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Annual Review of Biochemistry

Volume 92, 2023

The Activation Mechanism of the Insulin Receptor: A Structural Perspective

Abstract

The insulin receptor (IR) is a type II receptor tyrosine kinase that plays essential roles in metabolism, growth, and proliferation. Dysregulation of IR signaling is linked to many human diseases, such as diabetes and cancers. The resolution revolution in cryo–electron microscopy has led to the determination of several structures of IR with different numbers of bound insulin molecules in recent years, which have tremendously improved our understanding of how IR is activated by insulin. Here, we review the insulin-induced activation mechanism of IR, including () the detailed binding modes and functions of insulin at site 1 and site 2 and () the insulin-induced structural transitions that are required for IR activation. We highlight several other key aspects of the activation and regulation of IR signaling and discuss the remaining gaps in our understanding of the IR activation mechanism and potential avenues of future research.

Keyword(s): activation mechanism, cryo-EM, insulin, insulin receptor, insulin-binding site 1, insulin-binding site 2
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/content/journals/10.1146/annurev-biochem-052521-033250
2023-06-20
2024-04-29
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Literature Cited

  1. 1.
    Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. 1922. Pancreatic extracts in the treatment of diabetes mellitus. Can. Med. Assoc. J. 12:141–46
     [Google Scholar]
  2. 2.
    Levine R, Goldstein MS, Huddlestun B, Klein SP. 1950. Action of insulin on the ‘permeability’ of cells to free hexoses, as studied by its effect on the distribution of galactose. Am. J. Physiol. 163:70–76
     [Google Scholar]
  3. 3.
    Freychet P, Roth J, Neville DM Jr. 1971. Insulin receptors in the liver: specific binding of [125I]insulin to the plasma membrane and its relation to insulin bioactivity. PNAS 68:1833–37
     [Google Scholar]
  4. 4.
    Kasuga M, Karlsson FA, Kahn CR. 1982. Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science 215:185–87
     [Google Scholar]
  5. 5.
    Kasuga M, Zick Y, Blithe DL, Crettaz M, Kahn CR. 1982. Insulin stimulates tyrosine phosphorylation of the insulin receptor in a cell-free system. Nature 298:667–69
     [Google Scholar]
  6. 6.
    Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM et al. 1985. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756–61
     [Google Scholar]
  7. 7.
    Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L et al. 1985. The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell 40:747–58
     [Google Scholar]
  8. 8.
    Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M et al. 1986. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J. 5:2503–12
     [Google Scholar]
  9. 9.
    Shier P, Watt VM. 1989. Primary structure of a putative receptor for a ligand of the insulin family. J. Biol. Chem. 264:14605–8
     [Google Scholar]
  10. 10.
    Bravo DA, Gleason JB, Sanchez RI, Roth RA, Fuller RS. 1994. Accurate and efficient cleavage of the human insulin proreceptor by the human proprotein-processing protease furin. Characterization and kinetic parameters using the purified, secreted soluble protease expressed by a recombinant baculovirus. J. Biol. Chem. 269:25830–37
     [Google Scholar]
  11. 11.
    Bajaj M, Waterfield MD, Schlessinger J, Taylor WR, Blundell T. 1987. On the tertiary structure of the extracellular domains of the epidermal growth factor and insulin receptors. Biochim. Biophys. Acta 916:220–26
     [Google Scholar]
  12. 12.
    Schaffer L, Ljungqvist L. 1992. Identification of a disulfide bridge connecting the α-subunits of the extracellular domain of the insulin receptor. Biochem. Biophys. Res. Commun. 189:650–53
     [Google Scholar]
  13. 13.
    Sparrow LG, McKern NM, Gorman JJ, Strike PM, Robinson CP et al. 1997. The disulfide bonds in the C-terminal domains of the human insulin receptor ectodomain. J. Biol. Chem. 272:29460–67
     [Google Scholar]
  14. 14.
    Seino S, Bell GI. 1989. Alternative splicing of human insulin receptor messenger RNA. Biochem. Biophys. Res. Commun. 159:312–16
     [Google Scholar]
  15. 15.
    Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R et al. 1999. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol. Cell. Biol. 19:3278–88
     [Google Scholar]
  16. 16.
    Petersen MC, Shulman GI. 2018. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98:2133–223
     [Google Scholar]
  17. 17.
