Environment-Sensitive Ectodomain Shedding of Epithin/PRSS14 Increases Metastatic Potential of Breast Cancer Cells by Producing CCL2

Jiyoung Jang, Eun Hye Cho, Youngkyung Cho, Binderya Ganzorig, Ki Yeon Kim, Moon Gyo Kim, Chungho Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Epithin/PRSS14 is a membrane serine protease that plays a key role in tumor progression. The protease exists on the cell surface until its ectodomain shedding, which releases most of the extracellular domain. Previously, we showed that the remaining portion on the membrane undergoes intramembrane proteolysis, which results in the liberation of the intracellular domain and the intracellular domain-mediated gene expression. In this study, we investigated how the intramembrane proteolysis for the nuclear function is initiated. We observed that ectodomain shedding of epithin/PRSS14 in mouse breast cancer 4T1 cells increased depending on environmental conditions and was positively correlated with invasiveness of the cells and their pro-invasive cytokine production. We identified selenite as an environmental factor that can induce ectodomain shedding of the protease and increase C-C motif chemokine ligand 2 (CCL2) secretion in an epithin/PRSS14-dependent manner. Additionally, by demonstrating that the expression of the intracellular domain of epithin/PRSS14 is sufficient to induce CCL2 secretion, we established that epithin/PRSS14-dependent shedding and its subsequent intramembrane proteolysis are responsible for the metastatic conversion of 4T1 cells under these conditions. Consequently, we propose that epithin/PRSS14 can act as an environment-sensing receptor that promotes cancer metastasis by liberating the intracellular domain bearing transcriptional activity under conditions promoting ectodomain shedding.

Original languageEnglish
Pages (from-to)564-574
Number of pages11
JournalMolecules and cells
Volume45
Issue number8
DOIs
Publication statusPublished - 2022 Aug 31

Keywords

  • cancer microenvironment
  • CCL2
  • epithin/PRSS14
  • invasiveness
  • selenite

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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