RT Journal Article
SR Electronic
T1 The Dimer-dependent Catalytic Activity of RAF Family Kinases Is Revealed Through Characterizing Their Oncogenic Mutants
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 338293
DO 10.1101/338293
A1 Jimin Yuan
A1 Wan Hwa Ng
A1 Paula Y.P. Lam
A1 Yu Wang
A1 Hongping Xia
A1 Jiajun Yap
A1 Shou Ping Guan
A1 Ann S.G. Lee
A1 Mei Wang
A1 Manuela Baccarini
A1 Jiancheng Hu
YR 2018
UL http://biorxiv.org/content/early/2018/06/04/338293.abstract
AB 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 β3-αC 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.