    Santoro A, McGraw TE, Kahn BB. 2021. Insulin action in adipocytes, adipose remodeling, and systemic effects. Cell Metab. 33:748–57
     [Google Scholar]
  18. 18.
    Rask-Madsen C, Kahn CR. 2012. Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb. Vasc. Biol. 32:2052–59
     [Google Scholar]
  19. 19.
    Nandi A, Kitamura Y, Kahn CR, Accili D. 2004. Mouse models of insulin resistance. Physiol. Rev. 84:623–47
     [Google Scholar]
  20. 20.
    Samuel VT, Shulman GI. 2016. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J. Clin. Investig. 126:12–22
     [Google Scholar]
  21. 21.
    Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Haring HU. 2016. Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiol. Rev. 96:1169–209
     [Google Scholar]
  22. 22.
    Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang HY et al. 2018. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat. Rev. Neurol. 14:168–81
     [Google Scholar]
  23. 23.
    Tsai S, Clemente-Casares X, Zhou AC, Lei H, Ahn JJ et al. 2018. Insulin receptor-mediated stimulation boosts T cell immunity during inflammation and infection. Cell Metab. 28:922–34.e4
     [Google Scholar]
  24. 24.
    Pulgar VM. 2018. Transcytosis to cross the blood brain barrier, new advancements and challenges. Front. Neurosci. 12:1019
     [Google Scholar]
  25. 25.
    Lee WL, Klip A. 2016. Endothelial transcytosis of insulin: Does it contribute to insulin resistance?. Physiology 31:336–45
     [Google Scholar]
  26. 26.
    Hubbard SR, Wei L, Ellis L, Hendrickson WA. 1994. Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature 372:746–54
     [Google Scholar]
  27. 27.
    Eck MJ, Dhe-Paganon S, Trub T, Nolte RT, Shoelson SE. 1996. Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor. Cell 85:695–705
     [Google Scholar]
  28. 28.
    Salmeen A, Andersen JN, Myers MP, Tonks NK, Barford D. 2000. Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. Mol. Cell 6:1401–12
     [Google Scholar]
  29. 29.
    Hu J, Liu J, Ghirlando R, Saltiel AR, Hubbard SR. 2003. Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor. Mol. Cell 12:1379–89
     [Google Scholar]
  30. 30.
    Depetris RS, Hu J, Gimpelevich I, Holt LJ, Daly RJ, Hubbard SR. 2005. Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14. Mol. Cell 20:325–33
     [Google Scholar]
  31. 31.
    Haeusler RA, McGraw TE, Accili D. 2018. Biochemical and cellular properties of insulin receptor signalling. Nat. Rev. Mol. Cell Biol. 19:31–44
     [Google Scholar]
  32. 32.
    Boucher J, Kleinridders A, Kahn CR. 2014. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb. Perspect. Biol. 6:a009191
     [Google Scholar]
  33. 33.
    White MF, Kahn CR. 2021. Insulin action at a molecular level – 100 years of progress. Mol. Metab. 52:101304
     [Google Scholar]
  34. 34.
    Gavin JR 3rd, Gorden P, Roth J, Archer JA, Buell DN. 1973. Characteristics of the human lymphocyte insulin receptor. J. Biol. Chem. 248:2202–7
     [Google Scholar]
  35. 35.
    De Meyts P, Roth J, Neville DM Jr., Gavin JR 3rd, Lesniak MA. 1973. Insulin interactions with its receptors: experimental evidence for negative cooperativity. Biochem. Biophys. Res. Commun. 55:154–61
     [Google Scholar]
  36. 36.
    De Meyts P, Bainco AR, Roth J. 1976. Site-site interactions among insulin receptors. Characterization of the negative cooperativity. J. Biol. Chem. 251:1877–88
     [Google Scholar]
  37. 37.
    White MF, Shoelson SE, Keutmann H, Kahn CR. 1988. A cascade of tyrosine autophosphorylation in the β-subunit activates the phosphotransferase of the insulin receptor. J. Biol. Chem. 263:2969–80
     [Google Scholar]
  38. 38.
    Rajagopalan M, Neidigh JL, McClain DA. 1991. Amino acid sequences Gly-Pro-Leu-Tyr and Asn-Pro-Glu-Tyr in the submembranous domain of the insulin receptor are required for normal endocytosis. J. Biol. Chem. 266:23068–73
     [Google Scholar]
  39. 39.
