Journal
ONCOGENE
Volume 37, Issue 43, Pages 5719-5734Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-018-0365-2
Keywords
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Funding
- NCCRF startup grant (NCCRF-SUG-JH)
- NCCRF bridging grant [NCCRF-YR2016-JUL-BG1]
- NMRC seeding grants [NCCSPG-YR2015-JUL-14, NCCSPG-YR2016-JAN-17]
- Duke-NUS Khoo Bridge Funding Award [Duke-NUS-KBrFA/2017/0003]
- Asia Fund Cancer Research [AFCR2017/2019-JH]
- SHF Research Grant [SHF/FG692S/2016]
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Although extensively studied for three decades, the molecular mechanisms that regulate the RAF/MEK/ERK kinase cascade remain ambiguous. Recent studies identified the dimerization of RAF as a key event in the activation of this cascade. Here, we show that in-frame deletions in the beta 3-alpha C loop activate ARAF as well as BRAF and other oncogenic kinases by enforcing homodimerization. By characterizing these RAF mutants, we find that ARAF has less allosteric and catalytic activity than the other two RAF isoforms, which arises from its non-canonical APE motif. Further, these RAF mutants exhibit a strong oncogenic potential, and a differential inhibitor resistance that correlates with their dimer affinity. Using these unique mutants, we demonstrate that active RAFs, including the BRAF(V600E) mutant, phosphorylate MEK in a dimer-dependent manner. This study characterizes a special category of oncogenic kinase mutations, and elucidates the molecular basis that underlies the differential ability of RAF isoforms to stimulate MEK-ERK pathway. Further, this study reveals a unique catalytic feature of RAF family kinases that can be exploited to control their activities for cancer therapies.
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