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Title: Structural basis for Mob1-dependent activation of the core Mst–Lats kinase cascade in Hippo signaling

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.
 [1] ;  [2] ;  [1] ;  [2] ;  [1]
  1. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Pharmacology
  2. Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine. Dept. of Molecular Biology and Genetics. Howard Hughes Medical Inst.
Publication Date:
Grant/Contract Number:
AC02-06CH11357; S10RR026461-01; GM085004; EY015708
Accepted Manuscript
Journal Name:
Genes and Development
Additional Journal Information:
Journal Volume: 29; Journal Issue: 13; Journal ID: ISSN 0890-9369
Cold Springs Harbor Press
Research Org:
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
Sponsoring Org:
USDOE; National Inst. of Health (NIH) (United States)
Contributing Orgs:
Johns Hopkins Univ., Baltimore, MD (United States)
Country of Publication:
United States
phosphorylation; autoinhibition; Mst2; Lats1; Mob1; X-ray crystallography; NMR
OSTI Identifier: