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Gene Review

KRT18  -  keratin 18, type I

Homo sapiens

Synonyms: CK-18, CYK18, Cell proliferation-inducing gene 46 protein, Cytokeratin-18, K18, ...
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Disease relevance of KRT18

  • We recently described transgenic mice that express point-mutant human K18 (Ku, N.-O., S. Michie, R.G. Oshima, and M.B. Omary. 1995. J. Cell Biol. 131:1303-1314) and develop chronic hepatitis and hepatocyte fragility in association with hepatocyte keratin filament disruption [1].
  • Mutation of human keratin 18 in association with cryptogenic cirrhosis [2].
  • Studies of liver explants from a large cohort of U.S. patients showed that K8/K18 mutations confer a risk to developing end-stage liver diseases, though which diseases are preferentially involved is unknown [3].
  • Anti-CK18 antibodies reduced the binding and internalization of 125I-TAT by rat hepatoma cells [4].
  • To study molecular changes, K8 and K18 were purified from surgically removed colon cancer and normal epithelia tissues [5].
  • Docetaxel induced increased levels of caspase-cleaved CK18 in serum from breast cancer patients, indicating apoptosis [6].

Psychiatry related information on KRT18


High impact information on KRT18

  • We have previously described a mutation in the keratin 18 gene in a patient with cryptogenic cirrhosis, but the importance of mutations in the keratin 8 and keratin 18 genes in such patients is unclear [10].
  • To identify potential regulatory elements of the human K18 gene, various recombinant constructions were expressed in cultured cells [11].
  • Three neoplastic cell lines (colonic and esophageal) with varying degrees of expression of cytokeratin-18 were used [12].
  • An immunocytochemical assay for the epithelial cytokeratin protein (CK18) may fill this gap since it is a feature of epithelial cells but would not normally be in bone marrow [13].
  • In addition, both caspase-3 activation and K18 cleavage was inhibited by expression of DEDDDeltaNLS1-3, a cytosolic form of DEDD that cannot be ubiquitinated [14].

Chemical compound and disease context of KRT18


Biological context of KRT18

  • Our data demonstrate that a KRT18-driven expression vector delivered systemically can target gene expression to CF-affected tissues, despite an uneven distribution of plasmid DNA [20].
  • We delivered a KRT18-driven lacZ plasmid complexed with cationic liposomes intravenously to mice and examined expression in various tissues [20].
  • Dynamics of human keratin 18 phosphorylation: polarized distribution of phosphorylated keratins in simple epithelial tissues [21].
  • In addition, ser52 of human K18 is a highly dynamic phosphorylation site that undergoes modulation during the S and G2/M phases of the cell cycle in association with filament reorganization [21].
  • We have now identified human TNF receptor type 1 (TNFR1)-associated death domain protein (TRADD) to be the K18-interacting protein [22].

Anatomical context of KRT18

  • Endogenous TRADD coimmunoprecipitated with K18, and colocalized with K8/18 filaments in human mammary epithelial cells [22].
  • In contrast to other cytokeratins, K8 and K18 are persistently expressed during malignant transformation, but changes in cell morphology are accompanied by alterations in the intermediate filament network [5].
  • Cytokeratin 18 is expressed on the hepatocyte plasma membrane surface and interacts with thrombin-antithrombin complexes [4].
  • The cancer-associated forms of K8 and K18 are specifically recognized by the human antibody, COU-1, cloned from the B cells of a cancer patient [5].
  • Northern analysis detected CK 18 mRNA in extracts from 2/4 astrocytic cell lines [23].

