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- W1847717811 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." @default.
- W1847717811 created "2016-06-24" @default.
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- W1847717811 date "2015-06-05" @default.
- W1847717811 modified "2023-10-12" @default.
- W1847717811 title "Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway" @default.
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- W1847717811 doi "https://doi.org/10.1038/cr.2015.69" @default.
- W1847717811 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4493278" @default.
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