Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41388-018-0365-2
Title: The dimer-dependent catalytic activity of RAF family kinases is revealed through characterizing their oncogenic mutants
Authors: Yuan, J
Ng, W.H
Lam, P.Y.P 
Wang, Y
Xia, H
Yap, J
Guan, S.P 
Lee, A.S.G 
Wang, M 
Baccarini, M
Hu, J 
Keywords: A Raf kinase
B Raf kinase
dimer
glutamic acid
isoenzyme
mitogen activated protein kinase
mitogen activated protein kinase kinase
mutant protein
Raf protein
valine
Raf protein
allosterism
animal experiment
animal model
animal tissue
Article
binding affinity
cancer therapy
catalysis
controlled study
dimerization
enzyme activation
enzyme activity
enzyme analysis
enzyme phosphorylation
female
gene mutation
human
human cell
molecular biology
mouse
nonhuman
priority journal
protein family
protein motif
animal
catalysis
enzymology
genetics
knockout mouse
MAPK signaling
metabolism
mutation
neoplasm
pathology
protein multimerization
tumor cell line
Animals
Catalysis
Cell Line, Tumor
MAP Kinase Signaling System
Mice
Mice, Knockout
Mutation
Neoplasms
Protein Multimerization
raf Kinases
Issue Date: 2018
Publisher: Nature Publishing Group
Citation: Yuan, J, Ng, W.H, Lam, P.Y.P, Wang, Y, Xia, H, Yap, J, Guan, S.P, Lee, A.S.G, Wang, M, Baccarini, M, Hu, J (2018). The dimer-dependent catalytic activity of RAF family kinases is revealed through characterizing their oncogenic mutants. Oncogene 37 (43) : 5719-5734. ScholarBank@NUS Repository. https://doi.org/10.1038/s41388-018-0365-2
Abstract: 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 ?3-?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. © 2018, The Author(s).
Source Title: Oncogene
URI: https://scholarbank.nus.edu.sg/handle/10635/175101
ISSN: 0950-9232
DOI: 10.1038/s41388-018-0365-2
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