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

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Listed:
  • Ming Chen

    (Harvard Medical School)

  • Lixin Wan

    (Harvard Medical School
    H. Lee Moffitt Cancer Center and Research Institute)

  • Jiangwen Zhang

    (The University of Hong Kong)

  • Jinfang Zhang

    (Harvard Medical School)

  • Lourdes Mendez

    (Harvard Medical School)

  • John G. Clohessy

    (Harvard Medical School)

  • Kelsey Berry

    (Harvard Medical School)

  • Joshua Victor

    (Harvard Medical School)

  • Qing Yin

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Yuan Zhu

    (Harvard Medical School)

  • Wenyi Wei

    (Harvard Medical School)

  • Pier Paolo Pandolfi

    (Harvard Medical School)

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.

Suggested Citation

  • Ming Chen & Lixin Wan & Jiangwen Zhang & Jinfang Zhang & Lourdes Mendez & John G. Clohessy & Kelsey Berry & Joshua Victor & Qing Yin & Yuan Zhu & Wenyi Wei & Pier Paolo Pandolfi, 2018. "Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02272-y
    DOI: 10.1038/s41467-017-02272-y
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