PEA-15 facilitates EGFR dephosphorylation via ERK sequestration at increased ER-PM contacts in TNBC cells

FEBS Letters
Miyoung ShinHyun Kyu Song

Abstract

Phosphoprotein enriched in astrocytes of 15 kDa (PEA-15) is known to sequester extracellular signal-regulated kinase (ERK) in the cytoplasm, inhibiting tumorigenesis of human breast cancer cells. Here, we describe how PEA-15 expression affects the dephosphorylation of epidermal growth factor receptor (EGFR) through endoplasmic reticulum (ER)-plasma membrane (PM) contacts in MDA-MB-468, triple-negative breast cancer (TNBC) cells. The increased intracellular calcium concentration resulting from increased cytoplasmic phosphorylated ERK facilitates movement of ER-anchored calcium sensors to the PM. The driving force of trans-localization of calcium-dependent proteins enhances the contact between the activated EGFR and ER-localized phosphatase, PTP1B. Consequently, our findings suggest a mechanism underneath the facilitation of EGFR dephosphorylation by cytoplasmic PEA-15 expression inside TNBC cells, which may be one of the dynamic mechanisms for down-regulation of activated EGFR in cancer cells.

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Citations

Oct 30, 2016·Biochemical and Biophysical Research Communications·Soshi KanemotoKazunori Imaizumi
Apr 12, 2017·Expert Opinion on Therapeutic Targets·Francesca FioryFrancesco Beguinot
Apr 5, 2017·Journal of the National Cancer Institute·Masanori KawakamiEthan Dmitrovsky
Aug 9, 2020·Pigment Cell & Melanoma Research·Eirini ChristodoulouRemco van Doorn

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