Upregulation of fibronectin expression by COX-2 is mediated by interaction with ELMO1.
Engulfment and cell motility 1 (ELMO1), a bipartite guanine nucleotide exchange factor (GEF) for the small GTPase Rac 1, was identified as a susceptibility gene for glomerular disease. Here, we reported that ELMO1 interacted with COX-2 in human mesangial cells. Furthermore, we identified ELMO1 as a posttranslational regulator of COX-2 activity. We demonstrated that COX-2 cyclooxygenase activity increased fibronectin promoter activity. The protein-protein interaction between ELMO1 and COX-2 increased the cyclooxygenase activity of COX-2 and, correspondingly, fibronectin expression. We also found that ET625, the dominant negative form of ELMO1 lacking Rac1 activity, interacted with COX-2, increased cyclooxygenase activity of COX-2 and enhanced COX-2-mediated fibronectin upregulation. To further rule out Rac1 as an ELMO1-mediated regulator of COX-2 activity, we employed the constitutive active Rac1, Rac1(Q63E), and demonstrated that Rac1 signaling has no effect on COX-2-mediated fibronectin promoter activity. These results suggest that ELMO1 contributes to the development of glomerular injury through serving as a regulator of COX-2 activity. The interaction of ELMO1 with COX-2 could play an important role in the development and progression of renal glomerular injury.
Yang
Chen
C
Division of Nephrology and Kidney Disease Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Sorokin
Andrey
A
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050527:Mesangial Cells / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C465214:ELMO1 protein, human; D005353:Fibronectins; D051546:Cyclooxygenase 2; D020830:rac1 GTP-Binding Protein