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A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells

Author

Listed:
  • Tetsuro Yoshimaru

    (Institute for Genome Research, Tokushima University)

  • Masaya Ono

    (National Cancer Center Research Institute)

  • Yoshimi Bando

    (Tokushima University Hospital)

  • Yi-An Chen

    (National Institutes of Biomedical Innovation, Health and Nutrition)

  • Kenji Mizuguchi

    (National Institutes of Biomedical Innovation, Health and Nutrition)

  • Hiroshi Shima

    (Miyagi Cancer Center Research Institute)

  • Masato Komatsu

    (Institute for Genome Research, Tokushima University)

  • Issei Imoto

    (Institute of Biomedical Sciences, Tokushima University Graduate School)

  • Keisuke Izumi

    (Graduate School of Medicine, Tokushima University Graduate School)

  • Junko Honda

    (National Hospital Organization Higashitokushima Medical Center)

  • Yasuo Miyoshi

    (Hyogo College of Medicine)

  • Mitsunori Sasa

    (Tokushima Breast Care Clinic)

  • Toyomasa Katagiri

    (Institute for Genome Research, Tokushima University)

Abstract

Approximately 70% of breast cancer cells express oestrogen receptor alpha (ERα). Previous studies have shown that the Brefeldin A-inhibited guanine nucleotide-exchange protein 3–prohibitin 2 (BIG3-PHB2) complex has a crucial role in these cells. However, it remains unclear how BIG3 regulates the suppressive activity of PHB2. Here we demonstrate that BIG3 functions as an A-kinase anchoring protein that binds protein kinase A (PKA) and the α isoform of the catalytic subunit of protein phosphatase 1 (PP1Cα), thereby dephosphorylating and inactivating PHB2. E2-induced PKA-mediated phosphorylation of BIG3-S305 and -S1208 serves to enhance PP1Cα activity, resulting in E2/ERα signalling activation via PHB2 inactivation due to PHB2-S39 dephosphorylation. Furthermore, an analysis of independent cohorts of ERα-positive breast cancers patients reveal that both BIG3 overexpression and PHB2-S39 dephosphorylation are strongly associated with poor prognosis. This is the first demonstration of the mechanism of E2/ERα signalling activation via the BIG3–PKA–PP1Cα tri-complex in breast cancer cells.

Suggested Citation

  • Tetsuro Yoshimaru & Masaya Ono & Yoshimi Bando & Yi-An Chen & Kenji Mizuguchi & Hiroshi Shima & Masato Komatsu & Issei Imoto & Keisuke Izumi & Junko Honda & Yasuo Miyoshi & Mitsunori Sasa & Toyomasa K, 2017. "A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells," Nature Communications, Nature, vol. 8(1), pages 1-12, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15427
    DOI: 10.1038/ncomms15427
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