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

Approximately 70% of breast cancer cells express oestrogen receptor alpha (ER alpha). 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 alpha isoform of the catalytic subunit of protein phosphatase 1 (PP1C alpha), thereby dephosphorylating and inactivating PHB2. E2-induced PKA-mediated phosphorylation of BIG3-S305 and -S1208 serves to enhance PP1C alpha activity, resulting in E2/ER alpha signalling activation via PHB2 inactivation due to PHB2-S39 dephosphorylation. Furthermore, an analysis of independent cohorts of ER alpha-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/ER alpha signalling activation via the BIG3-PKA-PP1C alpha tri-complex in breast cancer cells.