Associations of KRT18 with chemical compounds

  • Using chemical analysis, the stoichiometry of glycosylation was found to be 1.5 and 2 molecules of N-acetylglucosamine/protein molecule of CK8 and CK18, respectively [24].
  • Acid hydrolysis of CK8 and CK18, purified from [3H]glucosamine-labeled cells, generated free glucosamine [24].
  • Transfection of K8 Ser-73 --> Ala or K8 Ser-73 --> Asp with K18 generates normal-appearing filaments [25].
  • In this system we used a human cytokeratin 18 expression cassette to drive epithelium-specific expression of the reverse tetracycline transactivator (rtTA), which turns on CFTR expression from a Tet-inducible promoter in the presence of doxycycline [26].
  • The majority of luminal cells expressed K18(++), but colocalization of K5+/18(++) were recognized [27].

Physical interactions of KRT18

  • The COOH-terminal region of TRADD interacted with the coil Ia of the rod domain of K18 [22].
  • Using surface plasmon resonance, the affinity of COU-1 for this epitope was determined to be 10(9) x m(-1), i.e. more than 2 orders of magnitude higher than for intact heterotypic K8/K18 complexes [5].
  • However, when K8 or K18 bound to nitrocellulose were incubated with complementary keratin they became reactive with this antibody [28].

Enzymatic interactions of KRT18


Regulatory relationships of KRT18


Other interactions of KRT18

  • Among IF proteins tested in two-hybrid systems, TRADD specifically bound K18 and K14, type I (acidic) keratins [22].
  • The four remaining patients had mutations at one K8 and three other K18 new sites [15].
  • In immortalized cells, which are preneoplastic or partially transformed, the levels of K5 mRNA and protein are lower than in normal cells, whereas the amount of K18 is increased [34].
  • In contrast, in both AC and ASC, the CK18 protein was diffusely distributed within the cytoplasm, and DP showed both membranous and cytoplasmic localization [35].
  • Immunofluorescence analysis revealed the expression of albumin (ALB) and cytokeratin-18 (CK-18) [36].

