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

Ming Chen1, Lixin Wan2,3, Jiangwen Zhang4

  • 1Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.

Nature Communications
|January 17, 2018
PubMed

Insights

Genomic amplification of PPP1CA gene drives metastatic prostate cancer by activating the MAPK pathway. The PML tumor suppressor counteracts this by sequestering PP1α, revealing a key cancer-driving molecular network.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Mitogen-activated protein kinase (MAPK) pathway hyperactivation is common in advanced cancers like metastatic prostate cancer (CaP).
  • Mechanisms of MAPK activation in cancers lacking Ras/Raf mutations are not fully understood.
  • Genomic alterations in MAPK pathway components are not always the cause of its aberrant activation.

Purpose of the Study:

  • To investigate novel mechanisms of MAPK pathway activation in metastatic prostate cancer.
  • To identify genetic alterations and signaling pathways contributing to MAPK hyperactivation.
  • To elucidate the role of the PML tumor suppressor in regulating MAPK signaling.

Main Methods:

  • Genomic analysis to identify enriched gene amplifications in metastatic CaP.
  • Signal transduction pathway analysis involving S6K, PP1α, B-Raf, and MAPK.
  • Investigation of protein-protein interactions and subcellular localization (PML nuclear bodies).

Main Results:

  • Genomic amplification of the PPP1CA gene is significantly enriched in metastatic human CaP.
  • An S6K/PP1α/B-Raf signaling cascade was identified, leading to MAPK activation.
  • PML tumor suppressor antagonizes MAPK activation by sequestering PP1α in nuclear bodies, preventing its activation.

Conclusions:

  • PP1α acts as a B-Raf activating phosphatase, crucial for MAPK pathway activation.
  • PML suppresses MAPK signaling by inhibiting PP1α phosphorylation and cytoplasmic accumulation.
  • The PP1α/PML molecular network is a novel, genetically altered pathway in cancer, offering therapeutic targets.

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