RRC ID 35936
Author Fukuda S, Nishida-Fukuda H, Nanba D, Nakashiro K, Nakayama H, Kubota H, Higashiyama S.
Title Reversible interconversion and maintenance of mammary epithelial cell characteristics by the ligand-regulated EGFR system.
Journal Sci Rep
Abstract 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.
Volume 6
Pages 20209
Published 2016-2-2
DOI 10.1038/srep20209
PII srep20209
PMID 26831618
PMC PMC4735799
MeSH Amphiregulin / metabolism Breast Neoplasms / genetics Breast Neoplasms / metabolism Breast Neoplasms / pathology Cell Line, Tumor Epidermal Growth Factor / metabolism Epithelial Cells / metabolism* Epithelial Cells / pathology Epithelial-Mesenchymal Transition / genetics Female Gene Expression Regulation Humans Ligands* MAP Kinase Signaling System Mammary Glands, Human / cytology* Mammary Glands, Human / metabolism* Mammary Glands, Human / pathology Phenotype Phosphorylation Receptor, Epidermal Growth Factor / metabolism* Signal Transduction Transforming Growth Factor beta / metabolism
IF 4.122
Times Cited 0
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393).