期刊
NATURE CHEMICAL BIOLOGY
卷 9, 期 7, 页码 428-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1257
关键词
-
资金
- Canadian Center of Excellence in Commercialization and Research
- Canada Foundation for Innovation
- Fonds de Recherche du Quebec en Sante
- Cancer Research Society
- Canadian Institutes for Health Research (CIHR)
- CIHR Canadian Graduate Scholarship
- Canadian Cancer Society [018046]
- CIHR [MOP119443, MOP36399]
RAF kinases have a prominent role in cancer. Their mode of activation is complex but critically requires dimerization of their kinase domains. Unexpectedly, several ATP-competitive RAF inhibitors were recently found to promote dimerization and transactivation of RAF kinases in a RAS-dependent manner and, as a result, undesirably stimulate RAS/ERK pathway-mediated cell growth. The mechanism by which these inhibitors induce RAF kinase domain dimerization remains unclear. Here we describe bioluminescence resonance energy transfer-based biosensors for the extended RAF family that enable the detection of RAF dimerization in living cells. Notably, we demonstrate the utility of these tools for profiling kinase inhibitors that selectively modulate RAF dimerization and for probing structural determinants of RAF dimerization in vivo. Our findings, which seem generalizable to other kinase families allosterically regulated by kinase domain dimerization, suggest a model whereby ATP-competitive inhibitors mediate RAF dimerization by stabilizing a rigid closed conformation of the kinase domain.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据