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Elife. 2020 Jan 8;9. pii: e53003. doi: 10.7554/eLife.53003.

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

Author information

1
Broad Institute of Harvard and MIT, Cambridge, United States.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.
3
Division of Medical Genetics, School of Medicine, University of California, San Diego, San Diego, United States.
4
Moores Cancer Center, University of California, San Diego, San Diego, United States.
5
Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, United States.
6
Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States.
7
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
8
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, United States.
9
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States.
10
Stowers Institute for Medical Research, Kansas City, United States.
11
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, United States.
12
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
#
Contributed equally

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.

KEYWORDS:

MAP4K4; PP2A; STRIPAK; cancer biology; human; small t; transformation

Conflict of interest statement

JK, CB, MK, AS, GA, HY, ED, AI, LF, MW, PT, OG No competing interests declared, KS has previously consulted for Novartis and Rigel Pharmaceuticals and receives grant funding from Novartis on unrelated topics, NG 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, JM serves on the SAB of 908 Devices and has received sponsored research funding from AstraZeneca and Vertex. JD has served as a consultant to Merck & Co, Inc and has received research funding from Constellation Pharmaceuticals, Inc, WH Reviewing editor, eLife

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