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

•COX-1 and COX-2 differ in their sensitivity to EP1 receptor-aided degradation.•Mutation of a putative target of ubiquitination on COX-2 (K432R) decreases its sensitivity to EP1.•Insertion of a parallel ubiquitination site (H446K′) into COX-1 increases its sensitivity to EP1.•Distinctive ubiquitination may regulate the stability of COX isoforms.