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-␣-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.The proteolytic cleavage and release of transmembrane cell surface proteins, termed ectodomain shedding, has emerged as an important post-translational mechanism for regulating the function of cell surface proteins (1). A wide variety of structurally diverse proteins including cytokines, growth factors, and adhesion molecules can be shed from the cell surface. In many cases, these shed ectodomains are biologically active. Ectodomain shedding can be mediated by both membrane-bound as well as soluble proteases. To date, members of the Zn 2ϩ -dependent protease superfamily, including the matrix metalloproteinases (MMPs), 1 membrane-tethered MMPs (MT-MMPs), and the disintegrin metalloproteinases (ADAMs), have been shown to be responsible for the cleavage of the majority of shed proteins identified. In addition, soluble neutrophil-derived proteases including neutrophil elastase, cathepsin G, and proteinase-3 have also been implicated in the shedding of cell surface proteins (2). Of the disintegrin and metalloproteinase (ADAM) family of proteases, tumor necrosis factor-␣-converting enzyme (TACE; ADAM 17) has emerged as a central mammalian ectodomain sheddase (3). TACE-deficient mice are not viable and show multiple developmental defects (4). Furthermore, cells isolated from TACE-deficient mice lack shedding of several unrelated cell surface proteins including tumor necrosis factor-␣, tumor necrosis factor-␣ receptor, several epidermal growth factor receptor ligands, Notch-1, amyloid precursor protein,...

Differential regulation of tumor necrosis factor-α-converting enzyme and angiotensin-converting enzyme by type I and II interferons in human normal and leukemic myeloid cells

“…ACE and TACE have been implicated in the control of major biological processes, including growth and secretion of inflammatory and angiogenic cytokines (Bauvois, 2004). Through its shedding activity, TACE is responsible for the conversion of the TNF-a precursor to TNF-a and for releasing other membrane-bound proteins such as TNFreceptor, amyloid-protein precursor, transforming growth factor-a, vascular cellular adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1), all proteins involved in the onset and/or progression of several diseases (Black et al, 1997;Garton et al, 2003;Bauvois, 2004;Tsakadze et al, 2006). In animal models, ACE inhibitors have been shown to reduce tumor growth and metastasis and to perturb angiogenesis (Bauvois, 2004;Lindberg et al, 2004;Yoshiji et al, 2004;Deshayes and Nahmias, 2005).…”

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis

“…28 Also, release of the two ADAM17 substrates, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, is enhanced in active AAV. 17,29,30 We, therefore, aimed to characterize the specific role of ADAM17 in PR3-AAV in more detail.…”

Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

“…Both membrane-anchored and secreted forms of ADAM8 would participate in matrix adhesion (Schlomann et al, 2002), whereas other MMPs could process the adhesive proteins resulting in migration (Gomez-Gaviro et al, 2007). A related mechanism has been suggested for the processing of vascular cell adhesion molecule on eosinophils (Garton et al, 2003, Matsuno et al, 2007 and L-selectin on neutrophils (Gomez-Gaviro et al, 2007). Interestingly, ADAM8 was found in intracellular vesicles (Gomez-Gaviro et al, 2007, Verrier et al, 2004, a location associated with the cargo transport of MMP and other molecules to the extracellular microenvironment, which would allow cell invasion.…”