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Annual Review of Physiology

Volume 87, 2025

Protein Tyrosine Phosphatases in Metabolism: A New Frontier for Therapeutics

  • Anton M. Bennett1,2 and Tony Tiganis3,4
  • 1Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA; email: [email protected] 2Yale Center for Molecular and Systems Metabolism, New Haven, Connecticut, USA 3Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia; email: [email protected] 4Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
  • Vol. 87:301-324 (Volume publication date February 2025)
  • First published as a Review in Advance on November 12, 2024
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

The increased prevalence of chronic metabolic disorders, including obesity and type 2 diabetes and their associated comorbidities, are among the world's greatest health and economic challenges. Metabolic homeostasis involves a complex interplay between hormones that act on different tissues to elicit changes in the storage and utilization of energy. Such processes are mediated by tyrosine phosphorylation-dependent signaling, which is coordinated by the opposing actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Perturbations in the functions of PTPs can be instrumental in the pathophysiology of metabolic diseases. The goal of this review is to highlight key advances in our understanding of how PTPs control body weight and glucose metabolism, as well as their contributions to obesity and type 2 diabetes. The emerging appreciation of the integrated functions of PTPs in metabolism, coupled with significant advances in pharmaceutical strategies aimed at targeting this class of enzymes, marks the advent of a new frontier in combating metabolic disorders.

Keyword(s): insulin, insulin resistance, leptin, MASH, MASLD, metabolic dysfunction-associated fatty liver disease, metabolic dysfunction-associated steatohepatitis, obesity, protein tyrosine kinase, protein tyrosine phosphatase, signaling, type 2 diabetes
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2025-02-10
2025-06-25
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Literature Cited

  1. 1.
    Rohm TV, Meier DT, Olefsky JM, Donath MY. 2022.. Inflammation in obesity, diabetes, and related disorders. . Immunity 55::31–55
     [Crossref] [Google Scholar]
  2. 2.
    Tiganis T, Bennett AM. 2007.. Protein tyrosine phosphatase function: the substrate perspective. . Biochem. J. 402::1–15
     [Crossref] [Google Scholar]
  3. 3.
    Tonks NK. 2006.. Protein tyrosine phosphatases: from genes, to function, to disease. . Nat. Rev. Mol. Cell Biol. 7::833–46
     [Crossref] [Google Scholar]
  4. 4.
    Saltiel AR. 2021.. Insulin signaling in health and disease. . J. Clin. Investig. 131::e142241
     [Crossref] [Google Scholar]
  5. 5.
    Petersen MC, Shulman GI. 2018.. Mechanisms of insulin action and insulin resistance. . Physiol. Rev. 98::2133–223
     [Crossref] [Google Scholar]
  6. 6.
    White MF, Kahn CR. 2021.. Insulin action at a molecular level-100 years of progress. . Mol. Metab. 52::101304
     [Crossref] [Google Scholar]
  7. 7.
    Tiganis T. 2013.. PTP1B and TCPTP—nonredundant phosphatases in insulin signaling and glucose homeostasis. . FEBS J. 280::445–58
     [Crossref] [Google Scholar]
  8. 8.
    Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, et al. 2000.. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. . Mol. Cell. Biol. 20::5479–89
     [Crossref] [Google Scholar]
  9. 9.
    Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, et al. 1999.. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. . Science 283::1544–48
     [Crossref] [Google Scholar]
  10. 10.
    Delibegovic M, Zimmer D, Kauffman C, Rak K, Hong EG, et al. 2009.. Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced ER stress. . Diabetes 58::590–99
     [Crossref] [Google Scholar]
  11. 11.
    Delibegovic M, Bence KK, Mody N, Hong EG, Ko HJ, et al. 2007.. Improved glucose homeostasis in mice with muscle-specific deletion of protein-tyrosine phosphatase 1B. . Mol. Cell. Biol. 27::7727–34
     [Crossref] [Google Scholar]
  12. 12.
    Haj FG, Zabolotny JM, Kim YB, Kahn BB, Neel BG. 2005.. Liver specific protein-tyrosine phosphatase 1B (PTP1B) re-expression alters glucose homeostasis of PTP1B−/− mice. . J. Biol. Chem. 280::15038–46
     [Crossref] [Google Scholar]
  13. 13.
    Ali MI, Ketsawatsomkron P, Belin de Chantemele EJ, Mintz JD, Muta K, et al. 2009.. Deletion of protein tyrosine phosphatase 1b improves peripheral insulin resistance and vascular function in obese, leptin-resistant mice via reduced oxidant tone. . Circ. Res. 105::1013–22
     [Crossref] [Google Scholar]
  14. 14.
    Galic S, Hauser C, Kahn BB, Haj FG, Neel BG, et al. 2005.. Coordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTP. . Mol. Cell. Biol. 25::819–29
     [Crossref] [Google Scholar]
  15. 15.
    Goldstein BJ, Bittner-Kowalczyk A, White MF, Harbeck M. 2000.. 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. 275::4283–89
     [Crossref] [Google Scholar]
  16. 16.
    Calera MR, Vallega G, Pilch PF. 2000.. Dynamics of protein-tyrosine phosphatases in rat adipocytes. . J. Biol. Chem. 275::6308–12
     [Crossref] [Google Scholar]
  17. 17.
    Venable CL, Frevert EU, Kim YB, Fischer BM, Kamatkar S, et al. 2000.. Overexpression of protein-tyrosine phosphatase-1B in adipocytes inhibits insulin-stimulated phosphoinositide 3-kinase activity without altering glucose transport or Akt/Protein kinase B activation. . J. Biol. Chem. 275::18318–26
     [Crossref] [Google Scholar]
  18. 18.
    Owen C, Czopek A, Agouni A, Grant L, Judson R, et al. 2012.. Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis. . PLOS ONE 7::e32700
     [Crossref] [Google Scholar]
  19. 19.
    Banh RS, Iorio C, Marcotte R, Xu Y, Cojocari D, et al. 2016.. PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia. . Nat. Cell Biol. 18::803–13
     [Crossref] [Google Scholar]
  20. 20.
    Sarkar P, Thirumurugan K. 2021.. New insights into TNFα/PTP1B and PPARγ pathway through RNF213-a link between inflammation, obesity, insulin resistance, and Moyamoya disease. . Gene 771::145340
     [Crossref] [Google Scholar]
  21. 21.
