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Structure of a c-kit product complex reveals the basis for kinase transactivation.

Mol CD, Lim KB, Sridhar V, Zou H, Chien EY, Sang BC, Nowakowski J, Kassel DB, Cronin CN, McRee DE
J Biol Chem 278 31461-4 (2003)
Cited: 166 times
EuropePMC logo PMID: 12824176

Abstract

The c-Kit proto-oncogene is a receptor protein-tyrosine kinase associated with several highly malignant human cancers. Upon binding its ligand, stem cell factor (SCF), c-Kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth. Disease-causing human mutations that activate SCF-independent constitutive expression of c-Kit are found in acute myelogenous leukemia, human mast cell disease, and gastrointestinal stromal tumors. We report on the phosphorylation state and crystal structure of a c-Kit product complex. The c-Kit structure is in a fully active form, with ordered kinase activation and phosphate-binding loops. These results provide key insights into the molecular basis for c-Kit kinase transactivation to assist in the design of new competitive inhibitors targeting activated mutant forms of c-Kit that are resistant to current chemotherapy regimes.

Reviews - 1pkg mentioned but not cited (6)

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Articles - 1pkg mentioned but not cited (44)

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  30. Two transmembrane dimers of the bovine papillomavirus E5 oncoprotein clamp the PDGF β receptor in an active dimeric conformation. Karabadzhak AG, Petti LM, Barrera FN, Edwards APB, Moya-Rodríguez A, Polikanov YS, Freites JA, Tobias DJ, Engelman DM, DiMaio D. Proc Natl Acad Sci U S A 114 E7262-E7271 (2017)
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  32. Consequences of replacing EGFR juxtamembrane domain with an unstructured sequence. He L, Hristova K. Sci Rep 2 854 (2012)
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  34. The strength and cooperativity of KIT ectodomain contacts determine normal ligand-dependent stimulation or oncogenic activation in cancer. Reshetnyak AV, Opatowsky Y, Boggon TJ, Folta-Stogniew E, Tome F, Lax I, Schlessinger J. Mol Cell 57 191-201 (2015)
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  36. Detailed conformational dynamics of juxtamembrane region and activation loop in c-Kit kinase activation process. Zou J, Wang YD, Ma FX, Xiang ML, Shi B, Wei YQ, Yang SY. Proteins 72 323-332 (2008)
  37. Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region. Reshetnyak AV, Nelson B, Shi X, Boggon TJ, Pavlenco A, Mandel-Bausch EM, Tome F, Suzuki Y, Sidhu SS, Lax I, Schlessinger J. Proc Natl Acad Sci U S A 110 17832-17837 (2013)
  38. A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome. Salemi S, Yousefi S, Simon D, Schmid I, Moretti L, Scapozza L, Simon HU. Allergy 64 913-918 (2009)
  39. KIT is required for hepatic function during mouse post-natal development. Magnol L, Chevallier MC, Nalesso V, Retif S, Fuchs H, Klempt M, Pereira P, Riottot M, Andrzejewski S, Doan BT, Panthier JJ, Puech A, Beloeil JC, de Angelis MH, Hérault Y. BMC Dev Biol 7 81 (2007)
  40. Repurposing Ponatinib as a Potent Agent against KIT Mutant Melanomas. Han Y, Gu Z, Wu J, Huang X, Zhou R, Shi C, Tao W, Wang L, Wang Y, Zhou G, Li J, Zhang Z, Sun S. Theranostics 9 1952-1964 (2019)
  41. Sunitinib: from charge-density studies to interaction with proteins. Malińska M, Jarzembska KN, Goral AM, Kutner A, Woźniak K, Dominiak PM. Acta Crystallogr D Biol Crystallogr 70 1257-1270 (2014)
  42. Insights into the characteristics of mammalian cardiomyocyte terminal differentiation shown through the study of mice with a dysfunctional c-kit. Naqvi N, Li M, Yahiro E, Graham RM, Husain A. Pediatr Cardiol 30 651-658 (2009)
  43. Mechanism of activation of human c-KIT kinase by internal tandem duplications of the juxtamembrane domain and point mutations at aspartic acid 816. Kim SY, Kang JJ, Lee HH, Kang JJ, Kim B, Kim CG, Park TK, Kang H. Biochem Biophys Res Commun 410 224-228 (2011)
  44. T670X KIT mutations in gastrointestinal stromal tumors: making sense of missense. Negri T, Pavan GM, Virdis E, Greco A, Fermeglia M, Sandri M, Pricl S, Pierotti MA, Pilotti S, Tamborini E. J Natl Cancer Inst 101 194-204 (2009)
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  46. Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer. Kaserer T, Blagg J. Cell Chem Biol 25 1359-1371.e2 (2018)
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  53. Synthesis and biological evaluation of analogues of the kinase inhibitor nilotinib as Abl and Kit inhibitors. Duveau DY, Hu X, Walsh MJ, Shukla S, Skoumbourdis AP, Boxer MB, Ambudkar SV, Shen M, Thomas CJ. Bioorg Med Chem Lett 23 682-686 (2013)
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  61. Discovery of amido-benzisoxazoles as potent c-Kit inhibitors. Kunz RK, Rumfelt S, Chen N, Zhang D, Tasker AS, Bürli R, Hungate R, Yu V, Nguyen Y, Whittington DA, Meagher KL, Plant M, Tudor Y, Schrag M, Xu Y, Ng GY, Hu E. Bioorg Med Chem Lett 18 5115-5117 (2008)
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  70. Selective KIT inhibitor KI-328 and HSP90 inhibitor show different potency against the type of KIT mutations recurrently identified in acute myeloid leukemia. Tsujimura A, Kiyoi H, Shiotsu Y, Ishikawa Y, Mori Y, Ishida H, Toki T, Ito E, Naoe T. Int J Hematol 92 624-633 (2010)
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