Prostaglandin receptor EP1-mediated differential degradation of cyclooxygenases involves a specific lysine residue

Almog Spector-Chotiner, Niva Shraga-Heled, Rapita Sood, Gilad Rimon, Liza Barki-Harrington

Research output: Contribution to journalArticlepeer-review

Abstract

The cyclooxygenase (COX) enzyme isoforms COX-1 and COX-2 catalyze the main step in the generation of prostanoids that mediate major physiological functions. Whereas COX-1 is a ubiquitously expressed stable protein, COX-2 is transiently upregulated in many pathologies and is often associated with a poor prognostic outcome. We have recently shown that an interaction of COX-2 with the prostaglandin EP1 receptor accelerates its degradation via a mechanism that augments its level of ubiquitination. Here we show that the sensitivity of both COX-1 and COX-2 to EP1 is altered upon modification of one lysine residue. A point mutation of lysine to-arginine in position 432 of COX-2 (K432R) yields an enzyme with decreased sensitivity to EP1-mediated degradation. In contrast, insertion of a putative ubiquitination site into the corresponding position of COX-1 (H446K′) yields an enzyme with higher levels of ubiquitination and reduced expression. Furthermore, compared to wild type COX-1, H446K′ is significantly more sensitive to downregulation by EP1. Together these data suggest that distinctive ubiquitination of COX-1 and COX-2 may be responsible for their different sensitivity to EP1-mediated degradation.

Original languageEnglish
Pages (from-to)738-742
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume443
Issue number2
DOIs
StatePublished - 10 Jan 2014

Bibliographical note

Funding Information:
We thank Dr. Sagie Schif-Zuck for her assistance and expertise in the flow cytometry analyses, and Waleed Minzel for his help in generating YFP-tagged COX-1. This work was supported by the BSF (United States-Israel Binational Scientific Foundation) , project number 2009246.

Keywords

  • COX-1
  • COX-2
  • Cyclooxygenase
  • Degradation
  • EP
  • Ubiquitination

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics
  • Biochemistry
  • Cell Biology

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