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STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells

  1. Jong Wook Kim
  2. Christian Berrios
  3. Miju Kim
  4. Amy E Schade
  5. Guillaume Adelmant
  6. Huwate Yeerna
  7. Emily Damato
  8. Amanda Balboni Iniguez
  9. Laurence Florens
  10. Michael P Washburn
  11. Kim Stegmaier
  12. Nathanael S Gray
  13. Pablo Tamayo
  14. Ole Gjoerup
  15. Jarrod A Marto
  16. James DeCaprio  Is a corresponding author
  17. William C Hahn  Is a corresponding author
  1. Broad Institute of Harvard and MIT, United States
  2. Dana-Farber Cancer Institute, United States
  3. University of California, San Diego, United States
  4. Stowers Institute for Medical Research, United States
  5. Dana-Farber Cancer Institue, United States
Research Article
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Cite this article as: eLife 2020;9:e53003 doi: 10.7554/eLife.53003

Abstract

Alterations involving serine-threonine phosphatase PP2A subunits occur in a range of human cancers and partial loss of PP2A function contributes to cell transformation. Displacement of regulatory B subunits by the SV40 Small T antigen (ST) or mutation/deletion of PP2A subunits alters the abundance and types of PP2A complexes in cells, leading to transformation. Here we show that ST not only displaces common PP2A B subunits but also promotes A-C subunit interactions with alternative B subunits (B', striatins) that are components of the Striatin-interacting phosphatase and kinase (STRIPAK) complex. We found that STRN4, a member of STRIPAK, is associated with ST and is required for ST-PP2A-induced cell transformation. ST recruitment of STRIPAK facilitates PP2A-mediated dephosphorylation of MAP4K4 and induces cell transformation through the activation of the Hippo pathway effector YAP1. These observations identify an unanticipated role of MAP4K4 in transformation and show that the STRIPAK complex regulates PP2A specificity and activity.

Article and author information

Author details

  1. Jong Wook Kim

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3021-7193
  2. Christian Berrios

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  3. Miju Kim

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  4. Amy E Schade

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0342-8251
  5. Guillaume Adelmant

    The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  6. Huwate Yeerna

    Division of Medical Genetics, School of Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    No competing interests declared.
  7. Emily Damato

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  8. Amanda Balboni Iniguez

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  9. Laurence Florens

    Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    No competing interests declared.
  10. Michael P Washburn

    Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7568-2585
  11. Kim Stegmaier

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    Kim Stegmaier, has previously consulted for Novartis and Rigel Pharmaceuticals and receives grant funding from Novartis on unrelated topics.
  12. Nathanael S Gray

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Nathanael S Gray, is a founder, science advisory board member (SAB) and equity holder in Gatekeeper, Syros, Petra, C4, B2S and Soltego. Also receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield and Sanofi.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5354-7403
  13. Pablo Tamayo

    Division of Medical Genetics, School of Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    No competing interests declared.
  14. Ole Gjoerup

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  15. Jarrod A Marto

    The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Jarrod A Marto, serves on the scientific advisory board of 908 Devices.
  16. James DeCaprio

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    For correspondence
    james_decaprio@dfci.harvard.edu
    Competing interests
    James DeCaprio, has served as a consultant to Merck & Co, Inc and has received research funding from Constellation Pharmaceuticals, Inc.
  17. William C Hahn

    Department of Medical Oncology, Dana-Farber Cancer Institue, Boston, United States
    For correspondence
    william_hahn@dfci.harvard.edu
    Competing interests
    William C Hahn, Reviewing editor, eLife, is a consultant for Thermo Fisher, AjuIB, MPM Capital, iTeos, Tyra Biosciences, Frontier Medicines and Parexel. WCH is a founder and serves on the scientific advisory board for KSQ Therapeutics.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2840-9791

Funding

National Cancer Institute (P01 CA203655)

  • James DeCaprio
  • William C Hahn

National Cancer Institute (U01 CA217885)

  • Jong Wook Kim
  • Huwate Yeerna
  • Pablo Tamayo

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the Dana-Farber Cancer Institute under assurance number A3023-01. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Dana-Farber Cancer Institute (Permit Number:04-101).

Reviewing Editor

  1. Roger J Davis, University of Massachusetts Medical School, United States

Publication history

  1. Received: October 23, 2019
  2. Accepted: January 7, 2020
  3. Accepted Manuscript published: January 8, 2020 (version 1)

Copyright

© 2020, Kim 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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