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

Lisheng Ni, Yonggang Zheng, Mayuko Hara, Duojia Pan, Xuelian Luo

Research output: Contribution to journalArticle

52 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1416-1431
Number of pages16
JournalGenes and Development
Volume29
Issue number13
DOIs
StatePublished - Jul 1 2015

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Phosphotransferases
Phosphorylation
Organ Size
Homeostasis
Ligands
Neoplasms
Proteins

Keywords

  • Autoinhibition
  • Lats1
  • Mob1
  • Mst2
  • NMR
  • Phosphorylation
  • X-ray crystallography

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Structural basis for Mob1-dependent activation of the core Mst–Lats kinase cascade in Hippo signaling. / Ni, Lisheng; Zheng, Yonggang; Hara, Mayuko; Pan, Duojia; Luo, Xuelian.

In: Genes and Development, Vol. 29, No. 13, 01.07.2015, p. 1416-1431.

Research output: Contribution to journalArticle

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AU - Hara, Mayuko

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AU - Luo, Xuelian

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