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SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

  1. Sung Jun Bae
  2. Lisheng Ni
  3. Adam Osinski
  4. Diana R Tomchick
  5. Chad A Brautigam
  6. Xuelian Luo  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
Research Article
  • Cited 16
  • Views 1,810
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Cite this article as: eLife 2017;6:e30278 doi: 10.7554/eLife.30278

Abstract

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.

Article and author information

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. Adam Osinski

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

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7529-4643
  5. Chad A Brautigam

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

    Department of Pharmacology, 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

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.

Reviewing Editor

  1. William I Weis, Stanford University Medical Center, United States

Publication history

  1. Received: July 8, 2017
  2. Accepted: October 22, 2017
  3. Accepted Manuscript published: October 24, 2017 (version 1)
  4. Version of Record published: October 31, 2017 (version 2)

Copyright

© 2017, 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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