Analytical, diagnostic and therapeutic context of KRT18


  1. Susceptibility to hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant. Ku, N.O., Michie, S.A., Soetikno, R.M., Resurreccion, E.Z., Broome, R.L., Oshima, R.G., Omary, M.B. J. Clin. Invest. (1996) [Pubmed]
  2. Mutation of human keratin 18 in association with cryptogenic cirrhosis. Ku, N.O., Wright, T.L., Terrault, N.A., Gish, R., Omary, M.B. J. Clin. Invest. (1997) [Pubmed]
  3. Keratin variants associate with progression of fibrosis during chronic hepatitis C infection. Strnad, P., Lienau, T.C., Tao, G.Z., Lazzeroni, L.C., Stickel, F., Schuppan, D., Omary, M.B. Hepatology (2006) [Pubmed]
  4. Cytokeratin 18 is expressed on the hepatocyte plasma membrane surface and interacts with thrombin-antithrombin complexes. Wells, M.J., Hatton, M.W., Hewlett, B., Podor, T.J., Sheffield, W.P., Blajchman, M.A. J. Biol. Chem. (1997) [Pubmed]
  5. Cancer-associated cleavage of cytokeratin 8/18 heterotypic complexes exposes a neoepitope in human adenocarcinomas. Ditzel, H.J., Strik, M.C., Larsen, M.K., Willis, A.C., Waseem, A., Kejling, K., Jensenius, J.C. J. Biol. Chem. (2002) [Pubmed]
  6. Cytokeratin-18 is a useful serum biomarker for early determination of response of breast carcinomas to chemotherapy. Olofsson, M.H., Ueno, T., Pan, Y., Xu, R., Cai, F., van der Kuip, H., Muerdter, T.E., Sonnenberg, M., Aulitzky, W.E., Schwarz, S., Andersson, E., Shoshan, M.C., Havelka, A.M., Toi, M., Linder, S. Clin. Cancer Res. (2007) [Pubmed]
  7. Does the immunocytochemical detection of epithelial cells in bone marrow (micrometastasis) influence the time to biochemical relapse after radical prostatectomy? Weckermann, D., Wawroschek, F., Krawczak, G., Haude, K.H., Harzmann, R. Urol. Res. (1999) [Pubmed]
  8. Differentiation between cell death modes using measurements of different soluble forms of extracellular cytokeratin 18. Kramer, G., Erdal, H., Mertens, H.J., Nap, M., Mauermann, J., Steiner, G., Marberger, M., Bivén, K., Shoshan, M.C., Linder, S. Cancer Res. (2004) [Pubmed]
  9. An immunohistochemical study of the clearance of apoptotic cellular fragments. Leers, M.P., Björklund, V., Björklund, B., Jörnvall, H., Nap, M. Cell. Mol. Life Sci. (2002) [Pubmed]
  10. Keratin 8 mutations in patients with cryptogenic liver disease. Ku, N.O., Gish, R., Wright, T.L., Omary, M.B. N. Engl. J. Med. (2001) [Pubmed]
  11. Activation of an intron enhancer within the keratin 18 gene by expression of c-fos and c-jun in undifferentiated F9 embryonal carcinoma cells. Oshima, R.G., Abrams, L., Kulesh, D. Genes Dev. (1990) [Pubmed]
  12. Micrometastases in bone marrow of patients undergoing "curative" surgery for gastrointestinal cancer. O'Sullivan, G.C., Collins, J.K., O'Brien, F., Crowley, B., Murphy, K., Lee, G., Shanahan, F. Gastroenterology (1995) [Pubmed]
  13. Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients. Lindemann, F., Schlimok, G., Dirschedl, P., Witte, J., Riethmüller, G. Lancet (1992) [Pubmed]
  14. DEDD regulates degradation of intermediate filaments during apoptosis. Lee, J.C., Schickling, O., Stegh, A.H., Oshima, R.G., Dinsdale, D., Cohen, G.M., Peter, M.E. J. Cell Biol. (2002) [Pubmed]
  15. Keratin 8 and 18 mutations are risk factors for developing liver disease of multiple etiologies. Ku, N.O., Darling, J.M., Krams, S.M., Esquivel, C.O., Keeffe, E.B., Sibley, R.K., Lee, Y.M., Wright, T.L., Omary, M.B. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  16. Expression of basal cell keratins in human prostate cancer metastases and cell lines. van Leenders, G.J., Aalders, T.W., Hulsbergen-van de Kaa, C.A., Ruiter, D.J., Schalken, J.A. J. Pathol. (2001) [Pubmed]
  17. Rescue of {Delta}F508-CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) by Curcumin: Involvement of the Keratin 18 Network. Lipecka, J., Norez, C., Bensalem, N., Baudouin-Legros, M., Planelles, G., Becq, F., Edelman, A., Davezac, N. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  18. Simple epithelial keratins are dispensable for cytoprotection in two pancreatitis models. Toivola, D.M., Baribault, H., Magin, T., Michie, S.A., Omary, M.B. Am. J. Physiol. Gastrointest. Liver Physiol. (2000) [Pubmed]
