Reversible interconversion and maintenance of mammary epithelial cell characteristics by the ligand-regulated EGFR system

Scientific Reports
Shinji FukudaShigeki Higashiyama

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 pr...Continue Reading

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Citations

Jan 20, 2018·American Journal of Physiology. Lung Cellular and Molecular Physiology·Marta StolarczykBob J Scholte
Nov 22, 2018·Nature Reviews. Molecular Cell Biology·Anushka Dongre, Robert A Weinberg
Apr 21, 2019·Archives of Pharmacal Research·Kyung Hwa ChoHoi Young Lee
Nov 13, 2020·Molecular and Cellular Endocrinology·Alessia MoratoPaolo Accornero

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Methods Mentioned

BETA
transfection
ubiquitination
Protein Assay
PCR
FACS

Software Mentioned

ImageQuant
Elements
ImageJ
Volocity
NIS
GeneSpring GX
Matlab
FlowJo
Jython script

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