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Updated: Mar 1, 2026

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

Tetsuro Yoshimaru1, Masaya Ono2, Yoshimi Bando3

  • 1Division of Genome Medicine, Institute for Genome Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.

Nature Communications
|May 31, 2017
PubMed

Insights

Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) inactivates prohibitin 2 (PHB2) in oestrogen receptor alpha-positive breast cancer cells. This BIG3-PKA-PP1Cα complex activation by oestrogen drives cancer growth and is linked to poor prognosis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Oestrogen receptor alpha (ERα) is expressed in ~70% of breast cancers.
  • The BIG3-PHB2 complex is crucial in ERα-positive breast cancer, but its regulatory mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which BIG3 regulates PHB2's suppressive activity.
  • To investigate the role of the BIG3-PKA-PP1Cα tri-complex in ERα signaling activation.

Main Methods:

  • Biochemical assays to demonstrate protein interactions and enzymatic activities.
  • Phosphorylation site analysis of BIG3 and PHB2.
  • Analysis of patient cohorts for correlation between molecular markers and prognosis.

Main Results:

  • BIG3 acts as an A-kinase anchoring protein, binding PKA and PP1Cα to inactivate PHB2.
  • Oestrogen (E2) induces PKA-mediated phosphorylation of BIG3, enhancing PP1Cα activity.
  • PHB2 dephosphorylation at S39 leads to ERα signaling activation.
  • BIG3 overexpression and PHB2-S39 dephosphorylation correlate with poor prognosis in ERα-positive breast cancer.

Conclusions:

  • This study reveals the mechanism of E2/ERα signaling activation via the BIG3-PKA-PP1Cα tri-complex.
  • BIG3-mediated PHB2 inactivation is a key driver in ERα-positive breast cancer.
  • BIG3 and PHB2-S39 dephosphorylation are potential prognostic biomarkers.

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