  19. Immunohistochemistry with keratin, vimentin, desmin, and alpha-smooth muscle actin monoclonal antibodies in canine mammary gland: malignant mammary tumours. Vos, J.H., van den Ingh, T.S., Misdorp, W., Molenbeek, R.F., van Mil, F.N., Rutteman, G.R., Ivanyi, D., Ramaekers, F.C. The Veterinary quarterly. (1993) [Pubmed]
  20. Targeting transgene expression for cystic fibrosis gene therapy. Koehler, D.R., Hannam, V., Belcastro, R., Steer, B., Wen, Y., Post, M., Downey, G., Tanswell, A.K., Hu, J. Mol. Ther. (2001) [Pubmed]
  21. Dynamics of human keratin 18 phosphorylation: polarized distribution of phosphorylated keratins in simple epithelial tissues. Liao, J., Lowthert, L.A., Ku, N.O., Fernandez, R., Omary, M.B. J. Cell Biol. (1995) [Pubmed]
  22. Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD. Inada, H., Izawa, I., Nishizawa, M., Fujita, E., Kiyono, T., Takahashi, T., Momoi, T., Inagaki, M. J. Cell Biol. (2001) [Pubmed]
  23. Keratin intermediate filament expression in astrocytic neoplasms: analysis by immunocytochemistry, western blot, and northern hybridization. Cosgrove, M.M., Rich, K.A., Kunin, S.A., Sherrod, A.E., Martin, S.E. Mod. Pathol. (1993) [Pubmed]
  24. Characterization and dynamics of O-linked glycosylation of human cytokeratin 8 and 18. Chou, C.F., Smith, A.J., Omary, M.B. J. Biol. Chem. (1992) [Pubmed]
  25. Keratin 8 phosphorylation by p38 kinase regulates cellular keratin filament reorganization: modulation by a keratin 1-like disease causing mutation. Ku, N.O., Azhar, S., Omary, M.B. J. Biol. Chem. (2002) [Pubmed]
  26. Regulated expression of the human CFTR gene in epithelial cells. Ye, L., Chan, S., Chow, Y.H., Tsui, L.C., Hu, J. Mol. Ther. (2001) [Pubmed]
  27. Demonstration of intermediate cells during human prostate epithelial differentiation in situ and in vitro using triple-staining confocal scanning microscopy. van Leenders, G., Dijkman, H., Hulsbergen-van de Kaa, C., Ruiter, D., Schalken, J. Lab. Invest. (2000) [Pubmed]
  28. A keratin antibody recognizing a heterotypic complex: epitope mapping to complementary locations on both components of the complex. Waseem, A., Lane, E.B., Harrison, D., Waseem, N. Exp. Cell Res. (1996) [Pubmed]
  29. Nuclear matrix-intermediate filament system and its alteration in adenovirus infected HeLa cell. Zhai, Z.H., Wang, X., Qian, X.Y. Cell Biol. Int. Rep. (1988) [Pubmed]
  30. Epithelium-specific ets transcription factor 2 upregulates cytokeratin 18 expression in pulmonary epithelial cells through an interaction with cytokeratin 18 intron 1. Yaniw, D., Hu, J. Cell Res. (2005) [Pubmed]
  31. Increased levels of IgA antibodies to cytokeratin-18 and epidermal keratin in rheumatoid arthritis. Borg, A.A., Dawes, P.T., Mattey, D.L. Arthritis Rheum. (1993) [Pubmed]
  32. Expression, glycosylation, and phosphorylation of human keratins 8 and 18 in insect cells. Ku, N.O., Omary, M.B. Exp. Cell Res. (1994) [Pubmed]
  33. In vivo observation of a nuclear channel-like system: evidence for a distinct interchromosomal domain compartment in interphase cells. Reichenzeller, M., Burzlaff, A., Lichter, P., Herrmann, H. J. Struct. Biol. (2000) [Pubmed]
  34. Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells. Trask, D.K., Band, V., Zajchowski, D.A., Yaswen, P., Suh, T., Sager, R. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  35. Differential expression and biodistribution of cytokeratin 18 and desmoplakins in non-small cell lung carcinoma subtypes. Young, G.D., Winokur, T.S., Cerfolio, R.J., Van Tine, B.A., Chow, L.T., Okoh, V., Garver, R.I. Lung Cancer (2002) [Pubmed]
  36. Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. Baharvand, H., Hashemi, S.M., Kazemi Ashtiani, S., Farrokhi, A. Int. J. Dev. Biol. (2006) [Pubmed]
  37. The mechanical properties of simple epithelial keratins 8 and 18: discriminating between interfacial and bulk elasticities. Yamada, S., Wirtz, D., Coulombe, P.A. J. Struct. Biol. (2003) [Pubmed]
  38. Mutation of keratin 8 in patients with liver disease. Schöniger-Hekele, M., Petermann, D., Müller, C. J. Gastroenterol. Hepatol. (2006) [Pubmed]
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