ADAM and ADAMTS Proteases in Hepatic Disorders

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Julia Bolik
Janina E. E. Tirnitz-Parker
Dirk Schmidt-Arras


ADAM, ADAMTS, metzincin superfamily, thrombotic thrombocytopenia purpura, von Willebrand Factor


Proteolysis is an irreversible post-translational modification that regulates protein function and signal transduction. This includes remodelling of the extracellular matrix, release of membrane-bound cytokines and receptor ectodomains, as well as the initiation of intracellular signalling cues. Members of the adamalysin protease subfamily, in particular the ADAM (a disintegrin and metalloprotease) and ADAMTS (the ADAM containing thrombospondin motif) families, are involved in these processes. This review presents an overview of how ADAM and ADAMTS proteins are involved in liver physiology and pathophysiology.


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1. Gilgenkrantz H, Collin de l’Hortet A. Understanding liver regeneration: From mechanisms to regenerative medicine. Am J Pathol. 2018;188:1316–27.
2. Köhn-Gaone J, Gogoi-Tiwari J, Ramm GA, Olynyk JK, Tirnitz-Parker JEE. The role of liver progenitor cells during liver regeneration, fibrogenesis, and carcinogenesis. Am J Physiol. 2016;310:G143–54.
3. Ruddell RG, Knight B, Tirnitz-Parker JEE, Akhurst B, Summerville L, Subramaniam VN, et al. Lymphotoxin-beta receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury. Hepatology. 2009;49:227–39.
4. Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. 2012;18:572–9.
5. Tirnitz-Parker JEE, Olynyk JK, Ramm GA. Role of TWEAK in coregulating liver progenitor cell and fibrogenic responses. Hepatology. 2014;59:1198–201.
6. Finkin S, Yuan D, Stein I, Taniguchi K, Weber A, Unger K, et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol. 2015;16:1235–44.
7. Huxley-Jones J, Clarke T-K, Beck C, Toubaris G, Robertson DL, Boot-Handford RP. The evolution of the vertebrate metzincins; insights from Ciona intestinalis and Danio rerio. BMC Evol Biol. 2007;7:63.
8. Gomis-Rüth FX. Catalytic domain architecture of metzincin metalloproteases. Biol Chem. 2009;284:15353–7.
9. Reiss K, Saftig P. The “a disintegrin and metalloprotease” (ADAM) family of sheddases: Physiological and cellular functions. Semin Cell Dev Biol. 2009;20:126–37.
10. Seegar TCM, Killingsworth LB, Saha N, Meyer PA, Patra D, Zimmerman B, et al. Structural basis for regulated proteolysis by the ?-secretase ADAM10. Cell. 2017;171:1638–48.
11. Mosyak L, Georgiadis K, Shane T, Svenson K, Hebert T, McDonagh T, et al. Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5. Protein Sci. 2008;17:16–21.
12. Düsterhöft S, Jung S, Hung C-W, Tholey A, Sönnichsen FD, Grötzinger J, et al. Membrane-proximal domain of a disintegrin and metalloprotease-17 represents the putative molecular switch of its shedding activity operated by protein-disulfide isomerase. J Am Chem Soc. 2013;135:5776–81.
13. Jones JC, Rustagi S, Dempsey PJ. ADAM proteases and gastrointestinal function. Annu Rev Physiol. 2016;78:243–76.
14. Howard L, Maciewicz RA, Blobel CP. Cloning and characterization of ADAM28: Evidence for autocatalytic pro-domain removal and for cell surface localization of mature ADAM28. Biochem J. 2000;348 Pt 1:21–7.
15. Schlomann U, Wildeboer D, Webster A, Antropova O, Zeuschner D, Knight CG, et al. The metalloprotease disintegrin ADAM8. Processing by autocatalysis is required for proteolytic activity and cell adhesion. J Biol Chem. 2002;277:48210–19.
16. Wong E, Cohen T, Romi E, Levin M, Peleg Y, Arad U, et al. Harnessing the natural inhibitory domain to control TNF? Converting Enzyme (TACE) activity in vivo. Sci Rep. 2016;6:35598.
17. Maskos K, Fernandez-Catalan C, Huber R, Bourenkov GP, Bartunik H, Ellestad GA, et al. Crystal structure of the catalytic domain of human tumor necrosis factor-alpha-converting enzyme. Proc Natl Acad Sci U S A. 1998;95:3408–12.
