Resumen
KIT, a type III tyrosine kinase receptor, plays a crucial role in haematopoietic development. The KIT receptor forms a dimer after ligand binding; this activates tyrosine kinase activity leading to downstream signal transduction. The D816V KIT mutation is extensively implicated in haematological malignancies, including mastocytosis and leukaemia. KIT D816V is constitutively active, but the molecular nuances that lead to constitutive tyrosine kinase activity are unclear. For the first time, we present experimental evidence that the KIT D816V mutant does not dimerize like KIT wild type. We further show evidence of decreased stabilization of the tyrosine kinase domain in the KIT D816V mutant, a phenomenon that might contribute to its constitutive activity. Since the mechanism of KIT D816V activation varies from that of the wild type, we explored downstream signal transduction events and found that even though KIT D816V targets similar signalling moieties, the signalling is amplified in the mutant compared to stem cell factor-activated wild type receptor. Uniquely, KIT D816V induces infection-related pathways and the spliceosome pathway, providing alternate options for selective as well as combinatorial therapeutic targeting.
Idioma original | English |
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Publicación | British Journal of Haematology |
DOI | |
Estado | Accepted/In press - 2022 |
Nota bibliográfica
Funding Information:The project was funded by Project Grant #287512 awarded to J. N. Berman by the Canadian Institutes of Health Research (CIHR). V. Rajan is funded by the NSHRF Scotia scholar award and the Cancer research trainee programme of the BHCRI through the Dr. Linnea Veinotte Memorial Graduate Student Award and the Terry Fox Research Institute. A. Pandey was supported by the Beatrice Hunter Cancer Research Institute with funds provided by the Canadian Imperial Bank of Commerce and the Harvey Graham Cancer Research Fund as part of The Terry Fox Strategic Health Research Training Program in Cancer Research at CIHR. The authors would also like to thank Dr. Graham Dellaire (Dalhousie University) and Dr. Christopher Sinal (Dalhousie University) for providing lab space and equipment access and Mr. Derek Rowter and Ms. Renee Raudonis for flow cytometry support.
Funding Information:
The current work was funded by CIHR Operating Grants held by J. N. Berman (Application #287512) and Jan K. Rainey (MOP‐111138). V. Rajan was funded by the Cancer Research Training Program of the BHCRI, with funds provided by the Terry Fox Research Institute through the Dr. Linnea Veinotte Memorial Graduate Student Award. V. Rajan was also funded by the Nova Scotia Health Research Foundation (NSHRF) Scotia Scholar award. A. Pandey was supported by the Beatrice Hunter Cancer Research Institute with funds provided by the Canadian Imperial Bank of Commerce and the Harvey Graham Cancer Research Fund as part of The Terry Fox Strategic Health Research Training Program in Cancer Research at CIHR. J. N. Berman serves on the scientific advisory board of Oxford Immune Algorithmics.
Publisher Copyright:
© 2022 British Society for Haematology and John Wiley & Sons Ltd.
ASJC Scopus Subject Areas
- Hematology
PubMed: MeSH publication types
- Journal Article