Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway

• DOI: 10.1038/cr.2015.69
• Publication Date: 2015-06-05T10:42:19Z
• Authors: Youjun Li; Hao Zhou; Fengzhi Li; Siew Wee Chan; Zhijie Lin; Zhiyi Wei; Zhou Yang; Fusheng Guo; Chun Jye Lim; Wancai Xing; Yuequan Shen; Wanjin Hong; Jiafu Long; Mingjie Zhang
• Keywords: Merlin (protein); Hippo signaling pathway

The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Lats1/2 and Mst1/2, as well nuclear E3 ubiquitin ligase CRL4DCAF1. Numerous mutations Merlin have been identified in Neurofibromatosis type 2 other cancer patients. Despite more than two decades research, regulator remains unknown. Here we show by high-resolution crystal structures that Lats1/2-binding site on FERM domain is physically blocked Merlin's auto-inhibitory tail. Angiomotin binding releases auto-inhibition promotes to Lats1/2. Phosphorylation Ser518 outside tail does not obviously alter conformation, but instead prevents angiomotin from thus inhibits kinase activation. Cancer-causing clustered angiomotin-binding impair angiomotin-mediated Our findings reveal respectively interface cortical actin filaments signaling, allow construction a complete signaling pathway.