8.

    CAS  PubMed  Google Scholar 

  75. Ziegler SF et al. Molecular cloning and characterization of a novel receptor protein tyrosine kinase from human placenta. Oncogene. 1993;8(3):663–70.

    CAS  PubMed  Google Scholar 

  76. Alessi DR et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997;7(4):261–9.

    CAS  PubMed  Google Scholar 

  77. Stephens L et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science. 1998;279(5351):710–4.

    CAS  PubMed  Google Scholar 

  78. Sarbassov DD et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098–101.

    CAS  PubMed  Google Scholar 

  79. Paz K et al. Phosphorylation of insulin receptor substrate-1 (IRS-1) by protein kinase B positively regulates IRS-1 function. J Biol Chem. 1999;274(40):28816–22.

    CAS  PubMed  Google Scholar 

  80. Standaert ML et al. Protein kinase C-zeta as a downstream effector of phosphatidylinositol 3-kinase during insulin stimulation in rat adipocytes. Potential role in glucose transport. J Biol Chem. 1997;272(48):30075–82.

    CAS  PubMed  Google Scholar 

  81. Chou MM et al. Regulation of protein kinase C zeta by PI 3-kinase and PDK-1. Curr Biol. 1998;8(19):1069–77.

    CAS  PubMed  Google Scholar 

  82. Scott PH et al. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci U S A. 1998;95(13):7772–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Cross DA et al. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378(6559):785–9.

    CAS  PubMed  Google Scholar 

  84. Li X et al. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature. 2007;447(7147):1012–6.

    CAS  PubMed  Google Scholar 

  85. Nakae J, Park BC, Accili D. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J Biol Chem. 1999;274(23):15982–5.

    CAS  PubMed  Google Scholar 

  86. Cook SA et al. Transcriptional effects of chronic Akt activation in the heart. J Biol Chem. 2002;277(25):22528–33.

    CAS  PubMed  Google Scholar 

  87. Yoon JC et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001;413(6852):131–8.

    CAS  PubMed  Google Scholar 

  88. Puigserver P et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 2003;423(6939):550–5.

    CAS  PubMed  Google Scholar 

  89. Boulton TG et al. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell. 1991;65(4):663–75.

    CAS  PubMed  Google Scholar 

  90. Lazar DF et al. Mitogen-activated protein kinase kinase inhibition does not block the stimulation of glucose utilization by insulin. J Biol Chem. 1995;270(35):20801–7.

    CAS  PubMed  Google Scholar 

  91. Noguchi T et al. Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. Mol Cell Biol. 1994;14(10):6674–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Sasaoka T et al. Evidence for a functional role of Shc proteins in mitogenic signaling induced by insulin, insulin-like growth factor-1, and epidermal growth factor. J Biol Chem. 1994;269(18):13689–94.

    CAS  PubMed  Google Scholar 

  93. Moscat J, Diaz-Meco MT. Feedback on fat: p62-mTORC1-autophagy connections. Cell. 2011;147(4):724–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Raught B, Gingras AC, Sonenberg N. The target of rapamycin (TOR) proteins. Proc Natl Acad Sci U S A. 2001;98(13):7037–44.

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471–84.

    CAS  PubMed  Google Scholar 

  96. Peterson TR et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137(5):873–86.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell. 2009;136(4):731–45.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Alessi DR, Pearce LR, Garcia-Martinez JM. New insights into mTOR signaling: mTORC2 and beyond. Sci Signal. 2009;2(67):pe27.

    PubMed  Google Scholar 

  99. Laplante M, Sabatini DM. An emerging role of mTOR in lipid biosynthesis. Curr Biol. 2009;19(22):R1046–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Avruch J et al. Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab. 2009;296(4):E592–602.

    CAS  PubMed  Google Scholar 

  101. Manning BD, Cantley LC. Rheb fills a GAP between TSC and TOR. Trends Biochem Sci. 2003;28(11):573–6.

    CAS  PubMed  Google Scholar 

  102. Nave BT et al. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J. 1999;344(Pt 2):427–31.

    CAS  PubMed  Google Scholar 

  103. Tzatsos A, Kandror KV. Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol Cell Biol. 2006;26(1):63–76.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Tremblay F, Marette A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem. 2001;276(41):38052–60.

    CAS  PubMed  Google Scholar 

  105. Tremblay F et al. Activation of the mammalian target of rapamycin pathway acutely inhibits insulin signaling to Akt and glucose transport in 3T3-L1 and human adipocytes. Endocrinology. 2005;146(3):1328–37.

    CAS  PubMed  Google Scholar 

  106. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000;106(2):171–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Hotamisligil GS. The role of TNFalpha and TNF receptors in obesity and insulin resistance. J Intern Med. 1999;245(6):621–5.

    CAS  PubMed  Google Scholar 

  108. Ogg S, Ruvkun G. The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol Cell. 1998;2(6):887–93.

    CAS  PubMed  Google Scholar 

  109. Wada T et al. Role of the Src homology 2 (SH2) domain and C-terminus tyrosine phosphorylation sites of SH2-containing inositol phosphatase (SHIP) in the regulation of insulin-induced mitogenesis. Endocrinology. 1999;140(10):4585–94.

    CAS  PubMed  Google Scholar 

  110. Lazar DF, Saltiel AR. Lipid phosphatases as drug discovery targets for type 2 diabetes. Nat Rev Drug Discov. 2006;5(4):333–42.

