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A disintegrin and metalloprotease 17(ADAM17) was discovered in 1997 as a soluble form of the enzyme that releases the membrane-bound tumor necrosis factor (TNF-α） precursor. ADAM17, also known as tumor necrosis factor-converting enzyme (TACE), is a widely expressed protease involved in the exfoliation of various transmembrane proteins, such as growth factor ligands, cytokines, and receptors. Since oxonate inhibitors reduce the release of soluble TNF-α from cells, the researchers speculate that the shed enzyme that cleaves membrane-bound TNF-α is a metalloenzyme.
The most important function of ADAM17 is hydrolase digestion of the extracellular domain of various transmembrane proteins, which are usually located near the membrane of the extracellular domain. More than 50 ADAM17 substrates have been identified, and more and more substrates will be discovered as the research progresses. The substrate of ADAM17 includes epidermal growth factor receptor ligand, pro-inflammatory cytokine, adhesion molecule, and starch precursor protein. ADAM17 is involved in the development of many diseases such as non-small cell lung cancer, ovarian cancer, breast cancer, inflammatory bowel disease, acute pneumonia, Alzheimer's disease and Down's syndrome.
Figure 1. A schematic illustration of the ADAM17 function as sheddase. (Lisi, S., et al. 2014)
Some membrane protein extracellular domains are digested with ADAM17 or other proteases, and the transmembrane domain can be further hydrolyzed and called RIP. It was found that the extracellular domain of Notch protein was first digested by ADAM17 or ADAM10 at the α-cleavage site, and then digested by a γ-secretase composed of multiple proteases (such as presenilin) in the membrane. The remaining intracellular portion after digestion with the γ-secretase is transferred to the nucleus to regulate the transcription of different genes.
ADAM17 and Multiple Sclerosis
Multiple sclerosis ADAM17 is also involved in neuroinflammatory diseases such as multiple sclerosis (MS). In patients with acute MS, peripheral monocyte ADAM17 activation is increased. Moreover, immunohistochemistry and studies of cadaveric patients who died of MS showed that MS plaques were activated in ADAM17 and TNFR2, and ADAM17 and soluble TNFR2 levels were increased in cerebrospinal fluid. Increased expression of ADAM17 in acute MS injury, endothelial cells, microglia, and astrocytes. The role of ADAM17 in MS may be through enzymatic cleavage of tyrosine kinase Axl and Mer decoy receptors, promoting plaque formation, altering growth factor signaling and prolonging injury activity, however, this possibility requires further validation.
ADAM17 and Alzheimer Diseases
ADAM17 plays an important role in senile dementia. ADAM17 acts as an α-secretase to amyloid precursor protein (APP) to produce soluble APPsα, and APPsα does not participate in extracellular senile plaques. If APP is digested with β-secretase to produce β amyloid (Aβ polypeptide), Aβ polypeptide is the main component of extracellular senile plaques. Around the amyloid plaques in the brain of Alzheimer's patients, microglia and astrocyte activation, as well as increased inflammatory mediators, were observed, confirming that Aβ peptides can induce inflammation. ADAM17 is localized in areas of the brain that contain amyloid plaques. Recent studies have shown that the ADAM17 intracellular domain binding protein FHL2, which regulates ADAM17 activity, is also required for the formation of APPsα.
ADAM17 and Tumor
ADAM17 is involved in the formation of cancer by enzymatically cutting the growth factors necessary for tumor growth. It has been found that the increased activity of ADAM17 in the tumor tissue, accompanied by an increase in the epidermal growth factor ligand in the tissue, promotes the development of tumor malignancy. The role of ADAM17 in various malignancies is currently known to be the most advanced in breast cancer. In breast cancer, ADAM17 overexpression is associated with TGFα expression, tumor progression, and metastasis, and increased ADAM17 activation predicts a shortened survival of breast cancer patients. In patients with metastatic breast cancer, the breast cancer marker nectin-4 is detected in the serum, and nectin-4 is digested by ADAM17. In vitro experiments have shown that ADAM17 induces breast cancer cell proliferation and metastasis by activating the EGFR-PI3K-AKT signaling pathway. Moreover, the malignant phenotype of breast cancer cells can return to the normal phenotype after interfering with ADAM17 activity by small RNA interference technology, further indicating the important pathophysiological role of ADAM17 in breast cancer.
ADAM17 and Abdominal Aortic Aneurysm
Abdominal aortic aneurysm (AAA) is a degenerative disease characterized by destruction of the abdominal aortic wall structure and progressive expansion into a pulsatile mass. Studies have shown that ADAM17 and ADAM10 also play a role in promoting the release of the pro-inflammatory factor TNF-α. Studies have further shown that TNF-α can activate c-JNK, and c-JNK may be an important factor in the pathogenesis of AAA. The expression of soluble TNF-α and ADAM17 in AAA tissues showed signs of up-regulation and a strong and close relationship with each other. Blocking TNF-α expression and c-JNK activation inhibited the formation of AAA in CaCl2-induced AAA-induced mice. In the rat model of thoracic artery tumor, the mRNA expression levels of ADAM17 and matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) were found to be elevated. ADAM17 can up-regulate the expression of MMP-2 and MMP-9 through the EGFR-MEK-ERK pathway, and their expression can degrade type 4 collagen, proteoglycan core protein and elastin to promote aneurysm. In addition, the specificity of the medial and adventitial walls of the aortic wall inhibited the expression of the tissue inhibitor of metalloproteinase (TIMP) expressed by the ADAM family, which is a significant inhibitor of TIAM17, TIMP3. In addition, the genetic polymorphism and sensitivity of the ADAM17 promoter are also closely related to the pathogenesis of sporadic AAA.