18. Stawikowska R, Cudic M, Giulianotti M, Houghten RA, Fields GB, Minond D. Activity of ADAM17 (a disintegrin and metalloprotease 17) is regulated by its noncatalytic domains and secondary structure of its substrates. J Biol Chem. 2013;288:22871–9.
19. Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SH, Nievergall E, et al. Adam meets Eph: An ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell. 2005;123:291–304.
20. Xu P, Derynck R. Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation. Mol Cell. 2010;37:551–66.
21. Xu P, Liu J, Sakaki-Yumoto M, Derynck R. TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association. Sci Signal. 2012;5:ra34.
22. Liu C, Xu P, Lamouille S, Xu J, Derynck R. TACE-mediated ectodomain shedding of the type I TGF-beta receptor downregulates TGF-beta signaling. Mol Cell. 2009;35:26–36.
23. Scheller J, Chalaris A, Garbers C, Rose-John S. ADAM17: A molecular switch to control inflammation and tissue regeneration Trends Immunol. 2011;32:380–7.
24. Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: From physiopathology to therapy. J Hepatol. 2016;64:1403–15.
25. Moss ML, Minond D. Recent advances in ADAM17 research: A promising target for cancer and inflammation. Mediators Inflamm. 2017;2017:9673537.
26. Hartmann D, de Strooper B, Serneels L, Craessaerts K, Herreman A, Annaert W, et al. The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum Mol Genet. 2002;11:2615–24.
27. White JM. ADAMs: Modulators of cell-cell and cell-matrix interactions. Curr Opin Cell Biol. 2003;15:598–606.
28. Oria VO, Lopatta P, Schilling O. The pleiotropic roles of ADAM9 in the biology of solid tumors. Cell Mol Life Sci. 2018;75:2291–301.
29. Schwettmann L, Wehmeier M, Jokovic D, Aleksandrova K, Brand K, Manns MP, et al. Hepatic expression of A disintegrin and metalloproteinase (ADAM) and ADAMs with thrombospondin motives (ADAM-TS) enzymes in patients with chronic liver diseases. J Hepatol. 2008;49:243–50.
30. Le Pabic H, Bonnier D, Wewer UM, Coutand A, Musso O, Baffet G, et al. ADAM12 in human liver cancers: TGF-beta-regulated expression in stellate cells is associated with matrix remodeling. Hepatology. 2003;37:1056–66.
31. Tannapfel A, Anhalt K, Häusermann P, Sommerer F, Benicke M, Uhlmann D, et al. Identification of novel proteins associated with hepatocellular carcinomas using protein microarrays. J Pathol. 2003;201:238–49.
32. Kohga K, Takehara T, Tatsumi T, Ishida H, Miyagi T, Hosui A, et al. Sorafenib inhibits the shedding of major histocompatibility complex class I-related chain A on hepatocellular carcinoma cells by down-regulating a disintegrin and metalloproteinase 9. Hepatology. 2010;51:1264–73.
33. Mazzocca A, Coppari R, De Franco R, Cho J-Y, Libermann TA, Pinzani M, et al. A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions. Cancer Res. 2005;65:4728–38.
34. Geisler F, Nagl F, Mazur PK, Lee M, Zimber-Strobl U, Strobl LJ, et al. Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology. 2008;48:607–16.
35. Sparks EE, Huppert KA, Brown MA, Washington MK, Huppert SS. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology. 2010;51:1391–400.
36. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A et al., Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997;16:235–42.
37. Müller M, Wetzel S, Köhn-Gaone J, Chalupsky K, Lüllmann-Rauch R, Barikbin R, et al. A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis. Oncotarget. 2016;7:17431–41.
38. Bourd-Boittin K, Basset L, Bonnier D, L’helgoualc’h A, Samson M, Théret N. CX3CL1/fractalkine shedding by human hepatic stellate cells: Contribution to chronic inflammation in the liver. J Cell Mol Med. 2009;13:1526–35.
39. Kohga K, Takehara T, Tatsumi T, Miyagi T, Ishida H, Ohkawa K, et al. Anticancer chemotherapy inhibits MHC class I-related chain a ectodomain shedding by downregulating ADAM10 expression in hepatocellular carcinoma. Cancer Res. 2009;69:8050–7.
