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Gene Review

ADAM17  -  ADAM metallopeptidase domain 17

Homo sapiens

Synonyms: ADAM 17, ADAM18, CD156B, CSVP, Disintegrin and metalloproteinase domain-containing protein 17, ...
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Disease relevance of ADAM17


Psychiatry related information on ADAM17

  • While the amyloidogenic processing of APP in neurons is linked to the pathogenesis of Alzheimer's disease (AD), the expression of TACE in neurons has not yet been examined [5].

High impact information on ADAM17

  • Structural comparisons with other disintegrin-containing enzymes indicate that TACE is unique, with noteable sequence identity to MADM, an enzyme implicated in myelin degradation, and to KUZ, a Drosophila homologue of MADM important for neuronal development [6].
  • A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE [7].
  • Targeting TACE-dependent EGFR ligand shedding in breast cancer [8].
  • Using existing patient outcome data, we demonstrated a strong correlation between TACE and TGFA expression in human breast cancers that was predictive of poor prognosis [8].
  • We show that TACE-dependent ligand shedding was prevalent in a series of additional breast cancer cell lines and, in all cases examined, was amenable to inhibition [8].

Chemical compound and disease context of ADAM17


Biological context of ADAM17

  • Since loss of cell adhesion is an early event in tumor development, these results suggest that ADAM17 is a useful target in anticancer therapy [13].
  • By screening a library of synthetic peptides as potential substrates, we show that soluble recombinant forms of these enzymes have similar proteolytic substrate specificity, clearly distinct from that of ADAM17 (TNFalpha-converting enzyme) [14].
  • These results demonstrate that GPV is cleaved upon agonist-induced platelet activation and show that ADAM17 is the major enzyme mediating this process [15].
  • Transfection analysis allowed us to further establish that the pro-hormone convertase 7 and ADAM10 but not ADAM17 (TACE, tumour necrosis factor alpha-converting enzyme) likely contribute to constitutive sAPPalpha secretion by LoVo cells [16].
  • Chromosomal mapping places TACE/ADAM17 on mouse chromosome 12 and human chromosome 2p25 [17].

Anatomical context of ADAM17


Associations of ADAM17 with chemical compounds

  • This shedding was inhibited by the broad range metalloproteinase inhibitor GM6001, the two potent ADAM17 inhibitors GW280264X and TAPI-2, and was absent in mice lacking functional ADAM17 (ADAM17 lacking Zn-binding domain; ADAM17(DeltaZn/DeltaZn)) [15].
  • Evidence for a role of ADAM17 (TACE) in the regulation of platelet glycoprotein V [15].
  • The role of ADAM10 and ADAM17 in the ectodomain shedding of angiotensin converting enzyme and the amyloid precursor protein [23].
  • TACE shows the presence of an unknown prodomain, a cysteine switch, a catalytic domain, a zinc binding region, a disintegrin region, an EGF-like domain, a transmembrane domain, and a unique cytoplasmic region [24].
  • Mutagenesis carried out on leucine 100 also upholds our previous findings that a leucine on the EF-loop is critical for TACE recognition [25].

Physical interactions of ADAM17

  • TACE/ADAM17 is a member of the adamalysin class of zinc-binding metalloproteases or ADAM (a disintegrin and metalloprotease) [17].
  • Also, mutations in the core of the MMP interaction surface of N-TIMP-3 dramatically reduce the binding affinity for MMPs but have little effect on the inhibitory activity for TACE [26].
  • Identification of SAP97 as an intracellular binding partner of TACE [27].

Enzymatic interactions of ADAM17


Regulatory relationships of ADAM17

  • Taken together, these data provided direct evidence for the involvement of ADAM17 in the regulated ectodomain shedding of ACE2 [2].
  • Furthermore, ADAM17/TACE mRNA expression was down-regulated in pancreatic cancer cells arrested in G(2)-M phase as well as in a time-dependent manner after TNF-alpha and interleukin-6 incubation [1].
  • Among the four mammalian TIMPs (TIMP-1 to -4), TACE is selectively inhibited by TIMP-3 [25].
  • Furthermore, constitutive N1 secretion is drastically reduced in fibroblasts deficient for ADAM10 whereas phorbol 12,13-dibutyrate-regulated N1 production is fully abolished in TACE-deficient cells [32].
  • Furthermore, introduction of siRNAs targeting ADAM17 transcripts resulted in suppression of DC-induced activation of EGFR and ERK1/2 [33].

