Structural Features of the Kinase Domain

  • Dániel Süveges
  • Natalia Jura


A fundamental role of receptor tyrosine kinases is to couple extracellular signals to tyrosine phosphorylation of cellular components. This reaction is carried out by an intracellular kinase domain, which becomes activated upon ligand binding to the receptor’s extracellular domain. The main substrates of the activated kinase are the phosphorylation sites located within the receptor. Those sites play two important roles—they regulate catalytic activity of the kinase and/or serve as docking sites that connect the receptors with high specificity to downstream effectors. The precise regulation of these phosphorylation events is therefore critical for receptor tyrosine kinase signaling and most frequently targeted by mutations in human diseases.

The most recognized and the best understood features that distinguish 58 receptor tyrosine kinases present in vertebrates are located within their extracellular ligand-binding domains, which share low or no homology between different receptor families. Another level of diversity is encoded by the flexible intracellular C-terminal tails, which contain different sets of tyrosine phosphorylation sites that couple receptors to unique effector repertoires. In contrast, the kinase domain is well conserved between different receptors. This is likely because the structural conservation within the catalytic domain is necessary to maintain its ability to catalyze phosphorylation. Surprisingly, the regulatory mechanisms that control catalysis differ significantly among receptors. These differences can be encoded by minor amino acid sequence changes in the kinase active site and/or allosteric modulation by the receptor regions that are adjacent to the kinase domain. This section reviews the currently understood structural features of the kinase domain and its activation mechanisms and their nuances operative in different receptor tyrosine kinase families.


Epidermal Growth Factor Receptor Receptor Tyrosine Kinase Kinase Domain Activation Loop Inactive Conformation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Eswaran J, Knapp S. Insights into protein kinase regulation and inhibition by large scale structural comparison. Biochim Biophys Acta. 2010;1804(3):429–32.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19(49):5548–57.PubMedGoogle Scholar
  3. 3.
    Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, et al. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science. 1991;253(5018):407–14.PubMedGoogle Scholar
  4. 4.
    Herberg FW, Doyle ML, Cox S, Taylor SS. Dissection of the nucleotide and metal-phosphate binding sites in cAMP-dependent protein kinase. Biochemistry. 1999;38(19):6352–60.PubMedGoogle Scholar
  5. 5.
    Bossemeyer D. The glycine-rich sequence of protein kinases: a multifunctional element. Trends Biochem Sci. 1994;19(5):201–5.PubMedGoogle Scholar
  6. 6.
    Kornev AP, Haste NM, Taylor SS, Eyck LF. Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism. Proc Natl Acad Sci U S A. 2006;103(47):17783–8.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Kornev AP, Taylor SS, Ten Eyck LF. A helix scaffold for the assembly of active protein kinases. Proc Natl Acad Sci U S A. 2008;105(38):14377–82.PubMedCentralPubMedGoogle Scholar
  8. 8.
    Azam M, Seeliger MA, Gray NS, Kuriyan J, Daley GQ. Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat Struct Mol Biol. 2008;15(10):1109–18.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Knight ZA, Shokat KM. Features of selective kinase inhibitors. Chem Biol. 2005;12(6):621–37.PubMedGoogle Scholar
  10. 10.
    De Bondt HL, Rosenblatt J, Jancarik J, Jones HD, Morgan DO, Kim SH. Crystal structure of cyclin-dependent kinase 2. Nature. 1993;363(6430):595–602.PubMedGoogle Scholar
  11. 11.
    Noble ME, Endicott JA, Johnson LN. Protein kinase inhibitors: insights into drug design from structure. Science. 2004;303(5665):1800–5.PubMedGoogle Scholar
  12. 12.
    Jura N, Zhang X, Endres NF, Seeliger MA, Schindler T, Kuriyan J. Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms. Mol Cell. 2011;42(1):9–22.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Shan Y, Seeliger MA, Eastwood MP, Frank F, Xu H, Jensen MO, et al. A conserved protonation-dependent switch controls drug binding in the Abl kinase. Proc Natl Acad Sci U S A. 2009;106(1):139–44.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Grant BD, Adams JA. Pre-steady-state kinetic analysis of cAMP-dependent protein kinase using rapid quench flow techniques. Biochemistry. 1996;35(6):2022–9.PubMedGoogle Scholar
  15. 15.