    Kahn CR, White MF. 1988. The insulin receptor and the molecular mechanism of insulin action. J. Clin. Investig. 82:1151–56
     [Google Scholar]
  40. 40.
    Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E et al. 1991. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352:73–77
     [Google Scholar]
  41. 41.
    White MF, Maron R, Kahn CR. 1985. Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells. Nature 318:183–86
     [Google Scholar]
  42. 42.
    Bjornholm M, He AR, Attersand A, Lake S, Liu SC et al. 2002. Absence of functional insulin receptor substrate-3 (IRS-3) gene in humans. Diabetologia 45:1697–702
     [Google Scholar]
  43. 43.
    Sadagurski M, Dong XC, Myers MG Jr., White MF. 2014. Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis. Mol. Metab. 3:55–63
     [Google Scholar]
  44. 44.
    White MF, Livingston JN, Backer JM, Lauris V, Dull TJ et al. 1988. Mutation of the insulin receptor at tyrosine 960 inhibits signal transmission but does not affect its tyrosine kinase activity. Cell 54:641–49
     [Google Scholar]
  45. 45.
    Backer JM, Myers MG Jr., Shoelson SE, Chin DJ, Sun XJ et al. 1992. Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J. 11:3469–79
     [Google Scholar]
  46. 46.
    Kohn AD, Kovacina KS, Roth RA. 1995. Insulin stimulates the kinase activity of RAC-PK, a pleckstrin homology domain containing ser/thr kinase. EMBO J. 14:4288–95
     [Google Scholar]
  47. 47.
    Cantley LC. 2002. The phosphoinositide 3-kinase pathway. Science 296:1655–57
     [Google Scholar]
  48. 48.
    Vanhaesebroeck B, Stephens L, Hawkins P. 2012. PI3K signalling: the path to discovery and understanding. Nat. Rev. Mol. Cell Biol. 13:195–203
     [Google Scholar]
  49. 49.
    Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR. 1994. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol. Cell. Biol. 14:4902–11
     [Google Scholar]
  50. 50.
    Hopkins BD, Pauli C, Du X, Wang DG, Li X et al. 2018. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560:499–503
     [Google Scholar]
  51. 51.
    Lu M, Wan M, Leavens KF, Chu Q, Monks BR et al. 2012. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat. Med. 18:388–95
     [Google Scholar]
  52. 52.
    Manning BD, Toker A. 2017. AKT/PKB Signaling: navigating the network. Cell 169:381–405
     [Google Scholar]
  53. 53.
    Suzuki K, Kono T. 1980. Evidence that insulin causes translocation of glucose transport activity to the plasma membrane from an intracellular storage site. PNAS 77:2542–45
     [Google Scholar]
  54. 54.
    Foley K, Boguslavsky S, Klip A. 2011. Endocytosis, recycling, and regulated exocytosis of glucose transporter 4. Biochemistry 50:3048–61
     [Google Scholar]
  55. 55.
    Huang S, Czech MP. 2007. The GLUT4 glucose transporter. Cell Metab. 5:237–52
     [Google Scholar]
  56. 56.
    Leto D, Saltiel AR. 2012. Regulation of glucose transport by insulin: traffic control of GLUT4. Nat. Rev. Mol. Cell Biol. 13:383–96
     [Google Scholar]
  57. 57.
    Cohen P. 1999. The Croonian Lecture 1998. Identification of a protein kinase cascade of major importance in insulin signal transduction. Philos. Trans. R. Soc. B 354:485–95
     [Google Scholar]
  58. 58.
    Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. 1995. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–89
     [Google Scholar]
  59. 59.
    Li S, Brown MS, Goldstein JL. 2010. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. PNAS 107:3441–46
     [Google Scholar]
  60. 60.
    Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA et al. 2011. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146:408–20
     [Google Scholar]
  61. 61.
    Laplante M, Sabatini DM. 2012. mTOR signaling in growth control and disease. Cell 149:274–93
     [Google Scholar]
  62. 62.
    Lin HV, Accili D. 2011. Hormonal regulation of hepatic glucose production in health and disease. Cell Metab. 14:9–19
     [Google Scholar]
  63. 63.
    Matsumoto M, Pocai A, Rossetti L, Depinho RA, Accili D. 2007. Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab. 6:208–16
     [Google Scholar]
  64. 64.
