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Cell Rep. 2017 Dec 19;21(12):3612-3623. doi: 10.1016/j.celrep.2017.11.076.

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

Author information

1
Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA. Electronic address: yonggang.zheng@utsouthwestern.edu.
2
Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA.
3
Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA. Electronic address: duojia.pan@utsouthwestern.edu.

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.

KEYWORDS:

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

PMID:
29262338
PMCID:
PMC5741103
DOI:
10.1016/j.celrep.2017.11.076
[Indexed for MEDLINE]
Free PMC Article

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