    CAS  PubMed  Google Scholar 

  111. Sigal YJ, McDermott MI, Morris AJ. Integral membrane lipid phosphatases/phosphotransferases: common structure and diverse functions. Biochem J. 2005;387(Pt 2):281–93.

    CAS  PubMed  Google Scholar 

  112. Mistafa O et al. Purinergic receptor-mediated rapid depletion of nuclear phosphorylated Akt depends on pleckstrin homology domain leucine-rich repeat phosphatase, calcineurin, protein phosphatase 2A, and PTEN phosphatases. J Biol Chem. 2010;285(36):27900–10.

    CAS  PubMed  Google Scholar 

  113. Finck BN et al. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab. 2006;4(3):199–210.

    CAS  PubMed  Google Scholar 

  114. Peterson TR et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell. 2011;146(3):408–20.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Armstrong CG, Doherty MJ, Cohen PT. Identification of the separate domains in the hepatic glycogen-targeting subunit of protein phosphatase 1 that interact with phosphorylase a, glycogen and protein phosphatase 1. Biochem J. 1998;336(Pt 3):699–704.

    CAS  PubMed  Google Scholar 

  116. Wong RH, Sul HS. Insulin signaling in fatty acid and fat synthesis: a transcriptional perspective. Curr Opin Pharmacol. 2010;10(6):684–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Galbo T et al. Free fatty acid-induced PP2A hyperactivity selectively impairs hepatic insulin action on glucose metabolism. PLoS One. 2011;6(11):e27424.

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Yan L, et al. The B55α-containing PP2A holoenzyme dephosphorylates FOXO1 in islet β-cells under oxidative stress. Biochem J. 2012;444(2):239–47.

    Google Scholar 

  119. Andreozzi F et al. Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance. Diabetologia. 2011;54(7):1879–87.

    CAS  PubMed  Google Scholar 

  120. Xiao L et al. Protein phosphatase-1 regulates Akt1 signal transduction pathway to control gene expression, cell survival and differentiation. Cell Death Differ. 2010;17(9):1448–62.

    CAS  PubMed  Google Scholar 

  121. Andjelkovic M et al. Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors. Proc Natl Acad Sci U S A. 1996;93(12):5699–704.

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Gao T, Furnari F, Newton AC. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell. 2005;18(1):13–24.

    CAS  PubMed  Google Scholar 

  123. Brautigan DL, Bornstein P, Gallis B. Phosphotyrosyl-protein phosphatase. Specific inhibition by Zn. J Biol Chem. 1981;256(13):6519–22.

    CAS  PubMed  Google Scholar 

  124. Schaapveld R, Wieringa B, Hendriks W. Receptor-like protein tyrosine phosphatases: alike and yet so different. Mol Biol Rep. 1997;24(4):247–62.

    CAS  PubMed  Google Scholar 

  125. Alonso A et al. Protein tyrosine phosphatases in the human genome. Cell. 2004;117(6):699–711.

    CAS  PubMed  Google Scholar 

  126. Koren S, Fantus IG. Inhibition of the protein tyrosine phosphatase PTP1B: potential therapy for obesity, insulin resistance and type-2 diabetes mellitus. Best Pract Res Clin Endocrinol Metab. 2007;21(4):621–40.

    CAS  PubMed  Google Scholar 

  127. Hashimoto N et al. Insulin receptor protein-tyrosine phosphatases. Leukocyte common antigen-related phosphatase rapidly deactivates the insulin receptor kinase by preferential dephosphorylation of the receptor regulatory domain. J Biol Chem. 1992;267(20):13811–4.

    CAS  PubMed  Google Scholar 

  128. Frangioni JV et al. The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence. Cell. 1992;68(3):545–60.

    CAS  PubMed  Google Scholar 

  129. Egawa K et al. Protein-tyrosine phosphatase-1B negatively regulates insulin signaling in l6 myocytes and Fao hepatoma cells. J Biol Chem. 2001;276(13):10207–11.

    CAS  PubMed  Google Scholar 

  130. Goldstein BJ et al. Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein. J Biol Chem. 2000;275(6):4283–9.

    CAS  PubMed  Google Scholar 

  131. Dubois MJ et al. The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis. Nat Med. 2006;12(5):549–56.

    CAS  PubMed  Google Scholar 

  132. Kuhne MR et al. Dephosphorylation of insulin receptor substrate 1 by the tyrosine phosphatase PTP2C. J Biol Chem. 1994;269(22):15833–7.

    CAS  PubMed  Google Scholar 

  133. Kulas DT et al. Insulin receptor signaling is augmented by antisense inhibition of the protein tyrosine phosphatase LAR. J Biol Chem. 1995;270(6):2435–8.

    CAS  PubMed  Google Scholar 

  134. Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia. 1978;14(3):141–8.

    CAS  PubMed  Google Scholar 

  135. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860–7.

    CAS  PubMed  Google Scholar 

  136. Plum L, Belgardt BF, Bruning JC. Central insulin action in energy and glucose homeostasis. J Clin Invest. 2006;116(7):1761–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012;489(7415):242–9.

    CAS  PubMed  Google Scholar 

  138. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140(6):900–17.

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Szendroedi J, Phielix E, Roden M. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(2):92–103.