    Ahmad F, Azevedo JL, Cortright R, Dohm GL, Goldstein BJ. 1997.. Alterations in skeletal muscle protein-tyrosine phosphatase activity and expression in insulin-resistant human obesity and diabetes. . J. Clin. Investig. 100::449–58
     [Crossref] [Google Scholar]
  22. 22.
    Ahmad F, Goldstein BJ. 1995.. Alterations in specific protein-tyrosine phosphatases accompany insulin resistance of streptozotocin diabetes. . Am. J. Physiol. 268::E932–40
     [Google Scholar]
  23. 23.
    Zabolotny JM, Kim YB, Welsh LA, Kershaw EE, Neel BG, Kahn BB. 2008.. Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo. . J. Biol. Chem. 283::14230–41
     [Crossref] [Google Scholar]
  24. 24.
    Sun C, Zhang F, Ge X, Yan T, Chen X, et al. 2007.. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. . Cell Metab. 6::307–19
     [Crossref] [Google Scholar]
  25. 25.
    Gonzalez-Rodriguez A, Mas-Gutierrez JA, Mirasierra M, Fernandez-Perez A, Lee YJ, et al. 2012.. Essential role of protein tyrosine phosphatase 1B in obesity-induced inflammation and peripheral insulin resistance during aging. . Aging Cell 11::284–96
     [Crossref] [Google Scholar]
  26. 26.
    Palmer ND, Bento JL, Mychaleckyj JC, Langefeld CD, Campbell JK, et al. 2004.. Association of protein tyrosine phosphatase 1B gene polymorphisms with measures of glucose homeostasis in Hispanic Americans: the insulin resistance atherosclerosis study (IRAS) family study. . Diabetes 53::3013–19
     [Crossref] [Google Scholar]
  27. 27.
    Cheyssac C, Lecoeur C, Dechaume A, Bibi A, Charpentier G, et al. 2006.. Analysis of common PTPN1 gene variants in type 2 diabetes, obesity and associated phenotypes in the French population. . BMC Med. Genet. 7::44
     [Crossref] [Google Scholar]
  28. 28.
    Bento JL, Palmer ND, Mychaleckyj JC, Lange LA, Langefeld CD, et al. 2004.. Association of protein tyrosine phosphatase 1B gene polymorphisms with type 2 diabetes. . Diabetes 53::3007–12
     [Crossref] [Google Scholar]
  29. 29.
    Di Paola R, Frittitta L, Miscio G, Bozzali M, Baratta R, et al. 2002.. A variation in 3′ UTR of hPTP1B increases specific gene expression and associates with insulin resistance. . Am. J. Hum. Genet. 70::806–12
     [Crossref] [Google Scholar]
  30. 30.
    Yamakage H, Konishi Y, Muranaka K, Hotta K, Miyamoto Y, et al. 2021.. Association of protein tyrosine phosphatase 1B gene polymorphism with the effects of weight reduction therapy on bodyweight and glycolipid profiles in obese patients. . J. Diabetes Investig. 12::1462–70
     [Crossref] [Google Scholar]
  31. 31.
    Florez JC, Agapakis CM, Burtt NP, Sun M, Almgren P, et al. 2005.. Association testing of the protein tyrosine phosphatase 1B gene (PTPN1) with type 2 diabetes in 7,883 people. . Diabetes 54::1884–91
     [Crossref] [Google Scholar]
  32. 32.
    Traurig M, Hanson RL, Kobes S, Bogardus C, Baier LJ. 2007.. Protein tyrosine phosphatase 1B is not a major susceptibility gene for type 2 diabetes mellitus or obesity among Pima Indians. . Diabetologia 50::985–89
     [Crossref] [Google Scholar]
  33. 33.
    Zabolotny JM, Haj FG, Kim YB, Kim HJ, Shulman GI, et al. 2004.. Transgenic overexpression of protein-tyrosine phosphatase 1B in muscle causes insulin resistance, but overexpression with leukocyte antigen-related phosphatase does not additively impair insulin action. . J. Biol. Chem. 279::24844–51
     [Crossref] [Google Scholar]
  34. 34.
    Grant L, Shearer KD, Czopek A, Lees EK, Owen C, et al. 2014.. Myeloid-cell protein tyrosine phosphatase-1B deficiency in mice protects against high-fat diet and lipopolysaccharide-induced inflammation, hyperinsulinemia, and endotoxemia through an IL-10 STAT3-dependent mechanism. . Diabetes 63::456–70
     [Crossref] [Google Scholar]
  35. 35.
    Traves PG, Pardo V, Pimentel-Santillana M, Gonzalez-Rodriguez A, Mojena M, et al. 2014.. Pivotal role of protein tyrosine phosphatase 1B (PTP1B) in the macrophage response to pro-inflammatory and anti-inflammatory challenge. . Cell Death Dis. 5::e1125
     [Crossref] [Google Scholar]
  36. 36.
    Heinonen KM, Dube N, Bourdeau A, Lapp WS, Tremblay ML. 2006.. Protein tyrosine phosphatase 1B negatively regulates macrophage development through CSF-1 signaling. . PNAS 103::2776–81
     [Crossref] [Google Scholar]
  37. 37.
    Xue B, Kim YB, Lee A, Toschi E, Bonner-Weir S, et al. 2007.. Protein-tyrosine phosphatase 1B deficiency reduces insulin resistance and the diabetic phenotype in mice with polygenic insulin resistance. . J. Biol. Chem. 282::23829–40
     [Crossref] [Google Scholar]
  38. 38.
    Kushner JA, Haj FG, Klaman LD, Dow MA, Kahn BB, et al. 2004.. Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice. . Diabetes 53::61–66
     [Crossref] [Google Scholar]
  39. 39.
    Fernandez-Ruiz R, Vieira E, Garcia-Roves PM, Gomis R. 2014.. Protein tyrosine phosphatase-1B modulates pancreatic β-cell mass. . PLOS ONE 9::e90344
     [Crossref] [Google Scholar]
  40. 40.
    Figueiredo H, Figueroa ALC, Garcia A, Fernandez-Ruiz R, Broca C, et al. 2019.. Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes. . Sci. Transl. Med. 11::eaar6294
     [Crossref] [Google Scholar]
  41. 41.
