Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism.
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 articleSubject
Cell Line, TumorHumans
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
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https://hdl.handle.net/10161/18168Published Version (Please cite this version)
10.1038/s41467-017-02272-yPublication 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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Show full item recordScholars@Duke
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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