title: Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway.
abstract: 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 CRL4(DCAF1). 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.
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong, China.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1] State Key Laboratory of Medicinal Chemical Biology, Nankai University, 94 Weijin Road, Tianjin 300071, China [2] College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: 1] State Key Laboratory of Medicinal Chemical Biology, Nankai University, 94 Weijin Road, Tianjin 300071, China [2] College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
authors.forename: Fengzhi
authors.initials: F
authors.lastname: Li
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61, Biopolis Drive, Proteos, Singapore 138673, Singapore.
authors.forename: Siew Wee
authors.initials: SW
authors.lastname: Chan
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong, China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Lin
authors.affiliation: 1] Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong, China [2] Department of Biology, South University of Science and Technology of China, Shenzhen, Guangdong 518055, China.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61, Biopolis Drive, Proteos, Singapore 138673, Singapore.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Guo
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61, Biopolis Drive, Proteos, Singapore 138673, Singapore.
authors.forename: Chun Jye
authors.initials: CJ
authors.lastname: Lim
authors.affiliation: 1] State Key Laboratory of Medicinal Chemical Biology, Nankai University, 94 Weijin Road, Tianjin 300071, China [2] College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
authors.forename: Wancai
authors.initials: W
authors.lastname: Xing
authors.affiliation: 1] State Key Laboratory of Medicinal Chemical Biology, Nankai University, 94 Weijin Road, Tianjin 300071, China [2] College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
authors.forename: Yuequan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61, Biopolis Drive, Proteos, Singapore 138673, Singapore.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.affiliation: 1] State Key Laboratory of Medicinal Chemical Biology, Nankai University, 94 Weijin Road, Tianjin 300071, China [2] College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
authors.forename: Jiafu
authors.initials: J
authors.lastname: Long
authors.affiliation: 1] Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong, China [2] Center 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.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000091082:Angiomotins; D002352:Carrier Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D000090683:Hippo Signaling Pathway; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008840:Microfilament Proteins; D025581:Neurofibromin 2 / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C423985:AMOT protein, human; D000091082:Angiomotins; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D025581:Neurofibromin 2; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases