A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells.
A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells.
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DOI：
10.1038/ncomms15427
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发表时间：
2017-05-30
影响因子：
16.6
通讯作者：
Katagiri T
中科院分区：
文献类型：
--
作者：
Yoshimaru T;Ono M;Bando Y;Chen YA;Mizuguchi K;Shima H;Komatsu M;Imoto I;Izumi K;Honda J;Miyoshi Y;Sasa M;Katagiri T
大约70%的乳腺癌细胞表达雌激素受体α（ERα）。以前的研究表明，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（BIG 3-PHB 2）复合物在这些细胞中具有至关重要的作用。然而，目前尚不清楚BIG 3如何调节PHB 2的抑制活性。在这里，我们证明了BIG 3作为A-激酶锚定蛋白，结合蛋白激酶A（PKA）和蛋白磷酸酶1（PP 1C α）的催化亚基的α亚型，从而去磷酸化和失活PHB 2。E2诱导的PKA介导的BIG 3-S305和-S1208磷酸化可增强PP 1C α活性，通过PHB 2-S39去磷酸化导致PHB 2失活，从而激活E2/ERα信号传导。此外，对ERα阳性乳腺癌患者独立队列的分析显示，BIG 3过表达和PHB 2-S39去磷酸化均与不良预后密切相关。这是首次证明乳腺癌细胞中通过BIG 3-PKA-PP 1C α三复合物激活E2/ERα信号传导的机制。BIG 3在乳腺癌中高度表达，其与PHB 2的相互作用导致E2/ER α信号传导的组成性激活。在这里，作者揭示了这种调节的机制细节，表明BIG 3结合PKA并以雌激素依赖性方式调节PP 1Ca活性。
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. BIG3 is highly expressed in breast cancers and its interaction with PHB2 results in constitutive activation of E2/ERa signalling. Here the authors unveil the mechanistic details of this regulation showing that BIG3 binds PKA and regulates PP1Ca activity in an oestrogen-dependent manner.
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影响因子：
64.5
作者：
Antal CE;Hudson AM;Kang E;Zanca C;Wirth C;Stephenson NL;Trotter EW;Gallegos LL;Miller CJ;Furnari FB;Hunter T;Brognard J;Newton AC
通讯作者：
Newton AC
一种新的人类乳腺癌细胞系 KPL-3C 分泌甲状旁腺激素相关蛋白，并在裸鼠体内产生与微钙化相关的肿瘤。
影响因子：
8.8
作者：
Kurebayashi, J;Kurosumi, M;Sonoo, H
通讯作者：
Sonoo, H
影响因子：
4.8
作者：
Hurley, Thomas D.;Yang, Jie;DePaoli-Roach, Anna A.
通讯作者：
DePaoli-Roach, Anna A.
DOI：
10.1073/pnas.91.18.8517
发表时间：
1994-08-30
影响因子：
11.1
作者：
ARONICA, SM;KRAUS, WL;KATZENELLENBOGEN, BS
通讯作者：
KATZENELLENBOGEN, BS
DOI：
10.1073/pnas.0611696104
发表时间：
2007-02-27
影响因子：
11.1
作者：
Kuroda, Fuminobu;Moss, Joel;Vaughan, Martha
通讯作者：
Vaughan, Martha