Reversible interconversion and maintenance of mammary epithelial cell characteristics by the ligand-regulated EGFR system.
Reversible interconversion and maintenance of mammary epithelial cell characteristics by the ligand-regulated EGFR system.
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DOI：
10.1038/srep20209
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发表时间：
2016-02-02
影响因子：
4.6
通讯作者：
Higashiyama S
中科院分区：
文献类型：
--
作者：
Fukuda S;Nishida-Fukuda H;Nanba D;Nakashiro K;Nakayama H;Kubota H;Higashiyama S
上皮细胞的可塑性受细胞外信号的控制，但其潜在的机制仍未完全清楚。表皮生长因子(EGF)和两性调节蛋白(AREG)分别是EGF受体(EGFR)的高亲和力和低亲和力配体。已知EGFR信号通过激活ERK和诱导EMT转录因子ZEB1来促进上皮-间充质转化(EMT)。在这里，我们证明了EGF和AREG在等摩尔浓度下的配基交换可逆地相互转换EGFR信号依赖的乳腺上皮细胞的上皮样和间充质样状态。EGF和AREG培养的细胞的上皮特征也不同，包括细胞表面标志物的表达、迁移方式和形成腺泡的能力。EGF和AREG之间的配基切换在时间上改变了共享的EGFR-ERK信号的强度。这种改变逆转了ZEB1及其拮抗的microRNAs、miR-205和miR-200C的相对表达水平，这些是上皮表型的关键决定因素。此外，AREG诱导的EGFR在质膜上的积累弥补了AREG和EGFR之间的弱关联。EGFR动力学使AREG能够在同等摩尔浓度下与EGF一样有效地支持增殖并保持上皮特征。我们的发现揭示了EGFR配体产生的信号强度在调节乳腺上皮细胞可塑性中的作用。
Epithelial cell plasticity is controlled by extracellular cues, but the underlying mechanisms remain to be fully understood. Epidermal growth factor (EGF) and amphiregulin (AREG) are high- and low-affinity ligands for EGF receptor (EGFR), respectively. EGFR signaling is known to promote epithelial-mesenchymal transition (EMT) by the activation of ERK and the induction of an EMT transcription factor, ZEB1. Here, we demonstrate that ligand-switching between EGF and AREG at equivalent molarity reversibly interconverts epithelial and mesenchymal-like states of EGFR signal-dependent mammary epithelial cells. The EGF- and AREG-cultured cells also differ in their epithelial characteristics, including the expression of cell surface markers, the mode of migration and the ability for acinus-formation. The ligand-switching between EGF and AREG temporally alters strength of the shared EGFR-ERK signaling. This alteration inverts relative expression levels of ZEB1 and its antagonizing microRNAs, miR-205 and miR-200c, those are critical determinants of the epithelial phenotype. Further, AREG-induced EGFR accumulation on the plasma membrane compensates for the weak association between AREG and EGFR. The EGFR dynamics enables AREG to support proliferation as efficiently as EGF at equivalent molarity and to maintain epithelial characteristics. Our findings reveal a role of EGFR ligands-generated signal strength in the regulation of mammary epithelial cell plasticity.