    Nakae J, Kitamura T, Silver DL, Accili D. 2001. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J. Clin. Investig. 108:1359–67
     [Google Scholar]
  65. 65.
    Haeusler RA, Hartil K, Vaitheesvaran B, Arrieta-Cruz I, Knight CM et al. 2014. Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors. Nat. Commun. 5:5190
     [Google Scholar]
  66. 66.
    Nakae J, Park BC, Accili D. 1999. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J. Biol. Chem. 274:15982–85
     [Google Scholar]
  67. 67.
    Biggs WH 3rd, Meisenhelder J, Hunter T, Cavenee WK, Arden KC. 1999. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. PNAS 96:7421–26
     [Google Scholar]
  68. 68.
    Gehart H, Kumpf S, Ittner A, Ricci R. 2010. MAPK signalling in cellular metabolism: stress or wellness?. EMBO Rep. 11:834–40
     [Google Scholar]
  69. 69.
    Pronk GJ, McGlade J, Pelicci G, Pawson T, Bos JL. 1993. Insulin-induced phosphorylation of the 46- and 52-kDa Shc proteins. J. Biol. Chem. 268:5748–53
     [Google Scholar]
  70. 70.
    English J, Pearson G, Wilsbacher J, Swantek J, Karandikar M et al. 1999. New insights into the control of MAP kinase pathways. Exp. Cell Res. 253:255–70
     [Google Scholar]
  71. 71.
    Cobb MH. 1999. MAP kinase pathways. Prog. Biophys. Mol. Biol. 71:479–500
     [Google Scholar]
  72. 72.
    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
     [Google Scholar]
  73. 73.
    Nichols RJ, Haderk F, Stahlhut C, Schulze CJ, Hemmati G et al. 2018. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat. Cell Biol. 20:1064–73
     [Google Scholar]
  74. 74.
    Hall C, Yu H, Choi E. 2020. Insulin receptor endocytosis in the pathophysiology of insulin resistance. Exp. Mol. Med. 52:911–20
     [Google Scholar]
  75. 75.
    McKern NM, Lawrence MC, Streltsov VA, Lou MZ, Adams TE et al. 2006. Structure of the insulin receptor ectodomain reveals a folded-over conformation. Nature 443:218–21
     [Google Scholar]
  76. 76.
    Croll TI, Smith BJ, Margetts MB, Whittaker J, Weiss MA et al. 2016. Higher-resolution structure of the human insulin receptor ectodomain: multi-modal inclusion of the insert domain. Structure 24:469–76
     [Google Scholar]
  77. 77.
    Menting JG, Whittaker J, Margetts MB, Whittaker LJ, Kong GK et al. 2013. How insulin engages its primary binding site on the insulin receptor. Nature 493:241–45
     [Google Scholar]
  78. 78.
    Bai XC, McMullan G, Scheres SH. 2015. How cryo-EM is revolutionizing structural biology. Trends Biochem. Sci. 40:49–57
     [Google Scholar]
  79. 79.
    Cai K, Zhang X, Bai XC. 2022. Cryo-electron microscopic analysis of single-pass transmembrane receptors. Chem. Rev. 122:13952–88
     [Google Scholar]
  80. 80.
    Scapin G, Dandey VP, Zhang Z, Prosise W, Hruza A et al. 2018. Structure of the insulin receptor–insulin complex by single-particle cryo-EM analysis. Nature 556:122–25
     [Google Scholar]
  81. 81.
    Weis F, Menting JG, Margetts MB, Chan SJ, Xu Y et al. 2018. The signalling conformation of the insulin receptor ectodomain. Nat. Commun. 9:4420
     [Google Scholar]
  82. 82.
    Schaffer L. 1994. A model for insulin binding to the insulin receptor. Eur. J. Biochem. 221:1127–32
     [Google Scholar]
  83. 83.
    De Meyts P, Whittaker J 2002. Structural biology of insulin and IGF1 receptors: implications for drug design. Nat. Rev. Drug Discov. 1:769–83
     [Google Scholar]
  84. 84.
    Whittaker J, Garcia P, Yu GQ, Mynarcik DC. 1994. Transmembrane domain interactions are necessary for negative cooperativity of the insulin receptor. Mol. Endocrinol. 8:1521–27
     [Google Scholar]
  85. 85.
    Uchikawa E, Choi E, Shang G, Yu H, Bai XC. 2019. Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor–ligand complex. eLife 8:e48630
     [Google Scholar]
  86. 86.