    CAS  Google Scholar 

  140. Patel N, Huang C, Klip A. Cellular location of insulin-triggered signals and implications for glucose uptake. Pflugers Arch. 2006;451(4):499–510.

    CAS  PubMed  Google Scholar 

  141. Filippi BM et al. Insulin activates Erk1/2 signaling in the dorsal vagal complex to inhibit glucose production. Cell Metab. 2012;16(4):500–10.

    CAS  PubMed  Google Scholar 

  142. Ozcan L et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009;9(1):35–51.

    CAS  PubMed  Google Scholar 

  143. Ahmad F, Goldstein BJ. Functional association between the insulin receptor and the transmembrane protein-tyrosine phosphatase LAR in intact cells. J Biol Chem. 1997;272(1):448–57.

    CAS  PubMed  Google Scholar 

  144. Norris K et al. Expression of protein-tyrosine phosphatases in the major insulin target tissues. FEBS Lett. 1997;415(3):243–8.

    CAS  PubMed  Google Scholar 

  145. Zhang WR et al. Modulation of insulin signal transduction by eutopic overexpression of the receptor-type protein-tyrosine phosphatase LAR. Mol Endocrinol. 1996;10(5):575–84.

    CAS  PubMed  Google Scholar 

  146. Li PM, Zhang WR, Goldstein BJ. Suppression of insulin receptor activation by overexpression of the protein-tyrosine phosphatase LAR in hepatoma cells. Cell Signal. 1996;8(7):467–73.

    CAS  PubMed  Google Scholar 

  147. Ren JM et al. Transgenic mice deficient in the LAR protein-tyrosine phosphatase exhibit profound defects in glucose homeostasis. Diabetes. 1998;47(3):493–7.

    CAS  PubMed  Google Scholar 

  148. Zabolotny JM et al. Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance. Proc Natl Acad Sci U S A. 2001;98(9):5187–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Ahmad F, Considine RV, Goldstein BJ. Increased abundance of the receptor-type protein-tyrosine phosphatase LAR accounts for the elevated insulin receptor dephosphorylating activity in adipose tissue of obese human subjects. J Clin Invest. 1995;95(6):2806–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Ahmad F, Goldstein BJ. Increased abundance of specific skeletal muscle protein-tyrosine phosphatases in a genetic model of insulin-resistant obesity and diabetes mellitus. Metabolism. 1995;44(9):1175–84.

    CAS  PubMed  Google Scholar 

  151. Um JW, Ko J. LAR-RPTPs: synaptic adhesion molecules that shape synapse development. Trends Cell Biol. 2013;23(10):465–75.

    Google Scholar 

  152. Garcia-San Frutos M et al. Involvement of protein tyrosine phosphatases and inflammation in hypothalamic insulin resistance associated with ageing: effect of caloric restriction. Mech Ageing Dev. 2012;133(7):489–97.

    CAS  PubMed  Google Scholar 

  153. Elchebly M et al. Neuroendocrine dysplasia in mice lacking protein tyrosine phosphatase sigma. Nat Genet. 1999;21(3):330–3.

    CAS  PubMed  Google Scholar 

  154. Wallace MJ et al. Neuronal defects and posterior pituitary hypoplasia in mice lacking the receptor tyrosine phosphatase PTPsigma. Nat Genet. 1999;21(3):334–8.

    CAS  PubMed  Google Scholar 

  155. Lam CK, Chari M, Lam TK. CNS regulation of glucose homeostasis. Physiology (Bethesda). 2009;24:159–70.

    CAS  Google Scholar 

  156. Hendriks WJ, Pulido R. Protein tyrosine phosphatase variants in human hereditary disorders and disease susceptibilities. Biochim Biophys Acta. 2013;1832(10):1673–96.

    CAS  PubMed  Google Scholar 

  157. Tagami S et al. Troglitazone ameliorates abnormal activity of protein tyrosine phosphatase in adipose tissues of Otsuka Long-Evans Tokushima Fatty rats. Tohoku J Exp Med. 2002;197(3):169–81.

    CAS  PubMed  Google Scholar 

  158. Gonzalez-Rodriguez A et al. Essential role of protein tyrosine phosphatase 1B in obesity-induced inflammation and peripheral insulin resistance during aging. Aging Cell. 2012;11(2):284–96.

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Zabolotny JM et al. Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo. J Biol Chem. 2008;283(21):14230–41.

    CAS  PubMed  Google Scholar 

  160. Elchebly M et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science. 1999;283(5407):1544–8.

    CAS  PubMed  Google Scholar 

  161. Delibegovic M et al. Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress. Diabetes. 2009;58(3):590–9.

    CAS  PubMed  Google Scholar 

  162. Agouni A, et al. Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress. Biochem J. 2011;438(2):369–78.

    Google Scholar 

  163. Owen C et al. Inducible liver-specific knockdown of protein tyrosine phosphatase 1B improves glucose and lipid homeostasis in adult mice. Diabetologia. 2013;56(10):2286–96.

    CAS  PubMed  Google Scholar 

  164. Bakke J et al. Regulation of the SNARE-interacting protein Munc18c tyrosine phosphorylation in adipocytes by protein-tyrosine phosphatase 1B. Cell Commun Signal. 2013;11(1):57.

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Song DD et al. Protein tyrosine phosphatase 1B inhibits adipocyte differentiation and mediates TNFalpha action in obesity. Biochim Biophys Acta. 2013;1831(8):1368–76.

