A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane‐bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10)

Abstract

The receptor for advanced glycation endproducts (RAGE) mediates responses to cell danger and stress. When bound by its many ligands (which include advanced glycation endproducts, certain members of the S100/calgranulin family, extracellular high-mobility group box 1, the integrin Mac-1, amyloid beta-peptide and fibrils), RAGE activates programs responsible for acute and chronic inflammation. RAGE is therefore also involved in cancer progression, diabetes, atherosclerosis, and Alzheimer's disease. RAGE has several isoforms deriving from alternative splicing, including a soluble form called endogenous secretory RAGE (esRAGE). We show here that most soluble RAGE, either produced by cell lines or present in human blood, is not recognized by an anti-esRAGE antibody. Cells transfected with the cDNA for full-length RAGE, and thus not expressing esRAGE, produce a form of soluble RAGE, cleaved RAGE (cRAGE) that derives from proteolytic cleavage of the membrane-bound molecules and acts as a decoy receptor. By screening chemical inhibitors and genetically modified mouse embryonic fibroblasts (MEFs), we identify the sheddase ADAM10 as a membrane protease responsible for RAGE cleavage. Binding of its ligand HMGB1 promotes RAGE shedding. Our data do not disprove the interpretation that high levels of soluble forms of RAGE protect against chronic inflammation, but rather suggest that they correlate with high levels of ongoing inflammation.

The Receptor for Advanced Glycation End-Products (RAGE) Protects Pancreatic Tumor Cells Against Oxidative Injury

“…Although other studies have shown that exogenous H 2 O 2 -induced activation of the transcriptional factors HSF (heat-shock transcription factor) (13) and STAT (signal transducer and activator of transcription) (3), which are powerful multifaceted modifiers of carcinogenesis, we do not yet know whether these factors regulate the expression of RAGE under oxidative stress in pancreatic tumors. Moreover, RAGE has several isoforms deriving from alternative splicing, including a soluble form called endogenous secretory RAGE (esRAGE) that acts as a decoy receptor (31). Additionally, there are several reports of cell membrane receptor protein ectodomain shedding (tumor necrosis factor receptor, betacellulin, calcineurin and RAGE) in response to stress (33,50).…”

AGE/RAGE as a Mediator of Insulin Resistance or Metabolic Syndrome: Another Aspect of Metabolic Memory?

“…This proteolytic generation of sRAGE was initially described as occurring in mice 103 . Recent studies suggest that ADAM10 and MMP9 to be involved in RAGE shedding 13,14 . ADAM is known as a shedase to shed several inflammatory receptors and can be involved in regulation of RAGE/sRAGE balance.…”

The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity

“…7,8 Up to now we know that there are a number of distinct splice variants of sRAGE. 7 Therefore, it has been suggested that esRAGE might constitute only a part, but not all of the human sRAGE in plasma.…”