    Liu S, Xi Y, Bettaieb A, Matsuo K, Matsuo I, et al. 2014.. Disruption of protein-tyrosine phosphatase 1B expression in the pancreas affects β-cell function. . Endocrinology 155::3329–38
     [Crossref] [Google Scholar]
  42. 42.
    Zinker BA, Rondinone CM, Trevillyan JM, Gum RJ, Clampit JE, et al. 2002.. PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. . PNAS 99::11357–62
     [Crossref] [Google Scholar]
  43. 43.
    Swarbrick MM, Havel PJ, Levin AA, Bremer AA, Stanhope KL, et al. 2009.. Inhibition of protein tyrosine phosphatase-1B with antisense oligonucleotides improves insulin sensitivity and increases adiponectin concentrations in monkeys. . Endocrinology 150::1670–79
     [Crossref] [Google Scholar]
  44. 44.
    Qin Z, Pandey NR, Zhou X, Stewart CA, Hari A, et al. 2015.. Functional properties of Claramine: a novel PTP1B inhibitor and insulin-mimetic compound. . Biochem. Biophys. Res. Commun. 458::21–27
     [Crossref] [Google Scholar]
  45. 45.
    Lantz KA, Hart SG, Planey SL, Roitman MF, Ruiz-White IA, et al. 2010.. Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice. . Obesity 18::1516–23
     [Crossref] [Google Scholar]
  46. 46.
    Krishnan N, Bonham CA, Rus IA, Shrestha OK, Gauss CM, et al. 2018.. Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development. . Nat. Commun. 9::283
     [Crossref] [Google Scholar]
  47. 47.
    Krishnan N, Konidaris KF, Gasser G, Tonks NK. 2018.. A potent, selective, and orally bioavailable inhibitor of the protein-tyrosine phosphatase PTP1B improves insulin and leptin signaling in animal models. . J. Biol. Chem. 293::1517–25
     [Crossref] [Google Scholar]
  48. 48.
    Digenio A, Pham NC, Watts LM, Morgan ES, Jung SW, et al. 2018.. Antisense inhibition of protein tyrosine phosphatase 1B with IONIS-PTP-1BRx improves insulin sensitivity and reduces weight in overweight patients with type 2 diabetes. . Diabetes Care 41::807–14
     [Crossref] [Google Scholar]
  49. 49.
    Thompson D, Morrice N, Grant L, Le Sommer S, Lees EK, et al. 2017.. Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR−/− mouse model of atherosclerosis. . Clin. Sci. 131::2489–501
     [Crossref] [Google Scholar]
  50. 50.
    Thompson D, Morrice N, Grant L, Le Sommer S, Ziegler K, et al. 2017.. Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE−/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway. . Mol. Metab. 6::845–53
     [Crossref] [Google Scholar]
  51. 51.
    Figueiredo A, Leal EC, Carvalho E. 2020.. Protein tyrosine phosphatase 1B inhibition as a potential therapeutic target for chronic wounds in diabetes. . Pharmacol. Res. 159::104977
     [Crossref] [Google Scholar]
  52. 52.
    Ito Y, Hsu MF, Bettaieb A, Koike S, Mello A, et al. 2017.. Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury. . Metabolism 76::56–69
     [Crossref] [Google Scholar]
  53. 53.
    Arroba AI, Valverde AM. 2015.. Inhibition of protein tyrosine phosphatase 1B improves IGF-I receptor signaling and protects against inflammation-induced gliosis in the retina. . Investig. Ophthalmol. Vis. Sci. 56::8031–44
     [Crossref] [Google Scholar]
  54. 54.
    Oliver H, Ruta D, Thompson D, Kamli-Salino S, Philip S, et al. 2023.. Myeloid PTP1B deficiency protects against atherosclerosis by improving cholesterol homeostasis through an AMPK-dependent mechanism. . J. Transl. Med. 21::715
     [Crossref] [Google Scholar]
  55. 55.
    Pandey SK, Yu XX, Watts LM, Michael MD, Sloop KW, et al. 2007.. Reduction of low molecular weight protein-tyrosine phosphatase expression improves hyperglycemia and insulin sensitivity in obese mice. . J. Biol. Chem. 282::14291–99
     [Crossref] [Google Scholar]
  56. 56.
    Stanford SM, Aleshin AE, Zhang V, Ardecky RJ, Hedrick MP, et al. 2017.. Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase. . Nat. Chem. Biol. 13::624–32
     [Crossref] [Google Scholar]
  57. 57.
    Xu E, Charbonneau A, Rolland Y, Bellmann K, Pao L, et al. 2012.. Hepatocyte-specific Ptpn6 deletion protects from obesity-linked hepatic insulin resistance. . Diabetes 61::1949–58
     [Crossref] [Google Scholar]
  58. 58.
    Dubois MJ, Bergeron S, Kim HJ, Dombrowski L, Perreault M, et al. 2006.. The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis. . Nat. Med. 12::549–56
     [Crossref] [Google Scholar]
  59. 59.
    Liu W, Yin Y, Wang MJ, Fan T, Zhu YY, et al. 2020.. Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels. . J. Biol. Chem. 295::10842–56
     [Crossref] [Google Scholar]
  60. 60.
    Fukushima A, Loh K, Galic S, Fam B, Shields B, et al. 2010.. T-cell protein tyrosine phosphatase attenuates STAT3 and insulin signaling in the liver to regulate gluconeogenesis. . Diabetes 59::1906–14
     [Crossref] [Google Scholar]
  61. 61.
    Aga-Mizrachi S, Brutman-Barazani T, Jacob AI, Bak A, Elson A, Sampson SR. 2008.. Cytosolic protein tyrosine phosphatase-epsilon is a negative regulator of insulin signaling in skeletal muscle. . Endocrinology 149::605–14
     [Crossref] [Google Scholar]
  62. 62.
    Wade F, Quijada P, Al-Haffar KM, Awad SM, Kunhi M, et al. 2015.. Deletion of low molecular weight protein tyrosine phosphatase (Acp1) protects against stress-induced cardiomyopathy. . J. Pathol. 237::482–94
     [Crossref] [Google Scholar]
  63. 63.
    Galic S, Klingler-Hoffmann M, Fodero-Tavoletti MT, Puryer MA, Meng TC, et al. 2003.. Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP. . Mol. Cell. Biol. 23::2096–108
     [Crossref] [Google Scholar]
  64. 64.
    Loh K, Fukushima A, Zhang X, Galic S, Briggs D, et al. 2011.. Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. . Cell Metab. 14::684–99
     [Crossref] [Google Scholar]
  65. 65.
