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Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway
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Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway
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Journal Article
Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway
2015
Overview
The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Latsl/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 Latsl/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 Latsl/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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Biomedical and Life Sciences
/ Carrier Proteins - metabolism
/ Cell Proliferation - physiology
/ Genes, Tumor Suppressor - physiology
/ Humans
/ Intercellular Signaling Peptides and Proteins - metabolism
/ Membrane Proteins - metabolism
/ Mutation
/ Neurofibromin 2 - metabolism
/ NF2
/ Original
/ Protein-Serine-Threonine Kinases - metabolism
/ Upstream
/ 信号转导通路
/ 信号通路
/ 梅林
/ 肌动蛋白
/ 血管生成抑制素
/ 诱导
/ 酶激活
