ADAM17

Official Full Name

ADAM metallopeptidase domain 17

Organism

Homo sapiens

GeneID

6868

Background

This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biologic processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded preproprotein is proteolytically processed to generate the mature protease. The encoded protease functions in the ectodomain shedding of tumor necrosis factor-alpha, in which soluble tumor necrosis factor-alpha is released from the membrane-bound precursor. This protease also functions in the processing of numerous other substrates, including cell adhesion proteins, cytokine and growth factor receptors and epidermal growth factor (EGF) receptor ligands, and plays a prominent role in the activation of the Notch signaling pathway. Elevated expression of this gene has been observed in specific cell types derived from psoriasis, rheumatoid arthritis, multiple sclerosis and Crohn's disease patients, suggesting that the encoded protein may play a role in autoimmune disease. Additionally, this protease may play a role in viral infection through its cleavage of ACE2, the cellular receptor for SARS-CoV and SARS-CoV-2. [provided by RefSeq, Aug 2020]

Synonyms

CSVP; TACE; NISBD; ADAM18; CD156B; NISBD1;

Bio Chemical Class

Peptidase

Protein Sequence

MRQSLLFLTSVVPFVLAPRPPDDPGFGPHQRLEKLDSLLSDYDILSLSNIQQHSVRKRDLQTSTHVETLLTFSALKRHFKLYLTSSTERFSQNFKVVVVDGKNESEYTVKWQDFFTGHVVGEPDSRVLAHIRDDDVIIRINTDGAEYNIEPLWRFVNDTKDKRMLVYKSEDIKNVSRLQSPKVCGYLKVDNEELLPKGLVDREPPEELVHRVKRRADPDPMKNTCKLLVVADHRFYRYMGRGEESTTTNYLIELIDRVDDIYRNTSWDNAGFKGYGIQIEQIRILKSPQEVKPGEKHYNMAKSYPNEEKDAWDVKMLLEQFSFDIAEEASKVCLAHLFTYQDFDMGTLGLAYVGSPRANSHGGVCPKAYYSPVGKKNIYLNSGLTSTKNYGKTILTKEADLVTTHELGHNFGAEHDPDGLAECAPNEDQGGKYVMYPIAVSGDHENNKMFSNCSKQSIYKTIESKAQECFQERSNKVCGNSRVDEGEECDPGIMYLNNDTCCNSDCTLKEGVQCSDRNSPCCKNCQFETAQKKCQEAINATCKGVSYCTGNSSECPPPGNAEDDTVCLDLGKCKDGKCIPFCEREQQLESCACNETDNSCKVCCRDLSGRCVPYVDAEQKNLFLRKGKPCTVGFCDMNGKCEKRVQDVIERFWDFIDQLSINTFGKFLADNIVGSVLVFSLIFWIPFSILVHCVDKKLDKQYESLSLFHPSNVEMLSSMDSASVRIIKPFPAPQTPGRLQPAPVIPSAPAAPKLDHQRMDTIQEDPSTDSHMDEDGFEKDPFPNSSTAAKSFEDLTDHPVTRSEKAASFKLQRQNRVDSKETEC

Open

Disease

Breast cancer, Chronic obstructive pulmonary disease, Indeterminate colitis, Rheumatoid arthritis

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

1 +

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Detailed Information

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.

ADAM17 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.

References:

Lv, X., Li, Y., Qian, M., Ma, C., Jing, H., & Wen, Z., et al. (2014). Adam17 silencing suppresses the migration and invasion of non-small cell lung cancer. Molecular Medicine Reports, 9(5), 1935-1940.
Shen, H., Li, L., Zhou, S., Yu, D., Yang, S., & Chen, X., et al. (2016). The role of adam17 in tumorigenesis and progression of breast cancer. Tumour Biology the Journal of the International Society for Oncodevelopmental Biology & Medicine, 37(12), 1-12.
Lisi, S., D'Amore, M., & Sisto, M. (2014). Adam17 at the interface between inflammation and autoimmunity. Immunology Letters, 162(1), 159-169.
Folkesson, M., Li, C., Frebelius, S., Swedenborg, J., Wågsäter, D., & Williams, K. J., et al. (2015). Proteolytically active adam10 and adam17 carried on membrane microvesicles in human abdominal aortic aneurysms. Thrombosis & Haemostasis, 114(6), 1165-74.
Li, Y., Yang, C., Ma, G., Cui, L., Gu, X., & Chen, Y., et al. (2014). Analysis of adam17 polymorphisms and susceptibility to sporadic abdominal aortic aneurysm. Cellular Physiology & Biochemistry International Journal of Experimental Cellular Physiology Biochemistry & Pharmacology, 33(5), 1426-1438.

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