Document Detail


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).
MedLine Citation:
PMID:  18603587     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Angela Raucci; Simona Cugusi; Antonella Antonelli; Silvia M Barabino; Lucilla Monti; Angelika Bierhaus; Karina Reiss; Paul Saftig; Marco E Bianchi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-07-04
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  22     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-01     Completed Date:  2008-10-21     Revised Date:  2012-02-15    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3716-27     Citation Subset:  IM    
Affiliation:
San Raffaele Scientific Institute, Milan, Italy.
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MeSH Terms
Descriptor/Qualifier:
ADAM Proteins / genetics,  metabolism*
Alternative Splicing
Amyloid Precursor Protein Secretases / genetics,  metabolism*
Animals
Cell Membrane / metabolism
Cells, Cultured
Humans
Lung / metabolism
Membrane Proteins / genetics,  metabolism*
Mice
Mice, Mutant Strains
Protein Isoforms / genetics,  metabolism
Receptors, Immunologic / genetics,  metabolism*
Solubility
Chemical
Reg. No./Substance:
0/Membrane Proteins; 0/Protein Isoforms; 0/Receptors, Immunologic; 0/advanced glycosylation end-product receptor; EC 3.4.-/Amyloid Precursor Protein Secretases; EC 3.4.24.-/ADAM Proteins; EC 3.4.24.81/ADAM10 protein, human; EC 3.4.24.81/Adam10 protein, mouse

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