    CAS  PubMed  Google Scholar 

  166. Owen C et al. Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis. PLoS One. 2012;7(2):e32700.

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Delibegovic M et al. Improved glucose homeostasis in mice with muscle-specific deletion of protein-tyrosine phosphatase 1B. Mol Cell Biol. 2007;27(21):7727–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  168. Picardi PK et al. Modulation of hypothalamic PTP1B in the TNF-alpha-induced insulin and leptin resistance. FEBS Lett. 2010;584(14):3179–84.

    CAS  PubMed  Google Scholar 

  169. Zhang J et al. Protein tyrosine phosphatase 1B deficiency ameliorates murine experimental colitis via the expansion of myeloid-derived suppressor cells. PLoS One. 2013;8(8):e70828.

    CAS  PubMed Central  PubMed  Google Scholar 

  170. Nasimian A et al. Protein tyrosine phosphatase 1B (PTP1B) modulates palmitate-induced cytokine production in macrophage cells. Inflamm Res. 2013;62(2):239–46.

    CAS  PubMed  Google Scholar 

  171. Xu H et al. Phosphatase PTP1B negatively regulates MyD88- and TRIF-dependent proinflammatory cytokine and type I interferon production in TLR-triggered macrophages. Mol Immunol. 2008;45(13):3545–52.

    CAS  PubMed  Google Scholar 

  172. Pandey NR et al. The LIM domain only 4 protein is a metabolic responsive inhibitor of protein tyrosine phosphatase 1B that controls hypothalamic leptin signaling. J Neurosci. 2013;33(31):12647–55.

    CAS  PubMed  Google Scholar 

  173. Bettaieb A et al. Differential regulation of endoplasmic reticulum stress by protein tyrosine phosphatase 1B and T cell protein tyrosine phosphatase. J Biol Chem. 2011;286(11):9225–35.

    CAS  PubMed  Google Scholar 

  174. White CL et al. HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms. Am J Physiol Endocrinol Metab. 2009;296(2):E291–9.

    CAS  PubMed  Google Scholar 

  175. Bence KK et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med. 2006;12(8):917–24.

    CAS  PubMed  Google Scholar 

  176. Banno R et al. PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. J Clin Invest. 2010;120(3):720–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  177. Gu F et al. Protein-tyrosine phosphatase 1B potentiates IRE1 signaling during endoplasmic reticulum stress. J Biol Chem. 2004;279(48):49689–93.

    CAS  PubMed  Google Scholar 

  178. Snider NT, Park H, Omary MB. A conserved rod domain phosphotyrosine that is targeted by the phosphatase PTP1B promotes keratin 8 insolubility and filament organization. J Biol Chem. 2013;288(43):31329–37.

    Google Scholar 

  179. Chiarugi P et al. LMW-PTP is a negative regulator of insulin-mediated mitotic and metabolic signalling. Biochem Biophys Res Commun. 1997;238(2):676–82.

    CAS  PubMed  Google Scholar 

  180. Pandey SK et al. Reduction of low molecular weight protein-tyrosine phosphatase expression improves hyperglycemia and insulin sensitivity in obese mice. J Biol Chem. 2007;282(19):14291–9.

    CAS  PubMed  Google Scholar 

  181. Cho CY et al. Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling. Cell Metab. 2006;3(5):367–78.

    CAS  PubMed  Google Scholar 

  182. Moller NP et al. Selective down-regulation of the insulin receptor signal by protein-tyrosine phosphatases alpha and epsilon. J Biol Chem. 1995;270(39):23126–31.

    CAS  PubMed  Google Scholar 

  183. Lammers R, Moller NP, Ullrich A. The transmembrane protein tyrosine phosphatase alpha dephosphorylates the insulin receptor in intact cells. FEBS Lett. 1997;404(1):37–40.

    CAS  PubMed  Google Scholar 

  184. Cong LN et al. Overexpression of protein tyrosine phosphatase-alpha (PTP-alpha) but not PTP-kappa inhibits translocation of GLUT4 in rat adipose cells. Biochem Biophys Res Commun. 1999;255(2):200–7.

    CAS  PubMed  Google Scholar 

  185. Kapp K et al. The protein tyrosine phosphatase alpha modifies insulin secretion in INS-1E cells. Biochem Biophys Res Commun. 2003;311(2):361–4.

    CAS  PubMed  Google Scholar 

  186. Arnott CH et al. Use of an antisense strategy to dissect the signaling role of protein-tyrosine phosphatase alpha. J Biol Chem. 1999;274(37):26105–12.

    CAS  PubMed  Google Scholar 

  187. Le HT, Ponniah S, Pallen CJ. Insulin signaling and glucose homeostasis in mice lacking protein tyrosine phosphatase alpha. Biochem Biophys Res Commun. 2004;314(2):321–9.

    CAS  PubMed  Google Scholar 

  188. Andersen JN et al. Comparative study of protein tyrosine phosphatase-epsilon isoforms: membrane localization confers specificity in cellular signalling. Biochem J. 2001;354(Pt 3):581–90.

    CAS  PubMed  Google Scholar 

  189. Aga-Mizrachi S et al. Cytosolic protein tyrosine phosphatase-epsilon is a negative regulator of insulin signaling in skeletal muscle. Endocrinology. 2008;149(2):605–14.