40. Yuan S, Lei S, Wu S. ADAM10 is overexpressed in human hepatocellular carcinoma and contributes to the proliferation, invasion and migration of HepG2 cells. Oncol Rep. 2013;30:1715–22.
41. Chalupský K, Kanchev I, Žbodáková O, Buryová H, Jiroušková M, Ko?ínek V, et al. ADAM10/17-dependent release of soluble c-Met correlates with hepatocellular damage. Folia Biol (Praha) 2013;59:76–86.
42. Zhang Y-W, Graveel C, Shinomiya N, Vande Woude GF. Met decoys: Will cancer take the bait? Cancer Cell. 2004;6:5–6.
43. Gavert N, Sheffer M, Raveh S, Spaderna S, Shtutman M, Brabletz T, et al. Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis. Cancer Res. 2007;67:7703–12.
44. Kopitz C, Gerg M, Bandapalli OR, Ister D, Pennington CJ, Hauser S, et al. Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling. Cancer Res. 2007;67:8615–23.
45. Schelter F, Grandl M, Seubert B, Schaten S, Hauser S, Gerg M, et al. Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10. Clin Exp Metastasis. 2011;28:793–802.
46. Grünwald B, Harant V, Schaten S, Frühschütz M, Spallek R, Höchst B et al., Pancreatic premalignant lesions secrete tissue inhibitor of metalloproteinases-1, which activates hepatic stellate cells via CD63 signaling to create a premetastatic niche in the liver. Gastroenterology. 2016;151:1011–24.e7.
47. Nyren-Erickson EK, Jones JM, Srivastava D, Mallik S. A disintegrin and metalloproteinase-12 ADAM12): Function, roles in disease progression, and clinical implications Biochim Biophys Acta. 2013;1830:4445–55.
48. Daduang J, Limpaiboon T, Daduang S. Biomarker to distinguish hepatocellular carcinoma from cholangiocarcinoma by serum a disintegrin and metalloprotease 12. Arch Med Sci. 2011;7:1013–16.
49. Fang T, Lin J, Wang Y, Chen G, Huang J, Chen J, et al. Tetraspanin-8 promotes hepatocellular carcinoma metastasis by increasing ADAM12m expression. Oncotarget. 2016;7:40630–43.
50. He G, Dhar D, Nakagawa H, Font-Burgada J, Ogata H, Jiang Y, et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell. 2013;155:384–96.
51. Argast GM, Campbell JS, Brooling JT, Fausto N. Epidermal growth factor receptor transactivation mediates tumor necrosis factor-induced hepatocyte replication. J Biol Chem. 2004;279:34530–6.
52. Murillo MM, del Castillo G, Sánchez A, Fernández M, Fabregat I. Involvement of EGF receptor and c-Src in the survival signals induced by TGF-beta1 in hepatocytes. Oncogene. 2005;24:4580–7.
53. Li Y, Ren Z, Wang Y, Dang Y-Z, Meng B-X, Wang G-D, et al. ADAM17 promotes cell migration and invasion through the integrin ?1 pathway in hepatocellular carcinoma. Exp Cell Res. 2018;370:373–82.
54. Wang R, Li Y, Tsung A, Huang H, Du Q, Yang M, et al. iNOS promotes CD24+, CD133+ liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway. Proc Natl Acad Sci U S A. 2018;115:E10127–36.
55. Hong SW, Hur W, Choi JE, Kim J-H, Hwang D, Yoon SK. Role of ADAM17 in invasion and migration of CD133-expressing liver cancer stem cells after irradiation. Oncotarget. 2016;7:23482–97.
56. Lu J, Ye X, Fan F, Xia L, Bhattacharya R, Bellister S, et al. Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell. 2013;23:171–85.
57. Bergmann J, Müller M, Baumann N, Reichert M, Heneweer C, Bolik J, et al. IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology. 2017;65:89–103.
58. Kelwick R, Desanlis I, Wheeler GN, Edwards DR. The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family. Genome Biol. 2015;16:113.
59. Stanton H, Melrose J, Little CB, Fosang AJ. Proteoglycan degradation by the ADAMTS family of proteinases. Biochim Biophys Acta. 2011;1812:1616–29.
