title: PEA-15 facilitates EGFR dephosphorylation via ERK sequestration at increased ER-PM contacts in TNBC cells.
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.
authors: Division of Life Sciences, Korea University, Seoul, South Korea.
authors: Miyoung
authors: M
authors: Shin
authors: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea; Advanced Analysis Center, Korea Institute of Science and Technology, Seoul, South Korea.
authors: Kyung-Eun
authors: KE
authors: Lee
authors: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea.
authors: Eun Gyeong
authors: EG
authors: Yang
authors: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: hjeon@red.dfci.harvard.edu.
authors: Hyesung
authors: H
authors: Jeon
authors: Division of Life Sciences, Korea University, Seoul, South Korea. Electronic address: hksong@korea.ac.kr.
authors: Hyun Kyu
authors: HK
authors: Song
mesh_terms: D051017:Apoptosis Regulatory Proteins; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium
keywords: EGFR dephosphorylation; ER–PM contact; PEA-15; PTP1B; Triple-negative breast cancer cells; pERK1/2