    CAS  PubMed  Google Scholar 

  190. Faisal A et al. Serine/threonine phosphorylation of ShcA. Regulation of protein-tyrosine phosphatase-pest binding and involvement in insulin signaling. J Biol Chem. 2002;277(33):30144–52.

    CAS  PubMed  Google Scholar 

  191. Galic S et al. Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP. Mol Cell Biol. 2003;23(6):2096–108.

    CAS  PubMed Central  PubMed  Google Scholar 

  192. Xu J et al. Effects of small interference RNA against PTP1B and TCPTP on insulin signaling pathway in mouse liver: evidence for non-synergetic cooperation. Cell Biol Int. 2007;31(1):88–91.

    CAS  PubMed  Google Scholar 

  193. Fukushima A et al. T-cell protein tyrosine phosphatase attenuates STAT3 and insulin signaling in the liver to regulate gluconeogenesis. Diabetes. 2010;59(8):1906–14.

    CAS  PubMed  Google Scholar 

  194. Loh K et al. T cell protein tyrosine phosphatase (TCPTP) deficiency in muscle does not alter insulin signalling and glucose homeostasis in mice. Diabetologia. 2012;55(2):468–78.

    CAS  PubMed  Google Scholar 

  195. Zee T et al. T-cell protein tyrosine phosphatase regulates bone resorption and whole-body insulin sensitivity through its expression in osteoblasts. Mol Cell Biol. 2012;32(6):1080–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  196. Rajshankar D et al. Role of PTPalpha in the destruction of periodontal connective tissues. PLoS One. 2013;8(8):e70659.

    CAS  PubMed Central  PubMed  Google Scholar 

  197. Tiganis T. PTP1B and TCPTP–nonredundant phosphatases in insulin signaling and glucose homeostasis. FEBS J. 2013;280(2):445–58.

    CAS  PubMed  Google Scholar 

  198. Loh K et al. Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metab. 2011;14(5):684–99.

    CAS  PubMed Central  PubMed  Google Scholar 

  199. Tsui HW et al. Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nat Genet. 1993;4(2):124–9.

    CAS  PubMed  Google Scholar 

  200. Shultz LD et al. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell. 1993;73(7):1445–54.

    CAS  PubMed  Google Scholar 

  201. Qu CK. Role of the SHP-2 tyrosine phosphatase in cytokine-induced signaling and cellular response. Biochim Biophys Acta. 2002;1592(3):297–301.

    CAS  PubMed  Google Scholar 

  202. Poole AW, Jones ML. A SHPing tale: perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail. Cell Signal. 2005;17(11):1323–32.

    CAS  PubMed  Google Scholar 

  203. Chong ZZ, Maiese K. The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: diversified control of cell growth, inflammation, and injury. Histol Histopathol. 2007;22(11):1251–67.

    CAS  PubMed Central  PubMed  Google Scholar 

  204. Banville D, Stocco R, Shen SH. Human protein tyrosine phosphatase 1C (PTPN6) gene structure: alternate promoter usage and exon skipping generate multiple transcripts. Genomics. 1995;27(1):165–73.

    CAS  PubMed  Google Scholar 

  205. Jin YJ, Yu CL, Burakoff SJ. Human 70-kDa SHP-1L differs from 68-kDa SHP-1 in its C-terminal structure and catalytic activity. J Biol Chem. 1999;274(40):28301–7.

    CAS  PubMed  Google Scholar 

  206. Yi TL, Cleveland JL, Ihle JN. Protein tyrosine phosphatase containing SH2 domains: characterization, preferential expression in hematopoietic cells, and localization to human chromosome 12p12-p13. Mol Cell Biol. 1992;12(2):836–46.

    CAS  PubMed Central  PubMed  Google Scholar 

  207. Horvat A et al. A novel role for protein tyrosine phosphatase shp1 in controlling glial activation in the normal and injured nervous system. J Neurosci. 2001;21(3):865–74.

    CAS  PubMed  Google Scholar 

  208. Lurie DI et al. Tyrosine phosphatase SHP-1 immunoreactivity increases in a subset of astrocytes following deafferentation of the chicken auditory brainstem. J Comp Neurol. 2000;421(2):199–214.

    CAS  PubMed  Google Scholar 

  209. Massa PT et al. Expression and function of the protein tyrosine phosphatase SHP-1 in oligodendrocytes. Glia. 2000;29(4):376–85.

    CAS  PubMed  Google Scholar 

  210. Kim HY et al. Raft-mediated Src homology 2 domain-containing proteintyrosine phosphatase 2 (SHP-2) regulation in microglia. J Biol Chem. 2006;281(17):11872–8.

    CAS  PubMed  Google Scholar 

  211. Valencia AM et al. Identification of a protein-tyrosine phosphatase (SHP1) different from that associated with acid phosphatase in rat prostate. FEBS Lett. 1997;406(1–2):42–8.

    CAS  PubMed  Google Scholar 

  212. Vogel W et al. Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Science. 1993;259(5101):1611–4.

    CAS  PubMed  Google Scholar 

  213. Yang J et al. Crystal structure of human protein-tyrosine phosphatase SHP-1. J Biol Chem. 2003;278(8):6516–20.

    CAS  PubMed  Google Scholar 

  214. Plutzky J, Neel BG, Rosenberg RD. Isolation of a src homology 2-containing tyrosine phosphatase. Proc Natl Acad Sci U S A. 1992;89(3):1123–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  215. Ren L et al. Substrate specificity of protein tyrosine phosphatases 1B, RPTPalpha, SHP-1, and SHP-2. Biochemistry. 2011;50(12):2339–56.

