Tumor necrosis factor-alpha converting enzyme

Abstract

Tumor necrosis factor-alpha converting enzyme (TACE/ADAM17/CD156q) is a member of the 'A Disintegrin And Metalloprotease', or ADAM, family. It is a multi-domain, type I transmembrane protein that includes an extracellular zinc-dependent protease domain. TACE expression is largely constitutive, but the surface pool is downregulated following cell activation. Cleavage by TACE generates the soluble forms of tumor necrosis factor, transforming growth factor-alpha, and other proteins from their membrane-bound precursors (a phenomenon termed 'shedding'). The recognition of substrates by TACE is poorly understood, but sites distal to the active site are probably involved, and in at least some cases both enzyme and substrate must be membrane-anchored. Cell-activators increase the rate of shedding. Activator-induced shedding is mediated by intracellular kinase cascades, but how these cascades affect the shedding machinery is unknown. The pharmaceutical industry is attempting to design specific TACE inhibitors to treat inflammatory diseases.