title: Structural basis for Mob1-dependent activation of the core Mst-Lats kinase cascade in Hippo signaling.
abstract: The Mst-Lats kinase cascade is central to the Hippo tumor-suppressive pathway that controls organ size and tissue homeostasis. The adaptor protein Mob1 promotes Lats activation by Mst, but the mechanism remains unknown. Here, we show that human Mob1 binds to autophosphorylated docking motifs in active Mst2. This binding enables Mob1 phosphorylation by Mst2. Phosphorylated Mob1 undergoes conformational activation and binds to Lats1. We determine the crystal structures of phospho-Mst2-Mob1 and phospho-Mob1-Lats1 complexes, revealing the structural basis of both phosphorylation-dependent binding events. Further biochemical and functional analyses demonstrate that Mob1 mediates Lats1 activation through dynamic scaffolding and allosteric mechanisms. Thus, Mob1 acts as a phosphorylation-regulated coupler of kinase activation by virtue of its ability to engage multiple ligands. We propose that stepwise, phosphorylation-triggered docking interactions of nonkinase elements enhance the specificity and robustness of kinase signaling cascades.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Lisheng
authors.initials: L
authors.lastname: Ni
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Mayuko
authors.initials: M
authors.lastname: Hara
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Duojia
authors.initials: D
authors.lastname: Pan
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Xuelian
authors.initials: X
authors.lastname: Luo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003460:Crystallization; D004331:Drosophila melanogaster; D000090683:Hippo Signaling Pathway; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D020836:Protein Structure, Quaternary; D016415:Sequence Alignment; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; C496256:MOB1A protein, human; C092745:LATS1 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases
keywords: Lats1; Mob1; Mst2; NMR; X-ray crystallography; autoinhibition; phosphorylation