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Nat Commun. 2017 May 30;8:15427. doi: 10.1038/ncomms15427.

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

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Division of Genome Medicine, Institute for Genome Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Division of Pathology, Tokushima University Hospital, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, 47-1 Nodayama, Medeshimashiote, Natori, Miyagi 981-1293, Japan.
Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Department of Molecular and Environmental Pathology, Graduate School of Medicine, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Department of Surgery, National Hospital Organization Higashitokushima Medical Center, 1-1 Ohmukai-kita, Ootera, Itano, Tokushima 779-0193, Japan.
Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
Department of Surgery, Tokushima Breast Care Clinic, 4-7-7 Nakashimada-cho, Tokushima 770-0052, Japan.


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.

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