title: The strength and cooperativity of KIT ectodomain contacts determine normal ligand-dependent stimulation or oncogenic activation in cancer.
abstract: The receptor tyrosine kinase KIT plays an important role in development of germ cells, hematopoietic cells, and interstitial pacemaker cells. Oncogenic KIT mutations play an important "driver" role in gastrointestinal stromal tumors, acute myeloid leukemias, and melanoma, among other cancers. Here we describe the crystal structure of a recurring somatic oncogenic mutation located in the C-terminal Ig-like domain (D5) of the ectodomain, rendering KIT tyrosine kinase activity constitutively activated. The structural analysis, together with biochemical and biophysical experiments and detailed analyses of the activities of a variety of oncogenic KIT mutations, reveals that the strength of homotypic contacts and the cooperativity in the action of D4D5 regions determines whether KIT is normally regulated or constitutively activated in cancers. We propose that cooperative interactions mediated by multiple weak homotypic contacts between receptor molecules are responsible for regulating normal ligand-dependent or oncogenic RTK activation via a "zipper-like" mechanism for receptor activation.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Reshetnyak
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yarden
authors.initials: Y
authors.lastname: Opatowsky
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.affiliation: The Biophysical Resource, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Folta-Stogniew
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Tome
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: irit.lax@yale.edu.
authors.forename: Irit
authors.initials: I
authors.lastname: Lax
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: joseph.schlessinger@yale.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
mesh_terms: D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000737:chemistry* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D061987:Sf9 Cells; D018411:Spodoptera
chemical_list: D008024:Ligands; D011994:Recombinant Proteins; D019009:Proto-Oncogene Proteins c-kit