    CAS  PubMed Central  PubMed  Google Scholar 

  216. Yang J et al. Crystal structure of the catalytic domain of protein-tyrosine phosphatase SHP-1. J Biol Chem. 1998;273(43):28199–207.

    CAS  PubMed  Google Scholar 

  217. Liu W, et al. Identification of cryptotanshinone as an inhibitor of Oncogenic protein tyrosine phosphatase SHP2 (PTPN11). J Med Chem. 2013;56(18):7212–21.

    Google Scholar 

  218. Pei D et al. Intramolecular regulation of protein tyrosine phosphatase SH-PTP1: a new function for Src homology 2 domains. Biochemistry. 1994;33(51):15483–93.

    CAS  PubMed  Google Scholar 

  219. Zhao Z et al. Purification and characterization of a protein tyrosine phosphatase containing SH2 domains. J Biol Chem. 1993;268(4):2816–20.

    CAS  PubMed  Google Scholar 

  220. Bennett AM et al. Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras. Proc Natl Acad Sci U S A. 1994;91(15):7335–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  221. Frank C et al. Effective dephosphorylation of Src substrates by SHP-1. J Biol Chem. 2004;279(12):11375–83.

    CAS  PubMed  Google Scholar 

  222. Uchida T et al. Insulin stimulates the phosphorylation of Tyr538 and the catalytic activity of PTP1C, a protein tyrosine phosphatase with Src homology-2 domains. J Biol Chem. 1994;269(16):12220–8.

    CAS  PubMed  Google Scholar 

  223. Hsu MF, Meng TC. Enhancement of insulin responsiveness by nitric oxide-mediated inactivation of protein-tyrosine phosphatases. J Biol Chem. 2009;285(11):7919–28.

    Google Scholar 

  224. Ozawa T et al. Negative autoregulation of Src homology region 2-domain-containing phosphatase-1 in rat basophilic leukemia-2H3 cells. Int Immunol. 2007;19(9):1049–61.

    CAS  PubMed  Google Scholar 

  225. Tenev T et al. Perinuclear localization of the protein-tyrosine phosphatase SHP-1 and inhibition of epidermal growth factor-stimulated STAT1/3 activation in A431 cells. Eur J Cell Biol. 2000;79(4):261–71.

    CAS  PubMed  Google Scholar 

  226. Ram PA, Waxman DJ. Interaction of growth hormone-activated STATs with SH2-containing phosphotyrosine phosphatase SHP-1 and nuclear JAK2 tyrosine kinase. J Biol Chem. 1997;272(28):17694–702.

    CAS  PubMed  Google Scholar 

  227. Yang W, Tabrizi M, Yi T. A bipartite NLS at the SHP-1 C-terminus mediates cytokine-induced SHP-1 nuclear localization in cell growth control. Blood Cells Mol Dis. 2002;28(1):63–74.

    PubMed  Google Scholar 

  228. Craggs G, Kellie S. A functional nuclear localization sequence in the C-terminal domain of SHP-1. J Biol Chem. 2001;276(26):23719–25.

    CAS  PubMed  Google Scholar 

  229. Watanabe N, et al. Heterogeneous nuclear ribonucleoprotein Q (hnRNP Q) is a novel substrate of SH2 domain-containing phosphatase-2 (SHP2). J Biochem. 2013;154(5):475–80.

    Google Scholar 

  230. Xu E, et al. Hepatocyte-specific Ptpn6 deletion protects from obesity-linked hepatic insulin resistance. Diabetes. 2012;61(8):1949–58.

    Google Scholar 

  231. Yu Z et al. SHP-1 associates with both platelet-derived growth factor receptor and the p85 subunit of phosphatidylinositol 3-kinase. J Biol Chem. 1998;273(6):3687–94.

    CAS  PubMed  Google Scholar 

  232. Cuevas BD et al. Tyrosine phosphorylation of p85 relieves its inhibitory activity on phosphatidylinositol 3-kinase. J Biol Chem. 2001;276(29):27455–61.

    CAS  PubMed  Google Scholar 

  233. Lu Y et al. Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase/AKT cascades. J Biol Chem. 2003;278(41):40057–66.

    CAS  PubMed  Google Scholar 

  234. Cui TX et al. Angiotensin II subtype 2 receptor activation inhibits insulin-induced phosphoinositide 3-kinase and Akt and induces apoptosis in PC12W cells. Mol Endocrinol. 2002;16(9):2113–23.

    CAS  PubMed  Google Scholar 

  235. Bergeron S et al. Inhibition of the protein tyrosine phosphatase SHP-1 increases glucose uptake in skeletal muscle cells by augmenting insulin receptor signaling and GLUT4 expression. Endocrinology. 2011;152(12):4581–8.

    CAS  PubMed  Google Scholar 

  236. Oriente F et al. Prep1 controls insulin glucoregulatory function in liver by transcriptional targeting of SHP1 tyrosine phosphatase. Diabetes. 2011;60(1):138–47.

    CAS  PubMed  Google Scholar 

  237. Fiset A et al. Compartmentalized CDK2 is connected with SHP-1 and beta-catenin and regulates insulin internalization. Cell Signal. 2011;23(5):911–9.

