Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism.
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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.
SubjectCell Line, Tumor
Proto-Oncogene Proteins B-raf
Ribosomal Protein S6 Kinases, 70-kDa
MAP Kinase Signaling System
Proto-Oncogene Proteins c-akt
Protein Phosphatase 1
Promyelocytic Leukemia Protein
Published Version (Please cite this version)10.1038/s41467-017-02272-y
Publication InfoChen, 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.
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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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