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Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism.

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Date
2018-01-15
Authors
Chen, Ming
Wan, Lixin
Zhang, Jiangwen
Zhang, Jinfang
Mendez, Lourdes
Clohessy, John G
Berry, Kelsey
Victor, Joshua
Yin, Qing
Zhu, Yuan
Wei, Wenyi
Pandolfi, Pier Paolo
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Abstract
The mitogen-activated protein kinase (MAPK) pathway is frequently aberrantly activated in advanced cancers, including metastatic prostate cancer (CaP). However, activating mutations or gene rearrangements among MAPK signaling components, such as Ras and Raf, are not always observed in cancers with hyperactivated MAPK. The mechanisms underlying MAPK activation in these cancers remain largely elusive. Here we discover that genomic amplification of the PPP1CA gene is highly enriched in metastatic human CaP. We further identify an S6K/PP1α/B-Raf signaling pathway leading to activation of MAPK signaling that is antagonized by the PML tumor suppressor. Mechanistically, we find that PP1α acts as a B-Raf activating phosphatase and that PML suppresses MAPK activation by sequestering PP1α into PML nuclear bodies, hence repressing S6K-dependent PP1α phosphorylation, 14-3-3 binding and cytoplasmic accumulation. Our findings therefore reveal a PP1α/PML molecular network that is genetically altered in human cancer towards aberrant MAPK activation, with important therapeutic implications.
Type
Journal article
Subject
Cell Line, Tumor
Humans
Prostatic Neoplasms
Neoplasm Metastasis
Proto-Oncogene Proteins B-raf
Ribosomal Protein S6 Kinases, 70-kDa
Signal Transduction
MAP Kinase Signaling System
Gene Amplification
Enzyme Activation
Male
Proto-Oncogene Proteins c-akt
Protein Phosphatase 1
Phosphatidylinositol 3-Kinases
Promyelocytic Leukemia Protein
PC-3 Cells
Permalink
https://hdl.handle.net/10161/18168
Published Version (Please cite this version)
10.1038/s41467-017-02272-y
Publication Info
Chen, Ming; Wan, Lixin; Zhang, Jiangwen; Zhang, Jinfang; Mendez, Lourdes; Clohessy, John G; ... Pandolfi, Pier Paolo (2018). Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism. Nature communications, 9(1). pp. 159. 10.1038/s41467-017-02272-y. Retrieved from https://hdl.handle.net/10161/18168.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Chen

Ming Chen

Assistant Professor in Pathology
Our laboratory is interested in understanding the molecular and genetic events underlying cancer progression and metastasis. The focus of our work is a series of genetically engineered mouse models that faithfully recapitulate human disease. Using a combination of mouse genetics, omics technologies, cross-species analyses and in vitro approaches, we aim to identify cancer cell–intrinsic and –extrinsic mechanisms driving metastatic cancer progression, with a long
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