title: KIT-D816V oncogenic activity is controlled by the juxtamembrane docking site Y568-Y570.
abstract: Mutation of KIT receptor tyrosine kinase at residue D816 results in ligand-independent constitutive kinase activity. This mutation occurs in most patients with mastocytosis, a myeloproliferative neoplasm, and is detected at lower frequencies in acute myeloid leukemia and in germ cell tumors. Other KIT mutations occur in gastrointestinal stromal tumors (GIST) and mucosal melanoma. KIT is considered as a bona fide therapeutic target as c-kit mutations are driving oncogenes in these pathologies. However, several evidences suggest that KIT-D816V mutant is not as aggressive as other KIT mutants. Here, we show that an intracellular docking site in the juxtamembrane region of KIT maintains a negative regulation on KIT-D816V transforming potential. Sixteen signaling proteins were shown to interact with this motif. We further demonstrate that mutation of this site results in signaling modifications, altered gene expression profile and increased transforming activity of KIT-D816V mutant. This result was unexpected as mutations of the homologous sites on wild-type (WT) KIT, or on the related oncogenic FLT3-ITD receptor, impair their function. Our results support the hypothesis that, KIT-D816V mutation is a mild oncogenic event that is sufficient to confer partial transforming properties, but requires additional mutations to acquire its full transforming potential.
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: A
authors: A
authors: Chaix
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: M-L
authors: ML
authors: Arcangeli
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: S
authors: S
authors: Lopez
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: E
authors: E
authors: Voisset
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: Y
authors: Y
authors: Yang
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: M
authors: M
authors: Vita
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: S
authors: S
authors: Letard
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: S
authors: S
authors: Audebert
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: P
authors: P
authors: Finetti
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: D
authors: D
authors: Birnbaum
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: F
authors: F
authors: Bertucci
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: M
authors: M
authors: Aurrand-Lions
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: P
authors: P
authors: Dubreuil
authors: 1] INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France [2] Institut Paoli-Calmettes, Marseille, France [3] Aix-Marseille University, Marseille, France.
authors: P
authors: P
authors: De Sepulveda
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D019009:Proto-Oncogene Proteins c-kit