Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism Article Swipe
Ming Chen
,
Lixin Wan
,
Jiangwen Zhang
,
Jinfang Zhang
,
Lourdes M. Mendez
,
John G. Clohessy
,
Kelsey Berry
,
Joshua Victor
,
Qing Yin
,
Zhu Yuan
,
Wenyi Wei
,
Pier Paolo Pandolfi
·
YOU?
·
· 2018
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-017-02272-y
YOU?
·
· 2018
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-017-02272-y
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.
Related Topics
Concepts
MAPK/ERK pathway
Phosphatase
Cancer research
Phosphorylation
Kinase
Biology
Cell biology
Suppressor
P70-S6 Kinase 1
Signal transduction
Protein phosphatase 1
Protein kinase A
Anti-apoptotic Ras signalling cascade
Cancer
Genetics
Protein kinase B
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1038/s41467-017-02272-y
- https://www.nature.com/articles/s41467-017-02272-y.pdf
- OA Status
- gold
- Cited By
- 62
- References
- 61
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W2782102424
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W2782102424Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1038/s41467-017-02272-yDigital Object Identifier
- Title
-
Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanismWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2018Year of publication
- Publication date
-
2018-01-05Full publication date if available
- Authors
-
Ming Chen, Lixin Wan, Jiangwen Zhang, Jinfang Zhang, Lourdes M. Mendez, John G. Clohessy, Kelsey Berry, Joshua Victor, Qing Yin, Zhu Yuan, Wenyi Wei, Pier Paolo PandolfiList of authors in order
- Landing page
-
https://doi.org/10.1038/s41467-017-02272-yPublisher landing page
- PDF URL
-
https://www.nature.com/articles/s41467-017-02272-y.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.nature.com/articles/s41467-017-02272-y.pdfDirect OA link when available
- Concepts
-
MAPK/ERK pathway, Phosphatase, Cancer research, Phosphorylation, Kinase, Biology, Cell biology, Suppressor, P70-S6 Kinase 1, Signal transduction, Protein phosphatase 1, Protein kinase A, Anti-apoptotic Ras signalling cascade, Cancer, Genetics, Protein kinase BTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
62Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 6, 2024: 5, 2023: 7, 2022: 13, 2021: 18Per-year citation counts (last 5 years)
- References (count)
-
61Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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