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Article: Deregulated PP1alpha phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism

TitleDeregulated PP1alpha phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism
Authors
Issue Date2018
PublisherNature Publishing Group: Nature Communications. The Journal's web site is located at http://www.nature.com/ncomms/index.html
Citation
Nature Communications, 2018, v. 9 n. 1, p. 159 How to Cite?
AbstractThe 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/PP1alpha/B-Raf signaling pathway leading to activation of MAPK signaling that is antagonized by the PML tumor suppressor. Mechanistically, we find that PP1alpha acts as a B-Raf activating phosphatase and that PML suppresses MAPK activation by sequestering PP1alpha into PML nuclear bodies, hence repressing S6K-dependent PP1alpha phosphorylation, 14-3-3 binding and cytoplasmic accumulation. Our findings therefore reveal a PP1alpha/PML molecular network that is genetically altered in human cancer towards aberrant MAPK activation, with important therapeutic implications.
Persistent Identifierhttp://hdl.handle.net/10722/261409
ISSN
2020 Impact Factor: 14.919
2020 SCImago Journal Rankings: 5.559
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorChen, M-
dc.contributor.authorWan, L-
dc.contributor.authorZhang, J-
dc.contributor.authorZhang, J-
dc.contributor.authorMendez, L-
dc.contributor.authorClohessy, JG-
dc.contributor.authorBerry, K-
dc.contributor.authorVictor, J-
dc.contributor.authorYin, Q-
dc.contributor.authorZhu, Y-
dc.contributor.authorWei, W-
dc.contributor.authorPandolfi, PP-
dc.date.accessioned2018-09-14T08:57:41Z-
dc.date.available2018-09-14T08:57:41Z-
dc.date.issued2018-
dc.identifier.citationNature Communications, 2018, v. 9 n. 1, p. 159-
dc.identifier.issn2041-1723-
dc.identifier.urihttp://hdl.handle.net/10722/261409-
dc.description.abstractThe 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/PP1alpha/B-Raf signaling pathway leading to activation of MAPK signaling that is antagonized by the PML tumor suppressor. Mechanistically, we find that PP1alpha acts as a B-Raf activating phosphatase and that PML suppresses MAPK activation by sequestering PP1alpha into PML nuclear bodies, hence repressing S6K-dependent PP1alpha phosphorylation, 14-3-3 binding and cytoplasmic accumulation. Our findings therefore reveal a PP1alpha/PML molecular network that is genetically altered in human cancer towards aberrant MAPK activation, with important therapeutic implications.-
dc.languageeng-
dc.publisherNature Publishing Group: Nature Communications. The Journal's web site is located at http://www.nature.com/ncomms/index.html-
dc.relation.ispartofNature Communications-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleDeregulated PP1alpha phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism-
dc.typeArticle-
dc.identifier.emailZhang, J: jzhang1@hku.hk-
dc.identifier.emailZhang, J: jzhang1@hku.hk-
dc.identifier.authorityZhang, J=rp01713-
dc.identifier.authorityZhang, J=rp01713-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41467-017-02272-y-
dc.identifier.scopuseid_2-s2.0-85040762963-
dc.identifier.hkuros291163-
dc.identifier.volume9-
dc.identifier.issue1-
dc.identifier.spage159-
dc.identifier.epage159-
dc.identifier.isiWOS:000422646200001-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl2041-1723-

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