title: Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-alpha-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-alpha-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.
authors.affiliation: Department of Pathology, University of Washington, Harborview Medical Center, Seattle, Washington 98104-2499, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Garton
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gough
authors.forename: Julie
authors.initials: J
authors.lastname: Philalay
authors.forename: Paul T
authors.initials: PT
authors.lastname: Wille
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
authors.forename: Robert H
authors.initials: RH
authors.lastname: Whitehead
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dempsey
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Raines
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D002460:Cell Line; D005260:Female; D008666:Metalloendopeptidases / Q000502:physiology*; D045726:Metalloproteases / Q000502:physiology; D051379:Mice; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D019010:Vascular Cell Adhesion Molecule-1; D045726:Metalloproteases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D013755:Tetradecanoylphorbol Acetate