    Grohmann M, Wiede F, Dodd GT, Gurzov EN, Ooi GJ, et al. 2018.. Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. . Cell 175::1289–306
     [Crossref] [Google Scholar]
  66. 66.
    Wiede F, Brodnicki TC, Goh PK, Leong YA, Jones GW, et al. 2019.. T-cell-specific PTPN2 deficiency in NOD mice accelerates the development of type 1 diabetes and autoimmune comorbidities. . Diabetes 68::1251–66
     [Crossref] [Google Scholar]
  67. 67.
    Wiede F, Sacirbegovic F, Leong YA, Yu D, Tiganis T. 2017.. PTPN2-deficiency exacerbates T follicular helper cell and B cell responses and promotes the development of autoimmunity. . J. Autoimmun. 76::85–100
     [Crossref] [Google Scholar]
  68. 68.
    Wiede F, Ziegler A, Zehn D, Tiganis T. 2014.. PTPN2 restrains CD8+ T cell responses after antigen cross-presentation for the maintenance of peripheral tolerance in mice. . J. Autoimmun. 53::105–14
     [Crossref] [Google Scholar]
  69. 69.
    Wiede F, La Gruta NL, Tiganis T. 2014.. PTPN2 attenuates T-cell lymphopenia-induced proliferation. . Nat. Commun. 5::3073
     [Crossref] [Google Scholar]
  70. 70.
    Wiede F, Shields BJ, Chew SH, Kyparissoudis K, van Vliet C, et al. 2011.. T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. . J. Clin. Investig. 121::4758–74
     [Crossref] [Google Scholar]
  71. 71.
    You-Ten KE, Muise ES, Itie A, Michaliszyn E, Wagner J, et al. 1997.. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. . J. Exp. Med. 186::683–93
     [Crossref] [Google Scholar]
  72. 72.
    Heinonen KM, Nestel FP, Newell EW, Charette G, Seemayer TA, et al. 2004.. T cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease. . Blood 103::3457–64
     [Crossref] [Google Scholar]
  73. 73.
    Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, et al. 2007.. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. . Nat. Genet. 39::857–64
     [Crossref] [Google Scholar]
  74. 74.
    WTCC Consortium. 2007.. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. . Nature 447::661–78
     [Crossref] [Google Scholar]
  75. 75.
    Long SA, Cerosaletti K, Wan JY, Ho JC, Tatum M, et al. 2011.. An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4+ T cells. . Genes Immun. 12::116–25
     [Crossref] [Google Scholar]
  76. 76.
    Okuno M, Ayabe T, Yokota I, Musha I, Shiga K, et al. 2018.. Protein-altering variants of PTPN2 in childhood-onset Type 1A diabetes. . Diabet. Med. 35::376–80
     [Crossref] [Google Scholar]
  77. 77.
    Baumgartner CK, Ebrahimi-Nik H, Iracheta-Vellve A, Hamel KM, Olander KE, et al. 2023.. The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity. . Nature 622::850–62
     [Crossref] [Google Scholar]
  78. 78.
    Liang S, Tran E, Du X, Dong J, Sudholz H, et al. 2023.. A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity. . Nat. Commun. 14::4524
     [Crossref] [Google Scholar]
  79. 79.
    Dong J, Miao J, Miao Y, Qu Z, Zhang S, et al. 2023.. Small molecule degraders of protein tyrosine phosphatase 1B and T-cell protein tyrosine phosphatase for cancer immunotherapy. . Angew. Chem. Int. Ed. 62::e202303818
     [Crossref] [Google Scholar]
  80. 80.
    Lorenz U. 2009.. SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. . Immunol. Rev. 228::342–59
     [Crossref] [Google Scholar]
  81. 81.
    Najjar SM, Perdomo G. 2019.. Hepatic insulin clearance: mechanism and physiology. . Physiology 34::198–215
     [Crossref] [Google Scholar]
  82. 82.
    Saxton TM, Henkemeyer M, Gasca S, Shen R, Rossi DJ, et al. 1997.. Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. . EMBO J. 16::2352–64
     [Crossref] [Google Scholar]
  83. 83.
    He Z, Zhu HH, Bauler TJ, Wang J, Ciaraldi T, et al. 2013.. Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase. . PNAS 110::E79–88
     [Google Scholar]
  84. 84.
    Princen F, Bard E, Sheikh F, Zhang SS, Wang J, et al. 2009.. Deletion of Shp2 tyrosine phosphatase in muscle leads to dilated cardiomyopathy, insulin resistance, and premature death. . Mol. Cell. Biol. 29::378–88
     [Crossref] [Google Scholar]
  85. 85.
    Krajewska M, Banares S, Zhang EE, Huang X, Scadeng M, et al. 2008.. Development of diabesity in mice with neuronal deletion of Shp2 tyrosine phosphatase. . Am. J. Pathol. 172::1312–24
     [Crossref] [Google Scholar]
  86. 86.
    Feng G-S. 2006.. Shp2 as a therapeutic target for leptin resistance and obesity. . Expert Opin. Ther. Targets 10::135–42
     [Crossref] [Google Scholar]
  87. 87.
    Zhang EE, Chapeau E, Hagihara K, Feng GS. 2004.. Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. . PNAS 101::16064–69
     [Crossref] [Google Scholar]
  88. 88.
    Nagata N, Matsuo K, Bettaieb A, Bakke J, Matsuo I, et al. 2012.. Hepatic Src homology phosphatase 2 regulates energy balance in mice. . Endocrinology 153::3158–69
     [Crossref] [Google Scholar]
  89. 89.
    Saint-Laurent C, Mazeyrie L, Tajan M, Paccoud R, Castan-Laurell I, et al. 2022.. The tyrosine phosphatase SHP2: A new target for insulin resistance?. Biomedicines 10::2139
     [Crossref] [Google Scholar]
  90. 90.
    Neel BG, Gu H, Pao L. 2003.. The ‘Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. . Trends Biochem. Sci. 28::284–93
     [Crossref] [Google Scholar]
  91. 91.
    Kontaridis MI, Yang W, Bence KK, Cullen D, Wang B, et al. 2008.. Deletion of Ptpn11 (Shp2) in cardiomyocytes causes dilated cardiomyopathy via effects on the extracellular signal-regulated kinase/mitogen-activated protein kinase and RhoA signaling pathways. . Circulation 117::1423–35
     [Crossref] [Google Scholar]
  92. 92.