Other interactions of ADAM17

  • Second, our study identifies ADAM10 and ADAM17 as the protease candidates responsible for normal cleavage of PrPc [32].
  • After pro-domain removal, additional steps, such as protein kinase C-dependent phosphorylation, may be involved in regulating the catalytic activity of MDC9, which is likely to target different substrates than the related TNF-alpha-convertase [34].
  • We conclude that HNE induces MUC5AC mucin expression via a cascade involving PKC-ROS-TACE in human airway epithelial cells [28].
  • Here, we examine the molecular basis of TIMP-TACE selectivity using TIMP-2 as the scaffold [25].
  • Small, interfering RNA directed against ADAM17 or MMP9 inhibited the acrolein-induced MUC5AC mRNA increase [35].

Analytical, diagnostic and therapeutic context of ADAM17


  1. Aberrant Expression of a Disintegrin and Metalloproteinase 17/Tumor Necrosis Factor-{alpha} Converting Enzyme Increases the Malignant Potential in Human Pancreatic Ductal Adenocarcinoma. Ringel, J., Jesnowski, R., Moniaux, N., Lüttges, J., Ringel, J., Choudhury, A., Batra, S.K., Klöppel, G., Löhr, M. Cancer Res. (2006) [Pubmed]
  2. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). Lambert, D.W., Yarski, M., Warner, F.J., Thornhill, P., Parkin, E.T., Smith, A.I., Hooper, N.M., Turner, A.J. J. Biol. Chem. (2005) [Pubmed]
  3. ADAM17 mRNA expression and pathological features of hepatocellular carcinoma. Ding, X., Yang, L.Y., Huang, G.W., Wang, W., Lu, W.Q. World J. Gastroenterol. (2004) [Pubmed]
  4. ADAM-17 expression in breast cancer correlates with variables of tumor progression. McGowan, P.M., Ryan, B.M., Hill, A.D., McDermott, E., O'Higgins, N., Duffy, M.J. Clin. Cancer Res. (2007) [Pubmed]
  5. Neuronal localization of the TNFalpha converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques. Skovronsky, D.M., Fath, S., Lee, V.M., Milla, M.E. J. Neurobiol. (2001) [Pubmed]
  6. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Moss, M.L., Jin, S.L., Milla, M.E., Bickett, D.M., Burkhart, W., Carter, H.L., Chen, W.J., Clay, W.C., Didsbury, J.R., Hassler, D., Hoffman, C.R., Kost, T.A., Lambert, M.H., Leesnitzer, M.A., McCauley, P., McGeehan, G., Mitchell, J., Moyer, M., Pahel, G., Rocque, W., Overton, L.K., Schoenen, F., Seaton, T., Su, J.L., Becherer, J.D. Nature (1997) [Pubmed]
  7. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Brou, C., Logeat, F., Gupta, N., Bessia, C., LeBail, O., Doedens, J.R., Cumano, A., Roux, P., Black, R.A., Israël, A. Mol. Cell (2000) [Pubmed]
  8. Targeting TACE-dependent EGFR ligand shedding in breast cancer. Kenny, P.A., Bissell, M.J. J. Clin. Invest. (2007) [Pubmed]
  9. Expression of ADAMs (a disintegrin and metalloproteases) and TIMP-3 (tissue inhibitor of metalloproteinase-3) in human prostatic adenocarcinomas. Karan, D., Lin, F.C., Bryan, M., Ringel, J., Moniaux, N., Lin, M.F., Batra, S.K. Int. J. Oncol. (2003) [Pubmed]
