TY - JOUR T1 - The Dimer-dependent Catalytic Activity of RAF Family Kinases Is Revealed Through Characterizing Their Oncogenic Mutants JF - bioRxiv DO - 10.1101/338293 SP - 338293 AU - Jimin Yuan AU - Wan Hwa Ng AU - Paula Y.P. Lam AU - Yu Wang AU - Hongping Xia AU - Jiajun Yap AU - Shou Ping Guan AU - Ann S.G. Lee AU - Mei Wang AU - Manuela Baccarini AU - Jiancheng Hu Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/06/04/338293.abstract N2 - 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. ER -