    Kjobsted R, Roll JLW, Jorgensen NO, Birk JB, Foretz M, et al. 2019.. AMPK and TBC1D1 regulate muscle glucose uptake after, but not during, exercise and contraction. . Diabetes 68::1427–40
     [Crossref] [Google Scholar]
  93. 93.
    Matsuo K, Delibegovic M, Matsuo I, Nagata N, Liu S, et al. 2010.. Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2. . J. Biol. Chem. 285::39750–58
     [Crossref] [Google Scholar]
  94. 94.
    Bard-Chapeau EA, Li S, Ding J, Zhang SS, Zhu HH, et al. 2011.. Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. . Cancer Cell 19::629–39
     [Crossref] [Google Scholar]
  95. 95.
    Murphy AJ, Kraakman MJ, Kammoun HL, Dragoljevic D, Lee MKS, et al. 2016.. IL-18 production from the NLRP1 inflammasome prevents obesity and metabolic syndrome. . Cell Metab. 23::155–64
     [Crossref] [Google Scholar]
  96. 96.
    Paccoud R, Saint-Laurent C, Piccolo E, Tajan M, Dortignac A, et al. 2021.. SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations. . Sci. Transl. Med. 13::eabe2587
     [Crossref] [Google Scholar]
  97. 97.
    Zabolotny JM, Kim YB, Peroni OD, Kim JK, Pani MA, et al. 2001.. Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance. . PNAS 98::5187–92
     [Crossref] [Google Scholar]
  98. 98.
    Shintani T, Higashi S, Takeuchi Y, Gaudio E, Trapasso F, et al. 2015.. The R3 receptor-like protein tyrosine phosphatase subfamily inhibits insulin signalling by dephosphorylating the insulin receptor at specific sites. . J. Biochem. 158::235–43
     [Crossref] [Google Scholar]
  99. 99.
    Kruger J, Brachs S, Trappiel M, Kintscher U, Meyborg H, et al. 2015.. Enhanced insulin signaling in density-enhanced phosphatase-1 (DEP-1) knockout mice. . Mol. Metab. 4::325–36
     [Crossref] [Google Scholar]
  100. 100.
    Kruger J, Trappiel M, Dagnell M, Stawowy P, Meyborg H, et al. 2013.. Targeting density-enhanced phosphatase-1 (DEP-1) with antisense oligonucleotides improves the metabolic phenotype in high-fat diet-fed mice. . Cell Commun. Signal. 11::49
     [Crossref] [Google Scholar]
  101. 101.
    Brenachot X, Ramadori G, Ioris RM, Veyrat-Durebex C, Altirriba J, et al. 2017.. Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance. . Nat. Commun. 8::1820
     [Crossref] [Google Scholar]
  102. 102.
    Shintani T, Suzuki R, Takeuchi Y, Shirasawa T, Noda M. 2023.. Deletion or inhibition of PTPRO prevents ectopic fat accumulation and induces healthy obesity with markedly reduced systemic inflammation. . Life Sci. 313::121292
     [Crossref] [Google Scholar]
  103. 103.
    Ahmad F, Considine RV, Goldstein BJ. 1995.. 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. Investig. 95::2806–12
     [Crossref] [Google Scholar]
  104. 104.
    Goldstein BJ, Ahmad F, Ding W, Li PM, Zhang WR. 1998.. Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases. . Mol. Cell Biochem. 182::91–99
     [Crossref] [Google Scholar]
  105. 105.
    Bence KK, Birnbaum MJ. 2021.. Metabolic drivers of non-alcoholic fatty liver disease. . Mol. Metab. 50::101143
     [Crossref] [Google Scholar]
  106. 106.
    Hirata Y, Hosaka T, Iwata T, Le CTK, Jambaldorj B, et al. 2011.. Vimentin binds IRAP and is involved in GLUT4 vesicle trafficking. . Biochem. Biophys. Res. Commun. 405::96–101
     [Crossref] [Google Scholar]
  107. 107.
    Blanchette-Mackie EJ, Dwyer NK, Barber T, Coxey RA, Takeda T, et al. 1995.. Perilipin is located on the surface-layer of intracellular lipid droplets in adipocytes. . J. Lipid Res. 36::1211–26
     [Crossref] [Google Scholar]
  108. 108.
    Heid H, Rickelt S, Zimbelmann R, Winter S, Schumacher H, et al. 2014.. On the formation of lipid droplets in human adipocytes: the organization of the perilipin-vimentin cortex. . PLOS ONE 9::e90386
     [Crossref] [Google Scholar]
  109. 109.
    Kim S, Kim I, Cho W, Oh GT, Park YM. 2021.. Vimentin deficiency prevents high-fat diet-induced obesity and insulin resistance in mice. . Diabetes Metab. J. 45::97–108
     [Crossref] [Google Scholar]
  110. 110.
    Cheng A, Uetani N, Simoncic PD, Chaubey VP, Lee-Loy A, et al. 2002.. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. . Dev. Cell 2::497–503
     [Crossref] [Google Scholar]
  111. 111.
    Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, et al. 2002.. PTP1B regulates leptin signal transduction in vivo. . Dev. Cell 2::489–95
     [Crossref] [Google Scholar]
  112. 112.
    Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, et al. 2006.. Neuronal PTP1B regulates body weight, adiposity and leptin action. . Nat. Med. 12::917–24
     [Crossref] [Google Scholar]
  113. 113.
    Banno R, Zimmer D, De Jonghe BC, Atienza M, Rak K, et al. 2010.. PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. . J. Clin. Investig. 120::720–34
     [Crossref] [Google Scholar]
  114. 114.
    Tsou RC, Zimmer DJ, De Jonghe BC, Bence KK. 2012.. Deficiency of PTP1B in leptin receptor-expressing neurons leads to decreased body weight and adiposity in mice. . Endocrinology 153::4227–37
     [Crossref] [Google Scholar]
  115. 115.
    Dodd GT, Xirouchaki CE, Eramo M, Mitchell CA, Andrews ZB, et al. 2019.. Intranasal targeting of hypothalamic PTP1B and TCPTP reinstates leptin and insulin sensitivity and promotes weight loss in obesity. . Cell Rep. 28::2905–22
     [Crossref] [Google Scholar]
  116. 116.
