title: Glycation & the RAGE axis: targeting signal transduction through DIAPH1.
abstract: The consequences of chronic disease are vast and unremitting; hence, understanding the pathogenic mechanisms mediating such disorders holds promise to identify therapeutics and diminish the consequences. The ligands of the receptor for advanced glycation end products (RAGE) accumulate in chronic diseases, particularly those characterized by inflammation and metabolic dysfunction. Although first discovered and reported as a receptor for advanced glycation end products (AGEs), the expansion of the repertoire of RAGE ligands implicates the receptor in diverse milieus, such as autoimmunity, chronic inflammation, obesity, diabetes, and neurodegeneration. Areas covered: This review summarizes current knowledge regarding the ligand families of RAGE and data from human subjects and animal models on the role of the RAGE axis in chronic diseases. The recent discovery that the cytoplasmic domain of RAGE binds to the formin homology 1 (FH1) domain, DIAPH1, and that this interaction is essential for RAGE ligand-stimulated signal transduction, is discussed. Finally, we review therapeutic opportunities targeting the RAGE axis as a means to mitigate chronic diseases. Expert commentary: With the aging of the population and the epidemic of cardiometabolic disease, therapeutic strategies to target molecular pathways that contribute to the sequelae of these chronic diseases are urgently needed. In this review, we propose that the ligand/RAGE axis and its signaling nexus is a key factor in the pathogenesis of chronic disease and that therapeutic interruption of this pathway may improve quality and duration of life.
authors.affiliation: a Department of Chemistry , University at Albany, State University of New York , Albany , NY , 12222 , USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Shekhtman
authors.affiliation: b Diabetes Research Program, Division of Endocrinology, Department of Medicine , NYU Langone Medical Center , New York , NY , 10016 , USA.
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
authors.affiliation: b Diabetes Research Program, Division of Endocrinology, Department of Medicine , NYU Langone Medical Center , New York , NY , 10016 , USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D048909:Diabetes Complications / Q000378:metabolism; D004195:Disease Models, Animal; D000080865:Formins; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000593873:Ager protein, mouse; D000951:Antigens, Neoplasm; C108962:DIAPH1 protein, human; D000080865:Formins; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases
keywords: DIAPH1; Glycation; RAGE; diabetes; inflammation; neurodegeneration; obesity; receptor for AGE