STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells
- Broad Institute of Harvard and MIT, United States
- Dana-Farber Cancer Institute, United States
- University of California, San Diego, United States
- Stowers Institute for Medical Research, United States
- Dana-Farber Cancer Institue, United States
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.
Data availability
The RNAseq data for MAP4K4 suppression experiments have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE118272. Raw mass spectrometry data files for SILAC and iTRAQ are available for free download at ftp://massive.ucsd.edu/MSV000084422/. MudPIT mass spectrometry data files are available for download at Massive: ftp://massive.ucsd.edu/MSV000084662/ and ProteomeXchange:http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD016628.
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STRIPAK directs PP2A activity to promote oncogenic transformationNCBI Gene Expression Omnibus, GSE118272.
Article and author information
Author details
Michael P Washburn
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
- Roger J Davis, University of Massachusetts Medical School, United States
Publication history
- Received: October 23, 2019
- Accepted: January 7, 2020
- Accepted Manuscript published: January 8, 2020 (version 1)
- Version of Record published: January 27, 2020 (version 2)
- Version of Record updated: January 28, 2020 (version 3)
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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STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells
eLife 9:e53003.
https://doi.org/10.7554/eLife.53003
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