1. Cell Biology

STK25 suppresses Hippo signaling by regulating SAV1-STRIPAK antagonism

  1. Sung Jun Bae
  2. Lisheng Ni
  3. Xuelian Luo  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
https://doi.org/10.7554/eLife.54863
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  1. Sung Jun Bae
  2. Lisheng Ni
  3. Xuelian Luo
(2020)
STK25 suppresses Hippo signaling by regulating SAV1-STRIPAK antagonism
eLife 9:e54863.
https://doi.org/10.7554/eLife.54863
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Abstract

The MST-LATS kinase cascade is central to the Hippo pathway that controls tissue homeostasis, development, and organ size. The PP2A complex STRIPAKSLMAP blocks MST1/2 activation. The GCKIII family kinases associate with STRIPAK, but the functions of these phosphatase-associated kinases remain elusive. We previously showed that the scaffolding protein SAV1 promotes Hippo signaling by counteracting STRIPAK (Bae et al. 2017). Here, we show that the GCKIII kinase STK25 promotes STRIPAK-mediated inhibition of MST2 in human cells. Depletion of STK25 enhances MST2 activation without affecting the integrity of STRIPAKSLMAP. STK25 directly phosphorylates SAV1 and diminishes the ability of SAV1 to inhibit STRIPAK. Thus, STK25 as the kinase component of STRIPAK can inhibit the function of the STRIPAK inhibitor SAV1. This mutual antagonism between STRIPAK and SAV1 controls the initiation of Hippo signaling.

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All data generated or analyses during this study are included in the manuscript and supporting files.

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Author details

  1. Sung Jun Bae

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Lisheng Ni

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Xuelian Luo

    Departments of Pharmacology and Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    xuelian.luo@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5058-4695

Funding

National Institute of General Medical Sciences (GM107415)

  • Xuelian Luo

National Institute of General Medical Sciences (GM132275)

  • Xuelian Luo

Welch Foundation (I-1932)

  • Xuelian Luo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, Bae et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sung Jun Bae
  2. Lisheng Ni
  3. Xuelian Luo
(2020)
STK25 suppresses Hippo signaling by regulating SAV1-STRIPAK antagonism
eLife 9:e54863.
https://doi.org/10.7554/eLife.54863

Share this article

https://doi.org/10.7554/eLife.54863

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    1. Cell Biology

    SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

    Sung Jun Bae, Lisheng Ni ... Xuelian Luo
    Research Article Updated

    The Hippo pathway controls tissue growth and homeostasis through a central MST-LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A phosphatase complex.