Master of Science (MS)
Biochemistry and Molecular Biology (Medicine)
Date of Defense
First Committee Member
Second Committee Member
Third Committee Member
The Receptor for Advanced Glycation End-products (RAGE) is a multi-ligand cell signaling receptor present on most cell types. Upregulation of RAGE is seen in a number of pathological states including various cancers, inflammatory and vascular disease, dementia and diabetes. Several studies have shown RAGE ectodomain shedding to be but little is known about the regulation and functional effects. Here we show evidence that human and mouse ectodomain shedding is inducible by several diverse shedding stimulators and the basic mechanism conserved. It is also shown here that RAGE shedding likely goes through different pathways, as ionomycin but not PMA shedding is inhibited by PI3K and PMA but not ionomycin shedding induced by PKC inhibitors. Preliminary support is established for ADAM17 cleavage of RAGE in addition to ADAM10. Honing in on the cleavage mechanism of rage, we show that one cleavage site is likely responsible for all RAGE ectodomain shedding. Finally, we show that cleavage increases cell invasion and migration, important for cancer associations. RAGE ECD shedding is a conserved and tightly regulated mechanism involving distinct signaling pathways. Shedding of RAGE regulates key cellular properties including adhesion and migration. Our data suggest that proteolysis of RAGE is a major regulatory process and may emerge as a novel therapeutic target for cardiovascular diseases.
Rage; Ectodomain Shedding; Matrix Metalloproteinase; Cell Migration; Protein Kinase C
Braley, Alexander E., "Rage Ectodomain Shedding is a Conserved and Differentially Regulated Process" (2013). Open Access Theses. 442.