A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells.
Tetsuro YoshimaruMasaya OnoYoshimi BandoYi-An ChenKenji MizuguchiHiroshi ShimaMasato KomatsuIssei ImotoKeisuke IzumiJunko HondaYasuo MiyoshiMitsunori SasaToyomasa KatagiriPublished in: Nature communications (2017)
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.
Keyphrases
- breast cancer cells
- big data
- protein kinase
- poor prognosis
- end stage renal disease
- protein protein
- machine learning
- artificial intelligence
- binding protein
- amino acid
- long non coding rna
- endoplasmic reticulum
- induced apoptosis
- estrogen receptor
- peritoneal dialysis
- gene expression
- ejection fraction
- high glucose
- deep learning
- young adults
- single cell
- cell cycle arrest
- diabetic rats
- cell death
- endothelial cells
- dna methylation