Volume 25, No 7, Jul 2015
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 25 Issue 7, July 2015: 801-817 | Open Access
ORIGINAL ARTICLES
Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway
Youjun Li1,*, Hao Zhou3,4,*, Fengzhi Li3,4, Siew Wee Chan5, Zhijie Lin1, Zhiyi Wei1,6, Zhou Yang1, Fusheng Guo5, Chun Jye Lim5, Wancai Xing3,4, Yuequan Shen3,4, Wanjin Hong5, Jiafu Long3,4 and Mingjie Zhang1,2
1Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong, China
2Center of Systems Biology and Human Health, School of Science and Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
3State Key Laboratory of Medicinal Chemical Biology, Nankai University, 94 Weijin Road, Tianjin 300071, China
4College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China
5Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61, Biopolis Drive, Proteos, Singapore 138673, Singapore
6Department of Biology, South University of Science and Technology of China, Shenzhen, Guangdong 518055, China
Correspondence: Jiafu Long ; Mingjie Zhang(jflong@nankai.edu.cn ; mzhang@ust.hk)
The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Lats1/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4DCAF1. Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Lats1/2-binding site on the Merlin FERM domain is physically blocked by Merlin's auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin's binding to Lats1/2. Phosphorylation of Ser518 outside the Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.
10.1038/cr.2015.69
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