    Balland E, Chen W, Dodd GT, Conductier G, Coppari R, et al. 2019.. Leptin signaling in the arcuate nucleus reduces insulin's capacity to suppress hepatic glucose production in obese mice. . Cell Rep. 26::346–55
     [Crossref] [Google Scholar]
  117. 117.
    Zhang ZY, Dodd GT, Tiganis T. 2015.. Protein tyrosine phosphatases in hypothalamic insulin and leptin signaling. . Trends Pharmacol. Sci. 36::661–74
     [Crossref] [Google Scholar]
  118. 118.
    Dodd GT, Decherf S, Loh K, Simonds SE, Wiede F, et al. 2015.. Leptin and insulin act on POMC neurons to promote the browning of white fat. . Cell 160::88–104
     [Crossref] [Google Scholar]
  119. 119.
    Dodd GT, Andrews ZB, Simonds SE, Michael NJ, DeVeer M, et al. 2017.. A hypothalamic phosphatase switch coordinates energy expenditure with feeding. . Cell Metab. 26::375–93
     [Crossref] [Google Scholar]
  120. 120.
    Dodd GT, Lee-Young RS, Bruning JC, Tiganis T. 2018.. TCPTP regulates insulin signaling in AgRP neurons to coordinate glucose metabolism with feeding. . Diabetes 67::1246–57
     [Crossref] [Google Scholar]
  121. 121.
    Dodd GT, Michael NJ, Lee-Young RS, Mangiafico SP, Pryor JT, et al. 2018.. Insulin regulates POMC neuronal plasticity to control glucose metabolism. . eLife 7::e38704
     [Crossref] [Google Scholar]
  122. 122.
    Dodd GT, Kim SJ, Mequinion M, Xirouchaki CE, Bruning JC, et al. 2021.. Insulin signaling in AgRP neurons regulates meal size to limit glucose excursions and insulin resistance. . Sci. Adv. 7::eabf4100
     [Crossref] [Google Scholar]
  123. 123.
    do Carmo JM, da Silva AA, Ebaady SE, Sessums PO, Abraham RS, et al. 2014.. Shp2 signaling in POMC neurons is important for leptin's actions on blood pressure, energy balance, and glucose regulation. . Am. J. Physiol. Regul. Integr. Comp. Physiol. 307::R1438–47
     [Crossref] [Google Scholar]
  124. 124.
    Rousso-Noori L, Knobler H, Levy-Apter E, Kuperman Y, Neufeld-Cohen A, et al. 2011.. Protein tyrosine phosphatase epsilon affects body weight by downregulating leptin signaling in a phosphorylation-dependent manner. . Cell Metab. 13::562–72
     [Crossref] [Google Scholar]
  125. 125.
    Shintani T, Higashi S, Suzuki R, Takeuchi Y, Ikaga R, et al. 2017.. PTPRJ inhibits leptin signaling, and induction of PTPRJ in the hypothalamus is a cause of the development of leptin resistance. . Sci. Rep. 7::11627
     [Crossref] [Google Scholar]
  126. 126.
    Cohen-Sharir Y, Kuperman Y, Apelblat D, den Hertog J, Spiegel I, et al. 2019.. Protein tyrosine phosphatase alpha inhibits hypothalamic leptin receptor signaling and regulates body weight in vivo. . FASEB J. 33::5101–11
     [Crossref] [Google Scholar]
  127. 127.
    Mishra I, Xie WR, Bournat JC, He Y, Wang C, et al. 2022.. Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor. . Cell Metab. 34::549–63
     [Crossref] [Google Scholar]
  128. 128.
    Lembertas AV, Perusse L, Chagnon YC, Fisler JS, Warden CH, et al. 1997.. Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q. . J. Clin. Investig. 100::1240–47
     [Crossref] [Google Scholar]
  129. 129.
    Lee JH, Reed DR, Li WD, Xu W, Joo EJ, et al. 1999.. Genome scan for human obesity and linkage to markers in 20q13. . Am. J. Hum. Genet. 64::196–209
     [Crossref] [Google Scholar]
  130. 130.
    Ukkola O, Rankinen T, Lakka T, Leon AS, Skinner JS, et al. 2005.. Protein tyrosine phosphatase 1B variant associated with fat distribution and insulin metabolism. . Obes. Res. 13::829–34
     [Crossref] [Google Scholar]
  131. 131.
    Mo J, Wu J, Sun Z, Yang H, Lei M, Liu W. 2010.. Association of PTP1B gene polymorphism with obesity in Chinese children. . J. Cent. South Univ. Med. Sci. 35::915–20
     [Google Scholar]
  132. 132.
    Pan WW, Myers MG Jr. 2018.. Leptin and the maintenance of elevated body weight. . Nat. Rev. Neurosci. 19::95–105
     [Crossref] [Google Scholar]
  133. 133.
    Myers MP, Andersen JN, Cheng A, Tremblay ML, Horvath CM, et al. 2001.. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. . J. Biol. Chem. 276::47771–74
     [Crossref] [Google Scholar]
  134. 134.
    White CL, Whittington A, Barnes MJ, Wang Z, Bray GA, Morrison CD. 2009.. HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms. . Am. J. Physiol. Endocrinol. Metab. 296::E291–99
     [Crossref] [Google Scholar]
  135. 135.
    Williams KW, Liu T, Kong X, Fukuda M, Deng Y, et al. 2014.. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. . Cell Metab. 20::471–82
     [Crossref] [Google Scholar]
  136. 136.
    Lindtner C, Scherer T, Zielinski E, Filatova N, Fasshauer M, et al. 2013.. Binge drinking induces whole-body insulin resistance by impairing hypothalamic insulin action. . Sci. Transl. Med. 5::170ra14
     [Crossref] [Google Scholar]
  137. 137.
    Kyriakou E, Schmidt S, Dodd GT, Pfuhlmann K, Simonds SE, et al. 2018.. Celastrol promotes weight loss in diet-induced obesity by inhibiting the protein tyrosine phosphatases PTP1B and TCPTP in the hypothalamus. . J. Med. Chem. 61::11144–57
     [Crossref] [Google Scholar]
  138. 138.
    Duerrschmid C, He YL, Wang CM, Li C, Bournat JC, et al. 2017.. Asporsin is a centrally acting orexigenic hormone. . Nat. Med. 23::1444–53
     [Crossref] [Google Scholar]
  139. 139.
