Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-α-converting enzyme (ADAM 17) Journal Article


Authors: Garton, K. J.; Gough, P. J.; Philalay, J.; Wille, P. T.; Blobel, C. P.; Whitehead, R. H.; Dempsey, P. J.; Raines, E. W.
Article Title: Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-α-converting enzyme (ADAM 17)
Abstract: A variety of cell surface adhesion molecules can exist as both transmembrane proteins and soluble circulating forms. Increases in the levels of soluble adhesion molecules have been correlated with a variety of inflammatory diseases, suggesting a pathological role. Although soluble forms are thought to result from proteolytic cleavage from the cell surface, relatively little is known about the proteases responsible for their release. In this report we demonstrate that under normal culture conditions, cells expressing vascular cell adhesion molecule 1 (VCAM-1) release a soluble form of the extracellular domain that is generated by metalloproteinase-mediated cleavage. VCAM-1 release can be rapidly simulated by phorbol 12-myristate 13-acetate (PMA), and this induced VCAM-1 shedding is mediated by metalloproteinase cleavage of VCAM-1 near the transmembrane domain. PMA-induced VCAM-1 shedding occurs as the result of activation of a specific pathway, as the generation of soluble forms of three other adhesion molecules, E-selectin, platelet-endothelial cell adhesion molecule 1, and intercellular adhesion molecule 1, are not altered by PMA stimulation. Using cells derived from genetically deficient mice, we identify tumor necrosis factor-α -converting enzyme (TACE or ADAM 17) as the protease responsible for PMA-induced VCAM-1 release, including shedding of endogenously expressed VCAM-1 by murine endothelial cells. Therefore, TACE-mediated shedding of VCAM-1 may be important for the regulation of VCAM-1 function at the cell surface.
Keywords: signal transduction; controlled study; protein expression; nonhuman; protein domain; protein function; proteins; animal cell; mouse; animals; mice; animal tissue; genes; protein degradation; vascular cell adhesion molecule 1; cell line; animal experiment; pathology; transgenic mouse; animalia; mus musculus; endothelium cell; cell culture; tumors; membrane protein; murinae; protein secretion; proteinase; cell stimulation; intercellular adhesion molecule 1; diseases; endothelial leukocyte adhesion molecule 1; metalloproteinase; adam proteins; cd31 antigen; cell adhesion molecule; inflammatory disease; solubility; phorbol 13 acetate 12 myristate; tetradecanoylphorbol acetate; cell surface; cells; adhesion; vascular cell adhesion molecule-1; metalloproteases; biological membranes; tumor necrosis factor alpha converting enzyme; metalloendopeptidases; male; female; priority journal; article; stimulated shedding
Journal Title: Journal of Biological Chemistry
Volume: 278
Issue: 39
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2003-09-26
Start Page: 37459
End Page: 37464
Language: English
DOI: 10.1074/jbc.M305877200
PUBMED: 12878595
PROVIDER: scopus
DOI/URL:
Notes: Export Date: 12 September 2014 -- Source: Scopus
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  1. Carl Blobel
    52 Blobel