    Gutmann T, Schafer IB, Poojari C, Brankatschk B, Vattulainen I et al. 2020. Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain. J. Cell Biol. 219:e201907210
     [Google Scholar]
  87. 87.
    Choi E, Zhang X, Xing C, Yu H. 2016. Mitotic checkpoint regulators control insulin signaling and metabolic homeostasis. Cell 166:567–81
     [Google Scholar]
  88. 88.
    Lu D, Shang G, Zhang H, Yu Q, Cong X et al. 2014. Structural insights into the T6SS effector protein Tse3 and the Tse3–Tsi3 complex from Pseudomonas aeruginosa reveal a calcium-dependent membrane-binding mechanism. Mol. Microbiol. 92:1092–112
     [Google Scholar]
  89. 89.
    De Meyts P. 2015. Insulin/receptor binding: the last piece of the puzzle? What recent progress on the structure of the insulin/receptor complex tells us (or not) about negative cooperativity and activation. Bioessays 37:389–97
     [Google Scholar]
  90. 90.
    Lawrence MC. 2021. Understanding insulin and its receptor from their three-dimensional structures. Mol. Metab. 52:101255
     [Google Scholar]
  91. 91.
    Kristensen C, Kjeldsen T, Wiberg FC, Schaffer L, Hach M et al. 1997. Alanine scanning mutagenesis of insulin. J. Biol. Chem. 272:12978–83
     [Google Scholar]
  92. 92.
    Li J, Park J, Mayer JP, Webb KJ, Uchikawa E et al. 2022. Synergistic activation of the insulin receptor via two distinct sites. Nat. Struct. Mol. Biol. 29:357–68
     [Google Scholar]
  93. 93.
    Nielsen J, Brandt J, Boesen T, Hummelshoj T, Slaaby R et al. 2022. Structural investigations of full-length insulin receptor dynamics and signalling. J. Mol. Biol. 434:167458
     [Google Scholar]
  94. 94.
    Li J, Choi E, Yu H, Bai XC. 2019. Structural basis of the activation of type 1 insulin-like growth factor receptor. Nat. Commun. 10:4567
     [Google Scholar]
  95. 95.
    Kavran JM, McCabe JM, Byrne PO, Connacher MK, Wang Z et al. 2014. How IGF-1 activates its receptor. eLife 3:e03772
     [Google Scholar]
  96. 96.
    Li J, Wu J, Hall C, Bai X-C, Choi E. 2022. Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor. eLife 11:e81286
     [Google Scholar]
  97. 97.
    Nakae J, Kido Y, Accili D. 2001. Distinct and overlapping functions of insulin and IGF-I receptors. Endocr. Rev. 22:818–35
     [Google Scholar]
  98. 98.
    Tengholm A, Gylfe E. 2009. Oscillatory control of insulin secretion. Mol. Cell Endocrinol. 297:58–72
     [Google Scholar]
  99. 99.
    Siddle K. 2012. Molecular basis of signaling specificity of insulin and IGF receptors: neglected corners and recent advances. Front. Endocrinol. 3:34
     [Google Scholar]
  100. 100.
    Kim JJ, Accili D. 2002. Signalling through IGF-I and insulin receptors: Where is the specificity?. Growth Horm. IGF Res. 12:84–90
     [Google Scholar]
  101. 101.
    Goh LK, Sorkin A. 2013. Endocytosis of receptor tyrosine kinases. Cold Spring Harb. Perspect. Biol. 5:a017459
     [Google Scholar]
  102. 102.
    Choi E, Yu H. 2018. Spindle checkpoint regulators in insulin signaling. Front. Cell Dev. Biol. 6:161
     [Google Scholar]
  103. 103.
    Carpentier JL. 1994. Insulin receptor internalization: molecular mechanisms and physiopathological implications. Diabetologia 37:Suppl. 2S117–24
     [Google Scholar]
  104. 104.
    Fagerholm S, Ortegren U, Karlsson M, Ruishalme I, Stralfors P. 2009. Rapid insulin-dependent endocytosis of the insulin receptor by caveolae in primary adipocytes. PLOS ONE 4:e5985
     [Google Scholar]
  105. 105.
    Backer JM, Kahn CR, Cahill DA, Ullrich A, White MF. 1990. Receptor-mediated internalization of insulin requires a 12-amino acid sequence in the juxtamembrane region of the insulin receptor β-subunit. J. Biol. Chem. 265:16450–54
     [Google Scholar]
  106. 106.
