ArticleProceedings of the National Academy of Sciences of the United States of America2023
Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 20 citations in OpenAlex.
- Molecular Mechanisms of KIT Receptor Dimerization and Oncogenic Activation Revealed by Multiscale Simulations.Journal of chemical information and modeling · 2026Article
- RET receptor tyrosine kinase architecture, assemblies, and activation.Endocrine-related cancer · 2026Review
- Lipids regulate epidermal growth factor receptor activation by its ligands.Biochemical Society transactions · 2026Review
- Article
- [Causal relationship between circulating cytokines and keloids: A Mendelian randomized study].Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2025Article
- A Mendelian randomization study on the causal association of circulating cytokines with diabetic nephropathy.Journal of diabetes investigation · 2025Article
- A CanineAnimals : an open access journal from MDPI · 2025Article
- Reanalysis of cryo-EM data reveals ALK-cytokine assemblies with both 2:1 and 2:2 stoichiometries.PLoS biology · 2025Article
- Single-molecule imaging and molecular dynamics simulations reveal early activation of the MET receptor in cells.Nature communications · 2024Article
- Article
- Molecular basis of VEGFR1 autoinhibition at the plasma membrane.Nature communications · 2024Article
- Structural dynamics of the active HER4 and HER2/HER4 complexes is finely tuned by different growth factors and glycosylation.bioRxiv : the preprint server for biology · 2024Article
- Article
- Not all kidney cysts are created equal: a distinct renal cystogenic mechanism in tuberous sclerosis complex (TSC).Frontiers in physiology · 2023Review
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The receptor tyrosine kinase KIT and its ligand stem cell factor (SCF) are required for the development of hematopoietic stem cells, germ cells, and other cells. A variety of human cancers, such as acute myeloid leukemia, gastrointestinal stromal tumor, and mast cell leukemia, are driven by somatic gain-of-function KIT mutations. Here, we report cryo electron microscopy (cryo-EM) structural analyses of full-length wild-type and two oncogenic KIT mutants, which show that the overall symmetric arrangement of the extracellular domain of ligand-occupied KIT dimers contains asymmetric D5 homotypic contacts juxtaposing the plasma membrane. Mutational analysis of KIT reveals in D5 region an "Achilles heel" for therapeutic intervention. A ligand-sensitized oncogenic KIT mutant exhibits a more comprehensive and stable D5 asymmetric conformation. A constitutively active ligand-independent oncogenic KIT mutant adopts a V-shaped conformation solely held by D5-mediated contacts. Binding of SCF to this mutant fully restores the conformation of wild-type KIT dimers, including the formation of salt bridges responsible for D4 homotypic contacts and other hallmarks of SCF-induced KIT dimerization. These experiments reveal an unexpected structural plasticity of oncogenic KIT mutants and a therapeutic target in D5.
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