A Brief History of Tumor Necrosis Factor α – converting Enzyme: An Overview of Ectodomain Shedding

Abstract

Many membrane-bound molecules are cleaved at the cell surface, thereby releasing their extracellular domains. This process, often referred to as ectodomain shedding, has emerged as a critical post-translational mechanism for various membrane-bound ligands, receptors, and adhesion molecules. Tumor necrosis factor α (TNFα)-converting enzyme (TACE/ADAM17) was originally identified as an enzyme responsible for releasing the membrane-bound TNFα precursor. However, subsequent studies found an exceptionally large number of target molecules of TACE, including the ligands for epidermal growth factor receptor, L-selectin, CD44, and vascular growth factor receptor 2. Furthermore, in vivo studies using TACE-conditional knockout mice demonstrated the crucial roles of TACE and ectodomain shedding under both physiological and pathological conditions. However, the potential clinical application of the manipulation of TACE activity remains to be investigated.

P159 from Mycoplasma hyopneumoniae Binds Porcine Cilia and Heparin and Is Cleaved in a Manner Akin to Ectodomain Shedding

“…Many P159 cleavage fragments are retained on heparin-agarose columns and span regions that bind to porcine cilia, indicating that processing releases functionally active fragments in a manner akin to ectodomain shedding in eukaryote cells. 35 Unlike the S/T-X-F↓X-D/E cleavage motif, we were not able to decipher the sequence of motifs that produced low abundance cleavage fragments. Nonetheless, three of the six N-terminal fragments were bona-fide tryptic peptides, suggesting that a trypsin-like protease may be functionally active on the surface of M. hyopneumoniae.…”

Papillon-Lefèvre syndrome patient reveals species-dependent requirements for neutrophil defenses

“…Patient neutrophils upregulated CD11b in response to fMLF as well as control neutrophils, indicating that stimulus-response coupling was normal in patient neutrophils. Shedding of CD62L by patient neutrophils, which is executed by the membrane-bound proteinase TNF-α-converting enzyme (TACE), also known as ADAM17 (25), was also normal (Figure 2A). The ability to mount a respiratory burst was evaluated by flow cytometry (Figure 2A) and showed activities in PLS neutrophils similar to those of control neutrophils.…”

Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets

“…This process is called "ectodomain shedding", which is primarily mediated by TNFa-converting enzyme (TACE), also known as a disintegrin and metalloprotease 17 (ADAM17) [27]. Evidence suggests that there exist some similar immune defects between cleavage-resistant TNFa mutant mice and TNFa-null mice, demonstrating an indispensable role of ADAM17-mediated ectodomain shedding in TNFa activation [28]. ADAM17 can be cleavageactivated at furin-like recognition site ( 212 RVKR) [29].…”