The Role of ADAM17 in Inflammation-Related Atherosclerosis

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

“…ADAM17 is a member of the adamalysins subfamily of metzincin metalloproteinases consisting of 824 amino acids with zinc-dependent catalytic activities (29). The human ADAM17 protein sequence contains an N-terminal signal sequence (SS), a prodomain (PD), a catalytic metalloprotease domain (MD), a disintegrin domain (DD), a membraneproximal protein domain (MPD), a conserved ADAM17 interaction sequence (CANDIS), a transmembrane domain (TM), and a C-terminal cytoplasmic domain (CD), which are located at amino acid residues 1-17, 18-216, 217-474, 480-559, 581-642, 643-666, 672-694, and 695-824, respectively (7,30) (Figure 1A). Among them, the first five protein sequences that make up its extracellular domain may be involved in regulating multiple biological functions, including angiogenesis, cell migration, cell proliferation, inflammation, and immune responses.…”

“…In addition, the positively charged motif (Arg 625 -Lys 628 ) in MPD binds to phosphatidylserine in the outer membrane, affects the conformation of ADAM17, and induces its activation (46). TM and CD mainly regulate the response of exocytodomain signaling molecule-related events (7,38,47), which may be attributed to the functional assembly of the Src SH3-binding motif (20). The CANDIS domain lies between MPD and TM, consisting of amino acid residues 643-666 (48), which binds to the type I transmembrane protein IL-6R but not the type II transmembrane protein TNF-a (49).…”

“…In addition to post-translational modifications, ADAM17 also affects post-transcriptional regulation. ADAM17 is highly expressed or upregulated in cancer (76,77) and other inflammation-related diseases, including kidney disease (78), sepsis (79), cicatrization (80), diabetic retinopathy (81), myocardial fibrosis (82), aortic dissection (83), arthritis (84) and atherosclerosis (7). The guanine-cytosine (G-C) sequences in the promoter region of ADAM17 are capable of binding specifically to many transcription factors (85)(86)(87).…”

“…Due to the shedding activity, ectodomains of many transmembrane proteins are hydrolyzed and released by ADAMs metalloproteinases. Studies over the past five years revealed that ADAM17 has more than 90 substrates (7,32) with distinct functions (Table 1), which are involved in various cellular processes, including cell adhesion, migration, development, inflammation, immune response, tumorigenesis, signal transduction. The cleavage and release of substrates (inflammatory cytokines, growth factors, receptors, adhesion molecules, and others) for ADAM17 may result in different functions of substrate proteins.…”

“…Activation of ADAM17 is required for the cleavage of its prodomain and exposure of the active site. In response to the inflammatory stimuli, activated ADAM17 prompts multiple receptor-mediated signal transduction by cleaving ectodomains of membrane proteins, including inflammatory cytokines, growth factors, receptors, and adhesion factors (7). The expression of ADAM17 in mouse articular cartilage is positively correlated with the development of arthritis, and its deletion attenuates articular cartilage degeneration (8).…”