60. Gerhardt S, Hassall G, Hawtin P, McCall E, Flavell L, Minshull C, et al. Crystal structures of human ADAMTS-1 reveal a conserved catalytic domain and a disintegrin-like domain with a fold homologous to cysteine-rich domains. J Mol Biol. 2007;373:891–902.
61. Bourd-Boittin K, Bonnier D, Leyme A, Mari B, Tuffery P, Samson M, et al. Protease profiling of liver fibrosis reveals the ADAM metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of transforming growth factor beta. Hepatology. 2011;54:2173–84.
62. Colige A, Sieron AL, Li SW, Schwarze U, Petty E, Wertelecki W, et al. Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene. Am J Hum Genet. 1999;65:308–17.
63. Kesteloot F, Desmoulière A, Leclercq I, Thiry M, Arrese JE, Prockop DJ, et al. ADAM metallopeptidase with thrombospondin type 1 motif 2 inactivation reduces the extent and stability of carbon tetrachloride-induced hepatic fibrosis in mice. Hepatology. 2007;46:1620–31.
64. Sadler JE. von Willebrand factor assembly and secretion. J Thromb Haemost. 2009;7 Suppl 1:24–7.
65. Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood. 2008;112:11–18.
66. Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413:488–94.
67. Zheng XL. ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic purpura. Annu Rev Med. 2015;66:211–25.
68. Bianchi V, Robles R, Alberio L, Furlan M, Lämmle B. Von Willebrand factor-cleaving protease ADAMTS13) in thrombocytopenic disorders: A severely deficient activity is specific for thrombotic thrombocytopenic purpura. Blood. 2002;100:710–13.
69. Ono T, Mimuro J, Madoiwa S, Soejima K, Kashiwakura Y, Ishiwata A, et al. Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: Its correlation with development of renal failure. Blood. 2006;107:528–34.
70. Azfar MF, Khan MF, Habib SS, Aseri ZA, Zubaidi AM, Aguila DO, et al. Prognostic value of ADAMTS13 in patients with severe sepsis and septic shock. Clin Invest Med. 2017;40:E49–58.
71. Levy GG, Motto DG, Ginsburg D. ADAMTS13 turns 3. Blood. 2005;106:11–17.
72. Uemura M, Matsuyama T, Ishikawa M, Fujimoto M, Kojima H, Sakurai S, et al. Decreased activity of plasma ADAMTS13 may contribute to the development of liver disturbance and multiorgan failure in patients with alcoholic hepatitis. Alcohol Clin Exp Res. 2005;29:264S–271S.
73. Hugenholtz GCG, Adelmeijer J, Meijers JCM, Porte RJ, Stravitz RT, Lisman T. An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: Implications for hemostasis and clinical outcome. Hepatology. 2013;58:752–61.
74. Uemura M, Tatsumi K, Matsumoto M, Fujimoto M, Matsuyama T, Ishikawa M, et al. Localization of ADAMTS13 to the stellate cells of human liver. Blood. 2005;106:922–4.
75. Niiya M, Uemura M, Zheng XW, Pollak ES, Dockal M, Scheiflinger F, et al. Increased ADAMTS-13 proteolytic activity in rat hepatic stellate cells upon activation in vitro and in vivo. J Thromb Haemost. 2006;4:1063–70.
76. Lisman T, Bongers TN, Adelmeijer J, Janssen HLA, de Maat MPM, de Groot PG, et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology. 2006;44:53–61.
77. Mannucci PM, Canciani MT, Forza I, Lussana F, Lattuada A, Rossi E. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood. 2001;98:2730–5.
78. Uemura M, Fujimura Y, Matsumoto M, Ishizashi H, Kato S, Matsuyama T, et al. Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis. Thromb Haemost. 2008;99:1019–29.
79. Lancellotti S, Basso M, Veca V, Sacco M, Riccardi L, Pompili M, et al. Presence of portal vein thrombosis in liver cirrhosis is strongly associated with low levels of ADAMTS-13: A pilot study. Intern Emerg Med. 2016;11:959–67.
80. Potze W, Siddiqui MS, Boyett SL, Adelmeijer J, Daita K, Sanyal AJ, et al. Preserved hemostatic status in patients with non-alcoholic fatty liver disease. J Hepatol. 2016;65:980–7.
81. Moss ML, Sklair-Tavron L, Nudelman R. Drug insight: Tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis Nat Clin Pract Rheumatol. 2008;4:300–9.

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