  10. ADAM17 mediates epidermal growth factor receptor transactivation and vascular smooth muscle cell hypertrophy induced by angiotensin II. Ohtsu, H., Dempsey, P.J., Frank, G.D., Brailoiu, E., Higuchi, S., Suzuki, H., Nakashima, H., Eguchi, K., Eguchi, S. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  11. ADAM17 Mediates Epidermal Growth Factor Receptor Transactivation and Vascular Smooth Muscle Cell Hypertrophy Induced by Angiotensin II. Ohtsu, H., Dempsey, P.J., Frank, G.D., Brailoiu, E., Higuchi, S., Suzuki, H., Nakashima, H., Eguchi, K., Eguchi, S. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  12. Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells. Shao, M.X., Ueki, I.F., Nadel, J.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  13. Proteomic identification of desmoglein 2 and activated leukocyte cell adhesion molecule as substrates of ADAM17 and ADAM10 by difference gel electrophoresis. Bech-Serra, J.J., Santiago-Josefat, B., Esselens, C., Saftig, P., Baselga, J., Arribas, J., Canals, F. Mol. Cell. Biol. (2006) [Pubmed]
  14. Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on synthetic peptide substrates and in ectodomain cleavage of CD23. Fourie, A.M., Coles, F., Moreno, V., Karlsson, L. J. Biol. Chem. (2003) [Pubmed]
  15. Evidence for a role of ADAM17 (TACE) in the regulation of platelet glycoprotein V. Rabie, T., Strehl, A., Ludwig, A., Nieswandt, B. J. Biol. Chem. (2005) [Pubmed]
  16. Constitutive alpha-secretase cleavage of the beta-amyloid precursor protein in the furin-deficient LoVo cell line: involvement of the pro-hormone convertase 7 and the disintegrin metalloprotease ADAM10. Lopez-Perez, E., Zhang, Y., Frank, S.J., Creemers, J., Seidah, N., Checler, F. J. Neurochem. (2001) [Pubmed]
  17. Characterization of the cDNA and gene for mouse tumour necrosis factor alpha converting enzyme (TACE/ADAM17) and its location to mouse chromosome 12 and human chromosome 2p25. Cerretti, D.P., Poindexter, K., Castner, B.J., Means, G., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Black, R.A., Nelson, N. Cytokine (1999) [Pubmed]
  18. The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10. Abel, S., Hundhausen, C., Mentlein, R., Schulte, A., Berkhout, T.A., Broadway, N., Hartmann, D., Sedlacek, R., Dietrich, S., Muetze, B., Schuster, B., Kallen, K.J., Saftig, P., Rose-John, S., Ludwig, A. J. Immunol. (2004) [Pubmed]
  19. Functional classification of ADAMs based on a conserved motif for binding to integrin alpha 9beta 1: implications for sperm-egg binding and other cell interactions. Eto, K., Huet, C., Tarui, T., Kupriyanov, S., Liu, H.Z., Puzon-McLaughlin, W., Zhang, X.P., Sheppard, D., Engvall, E., Takada, Y. J. Biol. Chem. (2002) [Pubmed]
  20. Evaluation of the contributions of ADAMs 9, 12, 15, 17, and 19 to heart development and ectodomain shedding of neuregulins beta1 and beta2. Horiuchi, K., Zhou, H.M., Kelly, K., Manova, K., Blobel, C.P. Dev. Biol. (2005) [Pubmed]
  21. Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase. Asai, M., Hattori, C., Szabó, B., Sasagawa, N., Maruyama, K., Tanuma, S., Ishiura, S. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  22. ADAM17 but not ADAM10 mediates tumor necrosis factor-alpha and L-selectin shedding from leukocyte membranes. Condon, T.P., Flournoy, S., Sawyer, G.J., Baker, B.F., Kishimoto, T.K., Bennett, C.F. Antisense Nucleic Acid Drug Dev. (2001) [Pubmed]
  23. The role of ADAM10 and ADAM17 in the ectodomain shedding of angiotensin converting enzyme and the amyloid precursor protein. Allinson, T.M., Parkin, E.T., Condon, T.P., Schwager, S.L., Sturrock, E.D., Turner, A.J., Hooper, N.M. Eur. J. Biochem. (2004) [Pubmed]
