Signaling Interface of Advanced Glycation Endproducts Receptor and Ubiquitin-Conjugating Enzyme Ubc9 Complex in Atherosclerosis and Cancer Cells

Abstract

The advanced glycation endproducts receptor (AGER) is a multiligand signal transduc-tion receptor. One of its ligands, S100b molecules activates vascular smooth muscle cells and endothelial cells via its receptor, thus triggering activation of signaling cas-cades and generation of cytokines and proinflammatory molecules. Ubiquitin-conju-gating enzyme Ubc9 is an E2 conjugating enzyme that transfers the activated small ubiquitin-related modifier to protein substrates, and thus it plays a critical role in SUR-Mylation-mediated cellular pathways. Previous studies have shown that both AGE-R and Ubc9 play roles in diverse cellular signaling pathways. However, until recently, little attention has been paid to interactions between AGE-R and Ubc9. In this study, se-quence database searches allowed us to identify a potential interaction motif between AGE-R and Ubc9. The subsequent biochemical and molecular biological analysis sug-gested that there may be specificity in AGE-R and Ubc9 complex signaling in athero-sclerosis and cancer cells in a cell-type specific manner. Although the determinant for specificity in AGE-R and Ubc9 complex signaling in cancer cells and atherosclerosis is yet to be determined, this study provides the basis to develop a specific therapeutic ap-plication of AGE-R, SURM (small ubiquitin-related modifier)-1, and Ubc9 complex acti-vation pathways in atherosclerosis, diabetes, cancer and inflammatory diseases.