    Lew J, Taylor SS, Adams JA. Identification of a partially rate-determining step in the catalytic mechanism of cAMP-dependent protein kinase: a transient kinetic study using stopped-flow fluorescence spectroscopy. Biochemistry. 1997;36(22):6717–24.PubMedGoogle Scholar
  16. 16.
    Hubbard SR, Wei L, Ellis L, Hendrickson WA. Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature. 1994;372(6508):746–54.PubMedGoogle Scholar
  17. 17.
    Till JH, Becerra M, Watty A, Lu Y, Ma Y, Neubert TA, et al. Crystal structure of the MuSK tyrosine kinase: insights into receptor autoregulation. Structure. 2002;10(9):1187–96.PubMedGoogle Scholar
  18. 18.
    Mohammadi M, Schlessinger J, Hubbard SR. Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism. Cell. 1996;86(4):577–87.PubMedGoogle Scholar
  19. 19.
    Huse M, Kuriyan J. The conformational plasticity of protein kinases. Cell. 2002;109(3):275–82.PubMedGoogle Scholar
  20. 20.
    Schlessinger J. Signal transduction. Autoinhibition control. Science. 2003;300(5620):750–2.PubMedGoogle Scholar
  21. 21.
    Rickert KW, Patel SB, Allison TJ, Byrne NJ, Darke PL, Ford RE, et al. Structural basis for selective small molecule kinase inhibition of activated c-Met. J Biol Chem. 2011;286(13):11218–25.PubMedCentralPubMedGoogle Scholar
  22. 22.
    Favelyukis S, Till JH, Hubbard SR, Miller WT. Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat Struct Biol. 2001;8(12):1058–63.PubMedGoogle Scholar
  23. 23.
    Hubbard SR. Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. EMBO J. 1997;16(18):5572–81.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Li W, Miller WT. Role of the activation loop tyrosines in regulation of the insulin-like growth factor I receptor-tyrosine kinase. J Biol Chem. 2006;281(33):23785–91.PubMedGoogle Scholar
  25. 25.
    Furdui CM, Lew ED, Schlessinger J, Anderson KS. Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol Cell. 2006;21(5):711–7.PubMedGoogle Scholar
  26. 26.
    Lochhead PA, Sibbet G, Morrice N, Cleghon V. Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs. Cell. 2005;121(6):925–36.PubMedGoogle Scholar
  27. 27.
    Pearce LR, Komander D, Alessi DR. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol. 2010;11(1):9–22.PubMedGoogle Scholar
  28. 28.
    Biscardi JS, Maa MC, Tice DA, Cox ME, Leu TH, Parsons SJ. c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J Biol Chem. 1999;274(12):8335–43.PubMedGoogle Scholar
  29. 29.
    Gotoh N, Tojo A, Hino M, Yazaki Y, Shibuya M. A highly conserved tyrosine residue at codon 845 within the kinase domain is not required for the transforming activity of human epidermal growth factor receptor. Biochem Biophys Res Commun. 1992;186(2):768–74.PubMedGoogle Scholar
  30. 30.
    Tice DA, Biscardi JS, Nickles AL, Parsons SJ. Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Proc Natl Acad Sci U S A. 1999;96(4):1415–20.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell. 2006;125(6):1137–49.PubMedGoogle Scholar
  32. 32.
    Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem. 2002;277(48):46265–72.PubMedGoogle Scholar
  33. 33.
    Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, et al. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004;64(18):6652–9.PubMedGoogle Scholar
  34. 34.
    Jura N, Shan Y, Cao X, Shaw DE, Kuriyan J. Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3. Proc Natl Acad Sci U S A. 2009;106(51):21608–13.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Qiu C, Tarrant MK, Choi SH, Sathyamurthy A, Bose R, Banjade S, et al. Mechanism of activation and inhibition of the HER4/ErbB4 kinase. Structure. 2008;16(3):460–7.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc Natl Acad Sci U S A. 2010;107(17):7692–7.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Aertgeerts K, Skene R, Yano J, Sang BC, Zou H, Snell G, et al. Structural analysis of the mechanism of inhibition and allosteric activation of the kinase domain of HER2 protein. J Biol Chem. 2011;286(21):18756–65.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massague J, et al. Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature. 1995;376(6538):313–20.PubMedGoogle Scholar
  39. 39.