  24. TNF-alpha convertase enzyme from human arthritis-affected cartilage: isolation of cDNA by differential display, expression of the active enzyme, and regulation of TNF-alpha. Patel, I.R., Attur, M.G., Patel, R.N., Stuchin, S.A., Abagyan, R.A., Abramson, S.B., Amin, A.R. J. Immunol. (1998) [Pubmed]
  25. Delineating the molecular basis of the inactivity of tissue inhibitor of metalloproteinase-2 against tumor necrosis factor-alpha-converting enzyme. Lee, M.H., Rapti, M., Murphy, G. J. Biol. Chem. (2004) [Pubmed]
  26. Reactive site mutations in tissue inhibitor of metalloproteinase-3 disrupt inhibition of matrix metalloproteinases but not tumor necrosis factor-alpha-converting enzyme. Wei, S., Kashiwagi, M., Kota, S., Xie, Z., Nagase, H., Brew, K. J. Biol. Chem. (2005) [Pubmed]
  27. Identification of SAP97 as an intracellular binding partner of TACE. Peiretti, F., Deprez-Beauclair, P., Bonardo, B., Aubert, H., Juhan-Vague, I., Nalbone, G. J. Cell. Sci. (2003) [Pubmed]
  28. Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-alpha-converting enzyme. Shao, M.X., Nadel, J.A. J. Immunol. (2005) [Pubmed]
  29. Contribution of TNF-alpha converting enzyme and proteinase-3 to TNF-alpha processing in human alveolar macrophages. Armstrong, L., Godinho, S.I., Uppington, K.M., Whittington, H.A., Millar, A.B. Am. J. Respir. Cell Mol. Biol. (2006) [Pubmed]
  30. The shedding activity of ADAM17 is sequestered in lipid rafts. Tellier, E., Canault, M., Rebsomen, L., Bonardo, B., Juhan-Vague, I., Nalbone, G., Peiretti, F. Exp. Cell Res. (2006) [Pubmed]
  31. Pseudomonas Lipopolysaccharide Accelerates Wound Repair via Activation of a Novel Epithelial Cell Signaling Cascade. Koff, J.L., Shao, M.X., Kim, S., Ueki, I.F., Nadel, J.A. J. Immunol. (2006) [Pubmed]
  32. The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein. Vincent, B., Paitel, E., Saftig, P., Frobert, Y., Hartmann, D., De Strooper, B., Grassi, J., Lopez-Perez, E., Checler, F. J. Biol. Chem. (2001) [Pubmed]
  33. Involvement of membrane-type bile acid receptor M-BAR/TGR5 in bile acid-induced activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells. Yasuda, H., Hirata, S., Inoue, K., Mashima, H., Ohnishi, H., Yoshiba, M. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  34. Metalloprotease-disintegrin MDC9: intracellular maturation and catalytic activity. Roghani, M., Becherer, J.D., Moss, M.L., Atherton, R.E., Erdjument-Bromage, H., Arribas, J., Blackburn, R.K., Weskamp, G., Tempst, P., Blobel, C.P. J. Biol. Chem. (1999) [Pubmed]
  35. Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. Deshmukh, H.S., Case, L.M., Wesselkamper, S.C., Borchers, M.T., Martin, L.D., Shertzer, H.G., Nadel, J.A., Leikauf, G.D. Am. J. Respir. Crit. Care Med. (2005) [Pubmed]
  36. TACE mRNA expression in peripheral mononudear cells precedes new lesions on MRI in multiple sclerosis. Seifert, T., Kieseier, B.C., Ropele, S., Strasser-Fuchs, S., Quehenberger, F., Fazekas, F., Hartung, H.P. Mult. Scler. (2002) [Pubmed]
  37. Up-regulated expression of ADAM17 in human colon carcinoma: co-expression with EGFR in neoplastic and endothelial cells. Blanchot-Jossic, F., Jarry, A., Masson, D., Bach-Ngohou, K., Paineau, J., Denis, M.G., Laboisse, C.L., Mosnier, J.F. J. Pathol. (2005) [Pubmed]
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