A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells.
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.
Mesh Terms:
A Kinase Anchor Proteins, Amino Acid Sequence, Breast Neoplasms, Cell Line, Tumor, Cyclic AMP-Dependent Protein Kinases, Estrogens, Female, Guanine Nucleotide Exchange Factors, Humans, Models, Biological, Phosphorylation, Phosphoserine, Prognosis, Protein Phosphatase 1, Protein Subunits, Repressor Proteins, Signal Transduction
A Kinase Anchor Proteins, Amino Acid Sequence, Breast Neoplasms, Cell Line, Tumor, Cyclic AMP-Dependent Protein Kinases, Estrogens, Female, Guanine Nucleotide Exchange Factors, Humans, Models, Biological, Phosphorylation, Phosphoserine, Prognosis, Protein Phosphatase 1, Protein Subunits, Repressor Proteins, Signal Transduction
Nat Commun
Date: Dec. 30, 2016
PubMed ID: 28555617
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