    Veeriah S, Brennan C, Meng SS, Singh B, Fagin JA, et al. 2009.. The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers. . PNAS 106::9435–40
     [Crossref] [Google Scholar]
  140. 140.
    Affinati AH, Myers MG Jr. 2021.. Neuroendocrine control of body energy homeostasis. . In Endotext, ed. KR Feingold, B Anawalt, MR Blackman, A Boyce, G Chrousos, et al. South Dartmouth, MA:: MDText.com
     [Google Scholar]
  141. 141.
    Myers MG Jr., Affinati AH, Richardson N, Schwartz MW. 2021.. Central nervous system regulation of organismal energy and glucose homeostasis. . Nat. Metab. 3::737–50
     [Crossref] [Google Scholar]
  142. 142.
    Scherer T, Sakamoto K, Buettner C. 2021.. Brain insulin signalling in metabolic homeostasis and disease. . Nat. Rev. Endocrinol. 17::468–83
     [Crossref] [Google Scholar]
  143. 143.
    Enriori PJ, Sinnayah P, Simonds SE, Garcia Rudaz C, Cowley MA. 2011.. Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance. . J. Neurosci. 31::12189–97
     [Crossref] [Google Scholar]
  144. 144.
    Plum L, Rother E, Munzberg H, Wunderlich FT, Morgan DA, et al. 2007.. Enhanced leptin-stimulated Pi3k activation in the CNS promotes white adipose tissue transdifferentiation. . Cell Metab. 6::431–45
     [Crossref] [Google Scholar]
  145. 145.
    Dodd GT, Worth AA, Nunn N, Korpal AK, Bechtold DA, et al. 2014.. The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus. . Cell Metab. 20::639–49
     [Crossref] [Google Scholar]
  146. 146.
    Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. 2002.. Sniffing neuropeptides: a transnasal approach to the human brain. . Nat. Neurosci. 5::514–16
     [Crossref] [Google Scholar]
  147. 147.
    Weston CR, Davis RJ. 2007.. The JNK signal transduction pathway. . Curr. Opin. Cell Biol. 19::142–49
     [Crossref] [Google Scholar]
  148. 148.
    Cuenda A, Rousseau S. 2007.. p38 MAP-Kinases pathway regulation, function and role in human diseases. . Biochim. Biophys. Acta 1773::1358–75
     [Crossref] [Google Scholar]
  149. 149.
    Raman M, Chen W, Cobb MH. 2007.. Differential regulation and properties of MAPKs. . Oncogene 26::3100–12
     [Crossref] [Google Scholar]
  150. 150.
    Lawan A, Bennett AM. 2017.. Mitogen-activated protein kinase regulation in hepatic metabolism. . Trends Endocrinol. Metab. 28::868–78
     [Crossref] [Google Scholar]
  151. 151.
    Seternes OM, Kidger AM, Keyse SM. 2019.. Dual-specificity MAP kinase phosphatases in health and disease. . Biochim. Biophys. Acta Mol. Cell Res. 1866::124–43
     [Crossref] [Google Scholar]
  152. 152.
    Boutros T, Chevet E, Metrakos P. 2008.. Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. . Pharmacol. Rev. 60::261–310
     [Crossref] [Google Scholar]
  153. 153.
    Muda M, Theodosiou A, Gillieron C, Smith A, Chabert C, et al. 1998.. The mitogen-activated protein kinase phosphatase-3 N-terminal noncatalytic region is responsible for tight substrate binding and enzymatic specificity. . J. Biol. Chem. 273::9323–29
     [Crossref] [Google Scholar]
  154. 154.
    Tanoue T, Adachi M, Moriguchi T, Nishida E. 2000.. A conserved docking motif in MAP kinases common to substrates, activators and regulators. . Nat. Cell Biol. 2::110–16
     [Crossref] [Google Scholar]
  155. 155.
    Wu JJ, Roth RJ, Anderson EJ, Hong EG, Lee MK, et al. 2006.. Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity. . Cell Metab. 4::61–73
     [Crossref] [Google Scholar]
  156. 156.
    Lawan A, Min K, Zhang L, Canfran-Duque A, Jurczak MJ, et al. 2018.. Skeletal muscle-specific deletion of MKP-1 reveals a p38 MAPK/JNK/Akt signaling node that regulates obesity-induced insulin resistance. . Diabetes 67::624–35
     [Crossref] [Google Scholar]
  157. 157.
    Roth RJ, Le AM, Zhang L, Kahn M, Samuel VT, et al. 2009.. MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice. . J. Clin. Investig. 119::3817–29
     [Crossref] [Google Scholar]
  158. 158.
    Lawan A, Zhang L, Gatzke F, Min K, Jurczak MJ, et al. 2015.. Hepatic mitogen-activated protein kinase phosphatase 1 selectively regulates glucose metabolism and energy homeostasis. . Mol. Cell. Biol. 35::26–40
     [Crossref] [Google Scholar]
  159. 159.
    Flach RJ, Qin H, Zhang L, Bennett AM. 2011.. Loss of mitogen-activated protein kinase phosphatase-1 protects from hepatic steatosis by repression of cell death-inducing DNA fragmentation factor A (DFFA)-like effector C (CIDEC)/fat-specific protein 27. . J. Biol. Chem. 286::22195–202
     [Crossref] [Google Scholar]
  160. 160.
    Qiu B, Lawan A, Xirouchaki CE, Yi JS, Robert M, et al. 2023.. MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention. . Nat. Commun. 14::5405
     [Crossref] [Google Scholar]
  161. 161.
    Bennett AM, Lawan A. 2020.. Improving obesity and insulin resistance by targeting skeletal muscle MKP-1. . J. Cell Signal. 1::160–68
     [Google Scholar]
  162. 162.
    Gannam ZTK, Min K, Shillingford SR, Zhang L, Herrington J, et al. 2020.. An allosteric site on MKP5 reveals a strategy for small-molecule inhibition. . Sci. Signal. 13::eaba3043
     [Crossref] [Google Scholar]
  163. 163.
    Fernando S, Sellers J, Smith S, Bhogoju S, Junkins S, et al. 2022.. Metabolic impact of MKP-2 upregulation in obesity promotes insulin resistance and fatty liver disease. . Nutrients 14::2475
     [Crossref] [Google Scholar]
  164. 164.
