ArticleOncogene2014
KIT-D816V oncogenic activity is controlled by the juxtamembrane docking site Y568-Y570.
Article in Oncogene, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 25 citations in OpenAlex.
- SHP2 inhibition and adjuvant therapy synergistically target KIT-mutant GISTs via ERK1/2-regulated GSK3β/cyclin D1 pathway.Clinical and translational medicine · 2025Article
- Gene Mutations in Gastrointestinal Stromal Tumors: Advances in Treatment and Mechanism Research.Global medical genetics · 2024Review
- KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST.Cell communication and signaling : CCS · 2024Review
- CRISPR/Cas9-engineering of HMC-1.2 cells renders a human mast cell line with a single D816V-KIT mutation: An improved preclinical model for research on mastocytosis.Frontiers in immunology · 2023Article
- Review
- The V654A second-site KIT mutation increases tumor oncogenesis and STAT activation in a mouse model of gastrointestinal stromal tumor.Oncogene · 2020Article
- Review
- Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Oncogenic signaling by Kit tyrosine kinase occurs selectively on the Golgi apparatus in gastrointestinal stromal tumors.Oncogene · 2017Article
- Observational
- Changes in allele frequencies ofHaematologica · 2017Article
- M-COPA suppresses endolysosomal Kit-Akt oncogenic signalling through inhibiting the secretory pathway in neoplastic mast cells.PloS one · 2017Article
- Article
- The activation loop tyrosine 823 is essential for the transforming capacity of the c-Kit oncogenic mutant D816V.Oncogene · 2015Article
- Hotspot mutations in KIT receptor differentially modulate its allosterically coupled conformational dynamics: impact on activation and drug sensitivity.PLoS computational biology · 2014Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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