Intramembrane proteolysis of an extracellular serine protease, epithin/PRSS14, enables its intracellular nuclear function

Youngkyung Cho, Sang Bum Kim, Jiyoon Kim, An Vuong Quynh Pham, Min Ji Yoon, Jeong Hwan Park, Ki Tae Hwang, Dongeun Park, Yongcheol Cho, Moon Gyo Kim, Chungho Kim

Research output: Contribution to journalArticle

Abstract

Background: Epithin/PRSS14, a type II transmembrane serine protease, is an emerging target of cancer therapy because of its critical roles in tumor progression and metastasis. In many circumstances, the protease, through its ectodomain shedding, exists as a soluble form and performs its proteolytic functions in extracellular environments increasing cellular invasiveness. The seemingly functional integrity of the soluble form raises the question of why the protease is initially made as a membrane-associated protein. Results: In this report, we show that the epithin/PRSS14 intracellular domain (EICD) can be released from the membrane by the action of signal peptide peptidase-like 2b (SPPL2b) after ectodomain shedding. The EICD preferentially localizes in the nucleus and can enhance migration, invasion, and metastasis of epithelial cancer when heterologously expressed. Unbiased RNA-seq analysis and subsequent antibody arrays showed that EICD could control the gene expression of chemokines involved in cell motility, by increasing their promoter activities. Finally, bioinformatics analysis provided evidence for the clinical significance of the intramembrane proteolysis of epithin/PRSS14 by revealing that the poor survival of estrogen receptor (ER)-negative breast cancer patients with high epithin/PRSS14 expression is further worsened by high levels of SPPL2b. Conclusions: These results show that ectodomain shedding of epithin/PRSS14 can initiate a unique and synchronized bidirectional signal for cancer metastasis: Extracellularly broadening proteolytic modification of the surrounding environment and intracellularly reprogramming the transcriptome for metastatic conversion. Clinically, this study also suggests that the intracellular function of epithin/PRSS14 should be considered for targeting this protease for anti-cancer treatment.

Original languageEnglish
Article number60
JournalBMC biology
Volume18
Issue number1
DOIs
Publication statusPublished - 2020 Jun 3

Keywords

  • Epithin/PRSS14
  • Metastasis
  • Regulated intramembrane proteolysis
  • Transcriptional regulation

ASJC Scopus subject areas

  • Biotechnology
  • Structural Biology
  • Ecology, Evolution, Behavior and Systematics
  • Physiology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Plant Science
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Cho, Y., Kim, S. B., Kim, J., Pham, A. V. Q., Yoon, M. J., Park, J. H., Hwang, K. T., Park, D., Cho, Y., Kim, M. G., & Kim, C. (2020). Intramembrane proteolysis of an extracellular serine protease, epithin/PRSS14, enables its intracellular nuclear function. BMC biology, 18(1), [60]. https://doi.org/10.1186/s12915-020-00787-3