    Backer JM, Shoelson SE, Haring E, White MF. 1991. Insulin receptors internalize by a rapid, saturable pathway requiring receptor autophosphorylation and an intact juxtamembrane region. J. Cell Biol. 115:1535–45
     [Google Scholar]
  107. 107.
    Tang R, Jiang Z, Chen F, Yu W, Fan K et al. 2020. The kinase activity of Drosophila BubR1 is required for insulin signaling-dependent stem cell maintenance. Cell Rep. 31:107794
     [Google Scholar]
  108. 108.
    Choi E, Kikuchi S, Gao H, Brodzik K, Nassour I et al. 2019. Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling. Nat. Commun. 10:1473
     [Google Scholar]
  109. 109.
    Caro JF, Ittoop O, Pories WJ, Meelheim D, Flickinger EG et al. 1986. Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity. J. Clin. Investig. 78:249–58
     [Google Scholar]
  110. 110.
    Soll AH, Kahn CR, Neville DM Jr. 1975. Insulin binding to liver plasma membranes in the obese hyperglycemic (ob/ob) mouse. Demonstration of a decreased number of functionally normal receptors. J. Biol. Chem. 250:4702–7
     [Google Scholar]
  111. 111.
    Howard JK, Flier JS. 2006. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol. Metab. 17:365–71
     [Google Scholar]
  112. 112.
    Song R, Peng W, Zhang Y, Lv F, Wu HK et al. 2013. Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. Nature 494:375–79
     [Google Scholar]
  113. 113.
    Yi JS, Park JS, Ham YM, Nguyen N, Lee NR et al. 2013. MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling. Nat. Commun. 4:2354
     [Google Scholar]
  114. 114.
    Nagarajan A, Petersen MC, Nasiri AR, Butrico G, Fung A et al. 2016. MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels. Nat. Commun. 7:12639
     [Google Scholar]
  115. 115.
    Carracedo A, Pandolfi PP. 2008. The PTEN–PI3K pathway: of feedbacks and cross-talks. Oncogene 27:5527–41
     [Google Scholar]
  116. 116.
    Clement S, Krause U, Desmedt F, Tanti JF, Behrends J et al. 2001. The lipid phosphatase SHIP2 controls insulin sensitivity. Nature 409:92–97
     [Google Scholar]
  117. 117.
    Lazar DF, Saltiel AR. 2006. Lipid phosphatases as drug discovery targets for type 2 diabetes. Nat. Rev. Drug Discov. 5:333–42
     [Google Scholar]
  118. 118.
    Anderie I, Schulz I, Schmid A. 2007. Direct interaction between ER membrane-bound PTP1B and its plasma membrane-anchored targets. Cell Signal. 19:582–92
     [Google Scholar]
  119. 119.
    Popov D. 2012. Endoplasmic reticulum stress and the on site function of resident PTP1B. Biochem. Biophys. Res. Commun. 422:535–38
     [Google Scholar]
  120. 120.
    Issad T, Boute N, Boubekeur S, Lacasa D. 2005. Interaction of PTPB with the insulin receptor precursor during its biosynthesis in the endoplasmic reticulum. Biochimie 87:111–16
     [Google Scholar]
  121. 121.
    Soos MA, Siddle K. 1989. Immunological relationships between receptors for insulin and insulin-like growth factor I. Evidence for structural heterogeneity of insulin-like growth factor I receptors involving hybrids with insulin receptors. Biochem. J. 263:553–63
     [Google Scholar]
  122. 122.
    Moxham CP, Duronio V, Jacobs S. 1989. Insulin-like growth factor I receptor β-subunit heterogeneity. Evidence for hybrid tetramers composed of insulin-like growth factor I and insulin receptor heterodimers. J. Biol. Chem. 264:13238–44
     [Google Scholar]
  123. 123.
    Soos MA, Whittaker J, Lammers R, Ullrich A, Siddle K. 1990. Receptors for insulin and insulin-like growth factor-I can form hybrid dimers. Characterisation of hybrid receptors in transfected cells. Biochem. J. 270:383–90
     [Google Scholar]
  124. 124.