    Hagopian JC, Kirtley MP, Stevenson LM, Gergis RM, Russo AA, Pavletich NP, et al. Kinetic basis for activation of CDK2/cyclin A by phosphorylation. J Biol Chem. 2001;276(1):275–80.PubMedGoogle Scholar
  40. 40.
    Zhang HT, O’Rourke DM, Zhao H, Murali R, Mikami Y, Davis JG, et al. Absence of autophosphorylation site Y882 in the p185neu oncogene product correlates with a reduction of transforming potential. Oncogene. 1998;16(22):2835–42.PubMedGoogle Scholar
  41. 41.
    Fan YX, Wong L, Deb TB, Johnson GR. Ligand regulates epidermal growth factor receptor kinase specificity: activation increases preference for GAB1 and SHC versus autophosphorylation sites. J Biol Chem. 2004;279(37):38143–50.PubMedGoogle Scholar
  42. 42.
    Kloth MT, Laughlin KK, Biscardi JS, Boerner JL, Parsons SJ, Silva CM. STAT5b, a mediator of synergism between c-Src and the epidermal growth factor receptor. J Biol Chem. 2003;278(3):1671–9.PubMedGoogle Scholar
  43. 43.
    Boerner JL, Demory ML, Silva C, Parsons SJ. Phosphorylation of Y845 on the epidermal growth factor receptor mediates binding to the mitochondrial protein cytochrome c oxidase subunit II. Mol Cell Biol. 2004;24(16):7059–71.PubMedCentralPubMedGoogle Scholar
  44. 44.
    Yang S, Park K, Turkson J, Arteaga CL. Ligand-independent phosphorylation of Y869 (Y845) links mutant EGFR signaling to stat-mediated gene expression. Exp Cell Res. 2008;314(2):413–9.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, et al. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell. 2007;11(3):217–27.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Zheng J, Knighton DR, ten Eyck LF, Karlsson R, Xuong N, Taylor SS, et al. Crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MgATP and peptide inhibitor. Biochemistry. 1993;32(9):2154–61.PubMedGoogle Scholar
  47. 47.
    Bossemeyer D, Engh RA, Kinzel V, Ponstingl H, Huber R. Phosphotransferase and substrate binding mechanism of the cAMP-dependent protein kinase catalytic subunit from porcine heart as deduced from the 2.0 A structure of the complex with Mn2+ adenylyl imidodiphosphate and inhibitor peptide PKI(5-24). EMBO J. 1993;12(3):849–59.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Knighton DR, Zheng JH, Ten Eyck LF, Xuong NH, Taylor SS, Sowadski JM. Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science. 1991;253(5018):414–20.PubMedGoogle Scholar
  49. 49.
    Chao LH, Stratton MM, Lee IH, Rosenberg OS, Levitz J, Mandell DJ, et al. A mechanism for tunable autoinhibition in the structure of a human Ca2+/calmodulin- dependent kinase II holoenzyme. Cell. 2011;146(5):732–45.PubMedCentralPubMedGoogle Scholar
  50. 50.
    Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367(6461):375–6.PubMedGoogle Scholar
  51. 51.
    Songyang Z, Carraway 3rd KL, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, et al. Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature. 1995;373(6514):536–9.PubMedGoogle Scholar
  52. 52.
    Pandit SD, Donis-Keller H, Iwamoto T, Tomich JM, Pike LJ. The multiple endocrine neoplasia type 2B point mutation alters long-term regulation and enhances the transforming capacity of the epidermal growth factor receptor. J Biol Chem. 1996;271(10):5850–8.PubMedGoogle Scholar
  53. 53.
    Zhu H, Klemic JF, Chang S, Bertone P, Casamayor A, Klemic KG, et al. Analysis of yeast protein kinases using protein chips. Nat Genet. 2000;26(3):283–9.PubMedGoogle Scholar
  54. 54.
    Ubersax JA, Ferrell Jr JE. Mechanisms of specificity in protein phosphorylation. Nat Rev Mol Cell Biol. 2007;8(7):530–41.PubMedGoogle Scholar
  55. 55.
