NHERF1/EBP50 controls lactation by establishing basal membrane polarity complexes with prolactin receptor
NHERF1/EBP50 controls lactation by establishing basal membrane polarity complexes with prolactin receptor
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DOI：
10.1038/cddis.2012.131
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发表时间：
2012-09-01
影响因子：
9
通讯作者：
Georgescu, M-M
中科院分区：
文献类型：
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作者：
Morales, F. C.;Hayashi, Y.;Georgescu, M-M
哺乳动物妊娠期乳腺的发育是一个复杂的多因素过程。我们在这里表明，这一过程需要NHERF 1/EBP 50（钠/氢交换调节因子1/ERM结合磷蛋白50）的表达，成功的泌乳取决于NHERF 1等位基因拷贝数，在NHERF 1（+/-）和（-/-）小鼠中的比率分别为50%和20%。催乳素受体（PRLR）-STAT 5信号传导提供了触发分泌性乳腺肺泡细胞分化的中心轴。在成功泌乳的腺体中，NHERF 1大量上调并与PRLR形成复合物，但也与肺泡基底膜处的β-连环蛋白、E-钙粘蛋白和埃兹蛋白形成复合物，从而建立基底极性。在NHERF 1缺陷的腺体中，基底极性被破坏，PRLR水平和基底膜定位被废除，下游STAT 5激活崩溃，从而减少乳蛋白合成。NHERF 1/EBP 50是一种在乳腺癌中失调的蛋白质，因此作为乳汁分泌的重要生理介质出现，通过在肺泡基底膜处的多聚体复合物中与PRLR接合，随后网络活化导致细胞分化。Cell Death and Disease（2012）3，e391; doi：10.1038/cddis.2012.131; 2012年9月20日在线发表
The development of the lactating mammary gland is a complex multifactorial process occurring in mammals during pregnancy. We show here that this process requires NHERF1/EBP50 (Na/H exchanger regulatory factor 1/ERM-binding phosphoprotein 50) expression and that successful lactation depends on NHERF1 allele copy number, with rates of 50 and 20% in NHERF1(+/-) and (-/-) mice, respectively. The prolactin receptor (PRLR)-STAT5 signaling provides the central axis triggering the differentiation of secretory mammary alveolar cells. In successfully lactating glands, NHERF1 is massively upregulated and forms complexes with PRLR, but also with beta-catenin, E-cadherin and ezrin at the alveolar basal membrane, establishing basal polarity. In NHERF1-deficient glands, the basal polarity is disrupted, the PRLR levels and basal membrane localization are abolished, and the downstream STAT5 activation collapses with consequent reduction of milk protein synthesis. NHERF1/EBP50, a protein deregulated in breast cancer, thus emerges as an important physiological mediator of milk secretion, by engagement of PRLR in multimeric complexes at the alveolar basal membrane with subsequent network activation leading to cell differentiation. Cell Death and Disease (2012) 3, e391; doi:10.1038/cddis.2012.131; published online 20 September 2012