    Wu Z, Jiao P, Huang X, Feng B, Feng Y, et al. 2010.. MAPK phosphatase-3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice. . J. Clin. Investig. 120::3901–11
     [Crossref] [Google Scholar]
  165. 165.
    Xu H, Yang Q, Shen M, Huang X, Dembski M, et al. 2005.. Dual specificity MAPK phosphatase 3 activates PEPCK gene transcription and increases gluconeogenesis in rat hepatoma cells. . J. Biol. Chem. 280::36013–18
     [Crossref] [Google Scholar]
  166. 166.
    Feng B, Jiao P, Helou Y, Li Y, He Q, et al. 2014.. Mitogen-activated protein kinase phosphatase 3 (MKP-3)-deficient mice are resistant to diet-induced obesity. . Diabetes 63::2924–34
     [Crossref] [Google Scholar]
  167. 167.
    Camps M, Nichols A, Gillieron C, Antonsson B, Muda M, et al. 1998.. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. . Science 280::1262–65
     [Crossref] [Google Scholar]
  168. 168.
    Hong SB, Lubben TH, Dolliver CM, Petrolonis AJ, Roy RA, et al. 2005.. Expression, purification, and enzymatic characterization of the dual specificity mitogen-activated protein kinase phosphatase. , MKP-4. Bioorg. Chem. 33::34–44
     [Crossref] [Google Scholar]
  169. 169.
    Dickinson RJ, Williams DJ, Slack DN, Williamson J, Seternes O-M, Keyse SM. 2002.. Characterization of a murine gene encoding a developmentally regulated cytoplasmic dual-specificity mitogen-activated protein kinase phosphatase. . Biochem. J. 364::145–55
     [Crossref] [Google Scholar]
  170. 170.
    Christie GR, Williams DJ, MacIsaac F, Dickinson RJ, Rosewell I, Keyse SM. 2005.. The dual-specificity protein phosphatase DUSP9/MKP-4 is essential for placental function but is not required for normal embryonic development. . Mol. Cell. Biol. 25::8323–33
     [Crossref] [Google Scholar]
  171. 171.
    Ye P, Xiang M, Liao H, Liu J, Luo H, et al. 2019.. Dual-specificity phosphatase 9 protects against nonalcoholic fatty liver disease in mice through ASK1 suppression. . Hepatology 69::76–93
     [Crossref] [Google Scholar]
  172. 172.
    Emanuelli B, Eberle D, Suzuki R, Kahn CR. 2008.. Overexpression of the dual-specificity phosphatase MKP-4/DUSP-9 protects against stress-induced insulin resistance. . PNAS 105::3545–50
     [Crossref] [Google Scholar]
  173. 173.
    Qian F, Deng J, Cheng N, Welch EJ, Zhang Y, et al. 2009.. A non-redundant role for MKP5 in limiting ROS production and preventing LPS-induced vascular injury. . EMBO J. 28::2896–907
     [Crossref] [Google Scholar]
  174. 174.
    Zhang Y, Blattman JN, Kennedy NJ, Duong J, Nguyen T, et al. 2004.. Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5. . Nature 430::793–97
     [Crossref] [Google Scholar]
  175. 175.
    Shi H, Verma M, Zhang L, Dong C, Flavell RA, Bennett AM. 2013.. Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5. . J. Clin. Investig. 123::2064–77
     [Crossref] [Google Scholar]
  176. 176.
    Zhang Y, Nguyen T, Tang P, Kennedy NJ, Jiao H, et al. 2015.. Regulation of adipose tissue inflammation and insulin resistance by MAP kinase phosphatase 5. . J. Biol. Chem. 290::14875–83
     [Crossref] [Google Scholar]
  177. 177.
    Tang P, Low HB, Png CW, Torta F, Kumar JK, et al. 2019.. Protective function of mitogen-activated protein kinase phosphatase 5 in aging- and diet-induced hepatic steatosis and steatohepatitis. . Hepatol. Commun. 3::748–62
     [Crossref] [Google Scholar]
  178. 178.
    Schriever SC, Kabra DG, Pfuhlmann K, Baumann P, Baumgart EV, et al. 2020.. Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity. . J. Clin. Investig. 130::6093–108
     [Crossref] [Google Scholar]
  179. 179.
    Baumann P, Schriever SC, Kullmann S, Zimprich A, Feuchtinger A, et al. 2019.. Dusp8 affects hippocampal size and behavior in mice and humans. . Sci. Rep. 9::19483
     [Crossref] [Google Scholar]
  180. 180.
    Campbell JE, Müller TD, Finan B, DiMarchi RD, Tschop MH, D'Alessio DA. 2023.. GIPR/GLP-1R dual agonist therapies for diabetes and weight loss-chemistry, physiology, and clinical applications. . Cell Metab. 35::1519–29
     [Crossref] [Google Scholar]
  181. 181.
    Chen YN, LaMarche MJ, Chan HM, Fekkes P, Garcia-Fortanet J, et al. 2016.. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. . Nature 535::148–52
     [Crossref] [Google Scholar]
  182. 182.
    Kerr DL, Haderk F, Bivona TG. 2021.. Allosteric SHP2 inhibitors in cancer: targeting the intersection of RAS, resistance, and the immune microenvironment. . Curr. Opin. Chem. Biol. 62::1–12
     [Crossref] [Google Scholar]
  183. 183.
    Krishnan N, Koveal D, Miller DH, Xue B, Akshinthala SD, et al. 2014.. Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. . Nat. Chem. Biol. 10::558–66
     [Crossref] [Google Scholar]
  184. 184.
    Békés M, Langley DR, Crews CM. 2022.. PROTAC targeted protein degraders: the past is prologue. . Nat. Rev. Drug Discov. 21::181–200
     [Crossref] [Google Scholar]
  185. 185.
    Stanford SM, Bottini N. 2017.. Targeting tyrosine phosphatases: time to end the stigma. . Trends Pharmacol. Sci. 38::524–40
     [Crossref] [Google Scholar]
  186. 186.
    Wiede F, Lu KH, Du X, Zeissig MN, Xu R, et al. 2022.. PTP1B is an intracellular checkpoint that limits T-cell and CAR T-cell antitumor immunity. . Cancer Discov. 12::752–73
     [Crossref] [Google Scholar]
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Protein Tyrosine Phosphatases in Metabolism: A New Frontier for Therapeutics
Annual Review of Physiology 87, 301 (2025); https://doi.org/10.1146/annurev-physiol-022724-105540
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