    Schulman BA, Lindstrom DL, Harlow E. Substrate recruitment to cyclin-dependent kinase 2 by a multipurpose docking site on cyclin A. Proc Natl Acad Sci U S A. 1998;95(18):10453–8.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Lo RS, Chen YG, Shi Y, Pavletich NP, Massague J. The L3 loop: a structural motif determining specific interactions between SMAD proteins and TGF-beta receptors. EMBO J. 1998;17(4):996–1005.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Chen YG, Hata A, Lo RS, Wotton D, Shi Y, Pavletich N, et al. Determinants of specificity in TGF-beta signal transduction. Genes Dev. 1998;12(14):2144–52.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Biondi RM, Cheung PC, Casamayor A, Deak M, Currie RA, Alessi DR. Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C-terminal residues of PKA. EMBO J. 2000;19(5):979–88.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Biondi RM, Nebreda AR. Signalling specificity of Ser/Thr protein kinases through docking-site-mediated interactions. Biochem J. 2003;372(Pt 1):1–13.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Levinson NM, Seeliger MA, Cole PA, Kuriyan J. Structural basis for the recognition of c-Src by its inactivator Csk. Cell. 2008;134(1):124–34.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Bae JH, Boggon TJ, Tome F, Mandiyan V, Lax I, Schlessinger J. Asymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cells. Proc Natl Acad Sci U S A. 2010;107(7):2866–71.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Rohmann E, Brunner HG, Kayserili H, Uyguner O, Nurnberg G, Lew ED, et al. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 2006;38(4):414–7.PubMedGoogle Scholar
  63. 63.
    Rand V, Huang J, Stockwell T, Ferriera S, Buzko O, Levy S, et al. Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas. Proc Natl Acad Sci U S A. 2005;102(40):14344–9.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Chen H, Xu CF, Ma J, Eliseenkova AV, Li W, Pollock PM, et al. A crystallographic snapshot of tyrosine trans-phosphorylation in action. Proc Natl Acad Sci U S A. 2008;105(50):19660–5.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Hubbard SR, Miller WT. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol. 2007;19(2):117–23.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Gadella Jr TW, Jovin TM. Oligomerization of epidermal growth factor receptors on A431 cells studied by time-resolved fluorescence imaging microscopy. A stereochemical model for tyrosine kinase receptor activation. J Cell Biol. 1995;129(6):1543–58.PubMedGoogle Scholar
  67. 67.
    Sako Y, Minoghchi S, Yanagida T. Single-molecule imaging of EGFR signalling on the surface of living cells. Nat Cell Biol. 2000;2(3):168–72.PubMedGoogle Scholar
  68. 68.
    Martin-Fernandez M, Clarke DT, Tobin MJ, Jones SV, Jones GR. Preformed oligomeric epidermal growth factor receptors undergo an ectodomain structure change during signaling. Biophys J. 2002;82(5):2415–27.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Clayton AH, Walker F, Orchard SG, Henderson C, Fuchs D, Rothacker J, et al. Ligand-induced dimer-tetramer transition during the activation of the cell surface epidermal growth factor receptor-A multidimensional microscopy analysis. J Biol Chem. 2005;280(34):30392–9.PubMedGoogle Scholar
  70. 70.
    Chung I, Akita R, Vandlen R, Toomre D, Schlessinger J, Mellman I. Spatial control of EGF receptor activation by reversible dimerization on living cells. Nature. 2010;464(7289):783–7.PubMedGoogle Scholar
  71. 71.
    Moriki T, Maruyama H, Maruyama IN. Activation of preformed EGF receptor dimers by ligand-induced rotation of the transmembrane domain. J Mol Biol. 2001;311(5):1011–26.PubMedGoogle Scholar
  72. 72.
    Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA. EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol Cell. 2003;11(2):507–17.PubMedGoogle Scholar
  73. 73.
    Landau M, Fleishman SJ, Ben-Tal N. A putative mechanism for downregulation of the catalytic activity of the EGF receptor via direct contact between its kinase and C-terminal domains. Structure. 2004;12(12):2265–75.PubMedGoogle Scholar
  74. 74.
    Jura N, Endres NF, Engel K, Deindl S, Das R, Lamers MH, et al. Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment. Cell. 2009;137(7):1293–307.PubMedCentralPubMedGoogle Scholar
  75. 75.