    CAS  PubMed  Google Scholar 

  238. Kahn CR et al. Quantitative aspects of the insulin-receptor interaction in liver plasma membranes. J Biol Chem. 1974;249(7):2249–57.

    CAS  PubMed  Google Scholar 

  239. Jaspan JB et al. Hepatic metabolism of glucagon in the dog: contribution of the liver to overall metabolic disposal of glucagon. Am J Physiol. 1981;240(3):E233–44.

    CAS  PubMed  Google Scholar 

  240. Sato H et al. Receptor-recycling model of clearance and distribution of insulin in the perfused mouse liver. Diabetologia. 1991;34(9):613–21.

    CAS  PubMed  Google Scholar 

  241. Burgess JW et al. Pharmacological doses of insulin equalize insulin receptor phosphotyrosine content but not tyrosine kinase activity in plasmalemmal and endosomal membranes. Biochem Cell Biol. 1992;70(10–11):1151–8.

    CAS  PubMed  Google Scholar 

  242. Bergeron JJ et al. Uptake of insulin and other ligands into receptor-rich endocytic components of target cells: the endosomal apparatus. Annu Rev Physiol. 1985;47:383–403.

    CAS  PubMed  Google Scholar 

  243. Yoshii H et al. Effects of portal free fatty acid elevation on insulin clearance and hepatic glucose flux. Am J Physiol Endocrinol Metab. 2006;290(6):E1089–97.

    CAS  PubMed  Google Scholar 

  244. Kotronen A et al. Effect of liver fat on insulin clearance. Am J Physiol Endocrinol Metab. 2007;293(6):E1709–15.

    CAS  PubMed  Google Scholar 

  245. Doherty 2nd JJ et al. Selective degradation of insulin within rat liver endosomes. J Cell Biol. 1990;110(1):35–42.

    CAS  PubMed  Google Scholar 

  246. Backer JM, Kahn CR, White MF. The dissociation and degradation of internalized insulin occur in the endosomes of rat hepatoma cells. J Biol Chem. 1990;265(25):14828–35.

    CAS  PubMed  Google Scholar 

  247. Di Guglielmo GM et al. Insulin receptor internalization and signalling. Mol Cell Biochem. 1998;182(1–2):59–63.

    PubMed  Google Scholar 

  248. Valera Mora ME et al. Insulin clearance in obesity. J Am Coll Nutr. 2003;22(6):487–93.

    PubMed  Google Scholar 

  249. Xu E et al. Targeted disruption of carcinoembryonic antigen-related cell adhesion molecule 1 promotes diet-induced hepatic steatosis and insulin resistance. Endocrinology. 2009;150(8):3503–12.

    CAS  PubMed  Google Scholar 

  250. Najjar SM. Regulation of insulin action by CEACAM1. Trends Endocrinol Metab. 2002;13(6):240–5.

    CAS  PubMed  Google Scholar 

  251. Huber M, Izzi L, Grondin P, Houde C, Kunath T, Veillette A, et al. The carboxyl-terminal region of biliary glycoprotein controls its tyrosine phosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells. J Biol Chem. 1999;274(1):335–44.

    CAS  PubMed  Google Scholar 

  252. Rocchi S et al. Interaction of SH2-containing protein tyrosine phosphatase 2 with the insulin receptor and the insulin-like growth factor-I receptor: studies of the domains involved using the yeast two-hybrid system. Endocrinology. 1996;137(11):4944–52.

    CAS  PubMed  Google Scholar 

  253. Walchli S et al. Identification of tyrosine phosphatases that dephosphorylate the insulin receptor. A brute force approach based on “substrate-trapping” mutants. J Biol Chem. 2000;275(13):9792–6.

    CAS  PubMed  Google Scholar 

  254. Maegawa H et al. SHPTP2 serves adapter protein linking between Janus kinase 2 and insulin receptor substrates. Biochem Biophys Res Commun. 1996;228(1):122–7.

    CAS  PubMed  Google Scholar 

  255. Arrandale JM et al. Insulin signaling in mice expressing reduced levels of Syp. J Biol Chem. 1996;271(35):21353–8.

    CAS  PubMed  Google Scholar 

  256. Maegawa H et al. Expression of a dominant negative SHP-2 in transgenic mice induces insulin resistance. J Biol Chem. 1999;274(42):30236–43.

    CAS  PubMed  Google Scholar 

  257. Fukunaga K et al. Requirement for protein-tyrosine phosphatase SHP-2 in insulin-induced activation of c-Jun NH(2)-terminal kinase. J Biol Chem. 2000;275(7):5208–13.

    CAS  PubMed  Google Scholar 

  258. Tanaka S et al. Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes. Hepatology. 1997;26(3):598–604.

    CAS  PubMed  Google Scholar 

  259. Hayashi K et al. Insulin receptor substrate-1/SHP-2 interaction, a phenotype-dependent switching machinery of insulin-like growth factor-I signaling in vascular smooth muscle cells. J Biol Chem. 2004;279(39):40807–18.

    CAS  PubMed  Google Scholar 

  260. Mussig K et al. Shp2 is required for protein kinase C-dependent phosphorylation of serine 307 in insulin receptor substrate-1. J Biol Chem. 2005;280(38):32693–9.

