2. Academic Validation
  3. The dimer-dependent catalytic activity of RAF family kinases is revealed through characterizing their oncogenic mutants

The dimer-dependent catalytic activity of RAF family kinases is revealed through characterizing their oncogenic mutants

  • Oncogene. 2018 Oct;37(43):5719-5734. doi: 10.1038/s41388-018-0365-2.
Jimin Yuan 1,  Wan Hwa Ng 1,  Paula Y P Lam 1 2,  Yu Wang 1,  Hongping Xia 1,  Jiajun Yap 1,  Shou Ping Guan 1,  Ann S G Lee 3 4 5,  Mei Wang 2,  Manuela Baccarini 6,  Jiancheng Hu 7 8
Affiliations

Affiliations

  • 1 Division of Cellular and Molecular Research, Singapore, Singapore.
  • 2 Cancer and Stem Cell Program, Duke-NUS Medical School, 8 College Road, 169857, Singapore, Singapore.
  • 3 Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
  • 4 Office of Clinical & Academic Faculty Affairs, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
  • 5 Department of Physiology, National University of Singapore, 2 Medical Drive, 117597, Singapore, Singapore.
  • 6 Max F. Perutz Laboratories, University of Vienna, Doktor-Bohr-Gasse 9, 1030, Vienna, Austria.
  • 7 Division of Cellular and Molecular Research, Singapore, Singapore. hu.jiancheng@nccs.com.sg.
  • 8 Cancer and Stem Cell Program, Duke-NUS Medical School, 8 College Road, 169857, Singapore, Singapore. hu.jiancheng@nccs.com.sg.
PMID: 29930381 DOI: 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 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.

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