    Kani K, Park E, Landgraf R. The extracellular domains of ErbB3 retain high ligand binding affinity at endosome pH and in the locked conformation. Biochemistry. 2005;44(48):15842–57.PubMedGoogle Scholar
  76. 76.
    Landgraf R, Eisenberg D. Heregulin reverses the oligomerization of HER3. Biochemistry. 2000;39(29):8503–11.PubMedGoogle Scholar
  77. 77.
    Berger MB, Mendrola JM, Lemmon MA. ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface. FEBS Lett. 2004;569(1–3):332–6.PubMedGoogle Scholar
  78. 78.
    Himanen JP, Saha N, Nikolov DB. Cell-cell signaling via Eph receptors and ephrins. Curr Opin Cell Biol. 2007;19(5):534–42.PubMedCentralPubMedGoogle Scholar
  79. 79.
    Himanen JP, Rajashankar KR, Lackmann M, Cowan CA, Henkemeyer M, Nikolov DB. Crystal structure of an Eph receptor-ephrin complex. Nature. 2001;414(6866):933–8.PubMedGoogle Scholar
  80. 80.
    Seiradake E, Harlos K, Sutton G, Aricescu AR, Jones EY. An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly. Nat Struct Mol Biol. 2010;17(4):398–402.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Salaita K, Nair PM, Petit RS, Neve RM, Das D, Gray JW, et al. Restriction of receptor movement alters cellular response: physical force sensing by EphA2. Science. 2010;327(5971):1380–5.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Wimmer-Kleikamp SH, Janes PW, Squire A, Bastiaens PI, Lackmann M. Recruitment of Eph receptors into signaling clusters does not require ephrin contact. J Cell Biol. 2004;164(5):661–6.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Hubbard SR. Juxtamembrane autoinhibition in receptor tyrosine kinases. Nat Rev Mol Cell Biol. 2004;5(6):464–71.PubMedGoogle Scholar
  84. 84.
    Wybenga-Groot LE, Baskin B, Ong SH, Tong J, Pawson T, Sicheri F. Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Cell. 2001;106(6):745–57.PubMedGoogle Scholar
  85. 85.
    Li S, Covino ND, Stein EG, Till JH, Hubbard SR. Structural and biochemical evidence for an autoinhibitory role for tyrosine 984 in the juxtamembrane region of the insulin receptor. J Biol Chem. 2003;278(28):26007–14.PubMedGoogle Scholar
  86. 86.
    Griffith J, Black J, Faerman C, Swenson L, Wynn M, Lu F, et al. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell. 2004;13(2):169–78.PubMedGoogle Scholar
  87. 87.
    Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577–80.PubMedGoogle Scholar
  88. 88.
    Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708–10.PubMedGoogle Scholar
  89. 89.
    Thiel KW, Carpenter G. Epidermal growth factor receptor juxtamembrane region regulates allosteric tyrosine kinase activation. Proc Natl Acad Sci U S A. 2007;104(49):19238–43.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Aifa S, Aydin J, Nordvall G, Lundstrom I, Svensson SP, Hermanson O. A basic peptide within the juxtamembrane region is required for EGF receptor dimerization. Exp Cell Res. 2005;302(1):108–14.PubMedGoogle Scholar
  91. 91.
    Macdonald-Obermann JL, Pike LJ. The intracellular juxtamembrane domain of the epidermal growth factor (EGF) receptor is responsible for the allosteric regulation of EGF binding. J Biol Chem. 2009;284(20):13570–6.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Red Brewer M, Choi SH, Alvarado D, Moravcevic K, Pozzi A, Lemmon MA, et al. The juxtamembrane region of the EGF receptor functions as an activation domain. Mol Cell. 2009;34(6):641–51.PubMedGoogle Scholar
  93. 93.
    Wood ER, Shewchuk LM, Ellis B, Brignola P, Brashear RL, Caferro TR, et al. 6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases. Proc Natl Acad Sci U S A. 2008;105(8):2773–8.PubMedCentralPubMedGoogle Scholar
  94. 94.
    McLaughlin S, Smith SO, Hayman MJ, Murray D. An electrostatic engine model for autoinhibition and activation of the epidermal growth factor receptor (EGFR/ErbB) family. J Gen Physiol. 2005;126(1):41–53.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Shewchuk LM, Hassell AM, Ellis B, Holmes WD, Davis R, Horne EL, et al. Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail. Structure. 2000;8(11):1105–13.PubMedGoogle Scholar
  96. 96.
