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.
Nat Commun. 2017 May 30;8:15427. doi: 10.1038/ncomms15427.
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.
约 70%的乳腺癌细胞表达雌激素受体 alpha（ERα）。先前的研究表明，布雷菲德菌素 A 抑制的鸟嘌呤核苷酸交换蛋白 3-抑制素 2（BIG3-PHB2）复合物在这些细胞中具有关键作用。然而，BIG3 如何调节 PHB2 的抑制活性仍不清楚。在这里，我们证明 BIG3 作为一种蛋白激酶 A（PKA）和蛋白磷酸酶 1 的α催化亚基（PP1Cα）的 A 激酶锚定蛋白发挥作用，从而使 PHB2 去磷酸化和失活。E2 诱导的 BIG3-S305 和 -S1208 的 PKA 介导的磷酸化有助于增强 PP1Cα 的活性，导致由于 PHB2-S39 的去磷酸化而导致 PHB2 失活，从而通过 PHB2 失活激活 E2/ERα 信号。此外，对独立的 ERα 阳性乳腺癌患者队列的分析表明，BIG3 过表达和 PHB2-S39 去磷酸化均与预后不良强烈相关。这是首次证明 BIG3-PKA-PP1Cα 三聚体通过乳腺癌细胞中 E2/ERα 信号的激活机制。
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