    PubMed  Google Scholar 

  261. Princen F et al. Deletion of Shp2 tyrosine phosphatase in muscle leads to dilated cardiomyopathy, insulin resistance, and premature death. Mol Cell Biol. 2009;29(2):378–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  262. Matsuo K et al. Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2. J Biol Chem. 2010;285(51):39750–8.

    CAS  PubMed  Google Scholar 

  263. Nagata N et al. Hepatic Src homology phosphatase 2 regulates energy balance in mice. Endocrinology. 2012;153(7):3158–69.

    CAS  PubMed  Google Scholar 

  264. Bettaieb A et al. Adipose-specific deletion of Src homology phosphatase 2 does not significantly alter systemic glucose homeostasis. Metabolism. 2011;60(8):1193–201.

    CAS  PubMed  Google Scholar 

  265. He Z et al. Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase. Proc Natl Acad Sci U S A. 2013;110(1):E79–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  266. Yu J et al. Modulation of fatty acid synthase degradation by concerted action of p38 MAP kinase, E3 ligase COP1, and SH2-tyrosine phosphatase Shp2. J Biol Chem. 2013;288(6):3823–30.

    CAS  PubMed  Google Scholar 

  267. Levy DE, Darnell Jr JE. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3(9):651–62.

    CAS  PubMed  Google Scholar 

  268. Reich NC, Liu L. Tracking STAT nuclear traffic. Nat Rev Immunol. 2006;6(8):602–12.

    CAS  PubMed  Google Scholar 

  269. Xu D, Qu CK. Protein tyrosine phosphatases in the JAK/STAT pathway. Front Biosci. 2008;13:4925–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  270. Tsou RC, Bence KK. Central regulation of metabolism by protein tyrosine phosphatases. Front Neurosci. 2012;6:192.

    PubMed Central  PubMed  Google Scholar 

  271. Takahashi A et al. SHP2 tyrosine phosphatase converts parafibromin/Cdc73 from a tumor suppressor to an oncogenic driver. Mol Cell. 2011;43(1):45–56.

    CAS  PubMed  Google Scholar 

  272. Duchesne C et al. Negative regulation of beta-catenin signaling by tyrosine phosphatase SHP-1 in intestinal epithelial cells. J Biol Chem. 2003;278(16):14274–83.

    CAS  PubMed  Google Scholar 

  273. Simoneau M et al. SHP-1 inhibits beta-catenin function by inducing its degradation and interfering with its association with TATA-binding protein. Cell Signal. 2011;23(1):269–79.

    CAS  PubMed  Google Scholar 

  274. Liang LF et al. Cembrane diterpenoids from the soft coral Sarcophyton trocheliophorum Marenzeller as a new class of PTP1B inhibitors. Bioorg Med Chem. 2013;21(17):5076–80.

    CAS  PubMed  Google Scholar 

  275. Zhang W et al. Ursolic acid and its derivative inhibit protein tyrosine phosphatase 1B, enhancing insulin receptor phosphorylation and stimulating glucose uptake. Biochim Biophys Acta. 2006;1760(10):1505–12.

    CAS  PubMed  Google Scholar 

  276. Hsu MF, Meng TC. Enhancement of insulin responsiveness by nitric oxide-mediated inactivation of protein-tyrosine phosphatases. J Biol Chem. 2010;285(11):7919–28.

    CAS  PubMed  Google Scholar 

  277. Zhang S et al. A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes. J Am Chem Soc. 2012;134(43):18116–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  278. Lorenzen JA, Dadabay CY, Fischer EH. COOH-terminal sequence motifs target the T cell protein tyrosine phosphatase to the ER and nucleus. J Cell Biol. 1995;131(3):631–43.

    CAS  PubMed  Google Scholar 

  279. Chughtai N et al. Prolactin induces SHP-2 association with Stat5, nuclear translocation, and binding to the beta-casein gene promoter in mammary cells. J Biol Chem. 2002;277(34):31107–14.

    CAS  PubMed  Google Scholar 

  280. Wu TR et al. SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei. J Biol Chem. 2002;277(49):47572–80.

    CAS  PubMed  Google Scholar 

  281. Wang Y et al. Proteomic analysis reveals novel molecules involved in insulin signaling pathway. J Proteome Res. 2006;5(4):846–55.

    CAS  PubMed  Google Scholar 

  282. Kruger M et al. Dissection of the insulin signaling pathway via quantitative phosphoproteomics. Proc Natl Acad Sci U S A. 2008;105(7):2451–6.

    PubMed Central  PubMed  Google Scholar 

  283. Hornbeck PV et al. PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse. Nucleic Acids Res. 2012;40(Database issue):D261–70.

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This review was written based on a literature search and some studies performed by the authors and that were supported by a grant from the Canadian Institutes of Health Research.

Conflict of interest

Authors declare no conflict of interest or financial relationship with the organization that sponsored some of the research described in this review article.

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Authors and Affiliations

  1. Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada, G1V 4G2

    Elaine Xu, Michael Schwab & André Marette

  2. Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada, G1V 4G5

    André Marette

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  1. Elaine Xu
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  2. Michael Schwab
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  3. André Marette
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Correspondence to André Marette.

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Xu, E., Schwab, M. & Marette, A. Role of protein tyrosine phosphatases in the modulation of insulin signaling and their implication in the pathogenesis of obesity-linked insulin resistance. Rev Endocr Metab Disord 15, 79–97 (2014). https://doi.org/10.1007/s11154-013-9282-4

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