    Niu XL, Peters KG, Kontos CD. Deletion of the carboxyl terminus of Tie2 enhances kinase activity, signaling, and function. Evidence for an autoinhibitory mechanism. J Biol Chem. 2002;277(35):31768–73.PubMedGoogle Scholar
  97. 97.
    Gamett DC, Tracy SE, Robinson HL. Differences in sequences encoding the carboxyl-terminal domain of the epidermal growth factor receptor correlate with differences in the disease potential of viral erbB genes. Proc Natl Acad Sci U S A. 1986;83(16):6053–7.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Khazaie K, Dull TJ, Graf T, Schlessinger J, Ullrich A, Beug H, et al. Truncation of the human EGF receptor leads to differential transforming potentials in primary avian fibroblasts and erythroblasts. EMBO J. 1988;7(10):3061–71.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Pines G, Huang PH, Zwang Y, White FM, Yarden Y. EGFRvIV: a previously uncharacterized oncogenic mutant reveals a kinase autoinhibitory mechanism. Oncogene. 2010;29:5850.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Frederick L, Wang XY, Eley G, James CD. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res. 2000;60(5):1383–7.PubMedGoogle Scholar
  101. 101.
    Gonfloni S, Frischknecht F, Way M, Superti-Furga G. Leucine 255 of Src couples intramolecular interactions to inhibition of catalysis. Nat Struct Biol. 1999;6(8):760–4.PubMedGoogle Scholar
  102. 102.
    Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J. Structural basis for the inhibition of tyrosine kinase activity of ZAP-70. Cell. 2007;129(4):735–46.PubMedGoogle Scholar
  103. 103.
    Bublil EM, Pines G, Patel G, Fruhwirth G, Ng T, Yarden Y. Kinase-mediated quasi-dimers of EGFR. FASEB J. 2010;24:4744.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Akiyama T, Matsuda S, Namba Y, Saito T, Toyoshima K, Yamamoto T. The transforming potential of the c-erbB-2 protein is regulated by its autophosphorylation at the carboxyl-terminal domain. Mol Cell Biol. 1991;11(2):833–42.PubMedCentralPubMedGoogle Scholar
  105. 105.
    Zhang X, Pickin KA, Bose R, Jura N, Cole PA, Kuriyan J. Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface. Nature. 2007;450(7170):741–4.PubMedCentralPubMedGoogle Scholar
  106. 106.
    Yokoyama N, Ischenko I, Hayman MJ, Miller WT. The C terminus of RON tyrosine kinase plays an autoinhibitory role. J Biol Chem. 2005;280(10):8893–900.PubMedGoogle Scholar
  107. 107.
    Bardelli A, Longati P, Williams TA, Benvenuti S, Comoglio PM. A peptide representing the carboxyl-terminal tail of the met receptor inhibits kinase activity and invasive growth. J Biol Chem. 1999;274(41):29274–81.PubMedGoogle Scholar
  108. 108.
    Chiara F, Bishayee S, Heldin CH, Demoulin JB. Autoinhibition of the platelet-derived growth factor beta-receptor tyrosine kinase by its C-terminal tail. J Biol Chem. 2004;279(19):19732–8.PubMedGoogle Scholar
  109. 109.
    Mi LZ, Lu C, Li Z, Nishida N, Walz T, Springer TA. Simultaneous visualization of the extracellular and cytoplasmic domains of the epidermal growth factor receptor. Nat Struct Mol Biol. 2011;18(9):984–9.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Lupardus PJ, Skiniotis G, Rice AJ, Thomas C, Fischer S, Walz T, et al. Structural snapshots of full-length Jak1, a transmembrane gp130/IL-6/IL-6Ralpha cytokine receptor complex, and the receptor-Jak1 holocomplex. Structure. 2011;19(1):45–55.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Nath A, Atkins WM, Sligar SG. Applications of phospholipid bilayer nanodiscs in the study of membranes and membrane proteins. Biochemistry. 2007;46(8):2059–69.PubMedGoogle Scholar

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© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Cellular and Molecular Pharmacology, Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.Department of Cellular and Molecular Pharmacology, Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoUSA

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