Homeostatic Control of Hpo/MST Kinase Activity through Autophosphorylation-Dependent Recruitment of the STRIPAK PP2A Phosphatase Complex

Yonggang Zheng, Bo Liu, Li Wang, Huiyan Lei, Katiuska Daniela Pulgar Prieto, Duojia Pan

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

The Hippo pathway controls organ size and tissue homeostasis through a kinase cascade leading from the Ste20-like kinase Hpo (MST1/2 in mammals) to the transcriptional coactivator Yki (YAP/TAZ in mammals). Whereas previous studies have uncovered positive and negative regulators of Hpo/MST, how they are integrated to maintain signaling homeostasis remains poorly understood. Here, we identify a self-restricting mechanism whereby autophosphorylation of an unstructured linker in Hpo/MST creates docking sites for the STRIPAK PP2A phosphatase complex to inactivate Hpo/MST. Mutation of the phospho-dependent docking sites in Hpo/MST or deletion of Slmap, the STRIPAK subunit recognizing these docking sites, results in constitutive activation of Hpo/MST in both Drosophila and mammalian cells. In contrast, autophosphorylation of the Hpo/MST linker at distinct sites is known to recruit Mats/MOB1 to facilitate Hippo signaling. Thus, multisite autophosphorylation of Hpo/MST linker provides an evolutionarily conserved built-in molecular platform to maintain signaling homeostasis by coupling antagonistic signaling activities. The Hippo pathway was named after the Ste20-like kinase Hpo/MST, but how its activity is regulated remains unclear. Zheng et al. identify a self-restricting mechanism whereby autophosphorylation of an unstructured linker in Hpo/MST creates docking sites for the STRIPAK PP2A phosphatase complex to inactivate Hpo/MST in both Drosophila and mammals.

Original languageEnglish (US)
Pages (from-to)3612-3623
Number of pages12
JournalCell Reports
Volume21
Issue number12
DOIs
StatePublished - Dec 19 2017

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Keywords

  • autophosphorylation
  • Hippo signaling
  • Hpo
  • MST1/2
  • PP2A
  • SLMAP
  • STRIPAK

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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