    Bailyes EM, Nave BT, Soos MA, Orr SR, Hayward AC, Siddle K. 1997. Insulin receptor/IGF-I receptor hybrids are widely distributed in mammalian tissues: quantification of individual receptor species by selective immunoprecipitation and immunoblotting. Biochem. J. 327:Part 1209–15
     [Google Scholar]
  125. 125.
    Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A. 2002. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J. Biol. Chem. 277:39684–95
     [Google Scholar]
  126. 126.
    Xu Y, Margetts MB, Venugopal H, Menting JG, Kirk NS et al. 2022. How insulin-like growth factor I binds to a hybrid insulin receptor type 1 insulin-like growth factor receptor. Structure 30:1098–108.e6
     [Google Scholar]
  127. 127.
    Xu Y, Kirk NS, Venugopal H, Margetts MB, Croll TI et al. 2020. How IGF-II binds to the human type 1 insulin-like growth factor receptor. Structure 28:786–98.e6
     [Google Scholar]
  128. 128.
    Zhang X, Yu D, Sun J, Wu Y, Gong J et al. 2020. Visualization of ligand-bound ectodomain assembly in the full-length human IGF-1 receptor by cryo-EM single-particle analysis. Structure 28:555–61.e4
     [Google Scholar]
  129. 129.
    Bai XC. 2021. Seeing atoms by single-particle cryo-EM. Trends Biochem. Sci. 46:253–54
     [Google Scholar]
  130. 130.
    Yamada K, Goncalves E, Kahn CR, Shoelson SE. 1992. Substitution of the insulin receptor transmembrane domain with the c-neu/erbB2 transmembrane domain constitutively activates the insulin receptor kinase in vitro. J. Biol. Chem. 267:12452–61
     [Google Scholar]
  131. 131.
    Cheatham B, Shoelson SE, Yamada K, Goncalves E, Kahn CR. 1993. Substitution of the erbB-2 oncoprotein transmembrane domain activates the insulin receptor and modulates the action of insulin and insulin-receptor substrate 1. PNAS 90:7336–40
     [Google Scholar]
  132. 132.
    McMahon C, Baier AS, Pascolutti R, Wegrecki M, Zheng S et al. 2018. Yeast surface display platform for rapid discovery of conformationally selective nanobodies. Nat. Struct. Mol. Biol. 25:289–96
     [Google Scholar]
  133. 133.
    Bai XC, Rajendra E, Yang G, Shi Y, Scheres SH. 2015. Sampling the conformational space of the catalytic subunit of human γ-secretase. eLife 4:e11182
     [Google Scholar]
  134. 134.
    Denisov IG, Sligar SG. 2016. Nanodiscs for structural and functional studies of membrane proteins. Nat. Struct. Mol. Biol. 23:481–86
     [Google Scholar]
  135. 135.
    Frauenfeld J, Loving R, Armache JP, Sonnen AF, Guettou F et al. 2016. A saposin-lipoprotein nanoparticle system for membrane proteins. Nat. Methods 13:345–51
     [Google Scholar]
  136. 136.
    Carlson ML, Young JW, Zhao Z, Fabre L, Jun D et al. 2018. The Peptidisc, a simple method for stabilizing membrane proteins in detergent-free solution. eLife 7:e34085
     [Google Scholar]
  137. 137.
    Michailidis IE, Rusinova R, Georgakopoulos A, Chen Y, Iyengar R et al. 2011. Phosphatidylinositol-4,5-bisphosphate regulates epidermal growth factor receptor activation. Pflugers Arch. 461:387–97
     [Google Scholar]
  138. 138.
    Virkamaki A, Ueki K, Kahn CR. 1999. Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J. Clin. Investig. 103:931–43
     [Google Scholar]
  139. 139.
    Turk M, Baumeister W. 2020. The promise and the challenges of cryo-electron tomography. FEBS Lett. 594:3243–61
     [Google Scholar]
  140. 140.
    Jumper J, Evans R, Pritzel A, Green T, Figurnov M et al. 2021. Highly accurate protein structure prediction with AlphaFold. Nature 596:583–89
     [Google Scholar]
/content/journals/10.1146/annurev-biochem-052521-033250
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The Activation Mechanism of the Insulin Receptor: A Structural Perspective
Annual Review of Biochemistry 92, 247 (2023); https://doi.org/10.1146/annurev-biochem-052521-033250
/content/journals/10.1146/annurev-biochem-052521-033250
/content/journals/10.1146/annurev-biochem-052521-033250
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