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Gene Review

KRT8  -  keratin 8, type II

Homo sapiens

Synonyms: CARD2, CK-8, CK8, CYK8, Cytokeratin-8, ...
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Disease relevance of KRT8

  • Also, ectopic expression of epidermal K14 in mouse liver results in chronic hepatitis, and disruption of mouse K8 leads to embryo lethality with extensive liver hemorrhage [1].
  • This moderation of the effects of TNF may be the fundamental function of K8 and K18 common to liver regeneration, inflammatory bowel disease, hepatotoxin sensitivity, and the diagnostic, persistent expression of these keratins in many carcinomas [2].
  • K8-deficient (K8(-)) mice, which escape embryonic lethality, develop inflammatory colorectal hyperplasia, mild liver abnormalities, and tolerate hepatectomy poorly [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].
  • Notably, there was a significant association of exonic, but not of intronic K8 variants with increased fibrosis [3].

Psychiatry related information on KRT8

  • Human kallikrein 8 (hK8), whose gene was originally cloned as the human ortholog of a mouse brain protease, is known to be associated with diseases such as ovarian cancer and Alzheimer's disease [4].

High impact information on KRT8


Chemical compound and disease context of KRT8


Biological context of KRT8


Anatomical context of KRT8

  • Old K18 null mice, however, developed a distinctive liver pathology with abnormal hepatocytes containing K8-positive aggregates [17].
  • We show that normal and malignant epithelial cells deficient in K8 and K18 are approximately 100 times more sensitive to TNF-induced death [2].
  • A K8 cDNA containing all coding sequences was isolated and expressed in mouse fibroblasts either singly or in combination with K18 [18].
  • 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 [19].
  • Mallory bodies (MBs) are cytoplasmic inclusions that contain keratin 8 (K8) and K18 and are present in hepatocytes of individuals with alcoholic liver disease, nonalcoholic steatohepatitis, or benign or malignant hepatocellular neoplasia [20].

Associations of KRT8 with chemical compounds


Physical interactions of KRT8

  • 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 [19].
  • We report that the MAb LE65 does not recognize individual keratin polypeptides but it instead reacts with a complex of K8 with K18 [25].
  • The plasminogen-binding site is located at the C-terminus of CK8 [26].
  • K8/18-bound grp78 can be dissociated by Mg-ATP and the association can be reconstituted in vitro using purified grp78, then redissociated again by Mg-ATP [27].
  • Normal nuclear morphology and k-8 immunofluorescence coupled with the lack of DNA laddering or other features of apoptosis indicated that K3-induced cytotoxicity, evident within 4 h of treatment and delayed but not prevented by MEK1/2 inhibition, was due to a form of stress-activated cell death known as oncosis [28].

Enzymatic interactions of KRT8

  • Furthermore, K8 was also phosphorylated on Ser-73 by JNK in vitro, yielding similar phosphopeptide maps as the in vivo phosphorylated material [29].
  • We show that K8 is strongly phosphorylated on Ser-73 upon stimulation of the pro-apoptotic cytokine receptor Fas/CD95/Apo-1 in HT-29 cells [29].
  • The kinase activity coimmunoprecipitated with CK8 and 18 and phosphorylated immunoprecipitates of the CK [30].
  • 2A proteinase of human rhinovirus cleaves cytokeratin 8 in infected HeLa cells [31].

Regulatory relationships of KRT8


Other interactions of KRT8


Analytical, diagnostic and therapeutic context of KRT8


  1. 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]
  2. Keratin-dependent, epithelial resistance to tumor necrosis factor-induced apoptosis. Caulin, C., Ware, C.F., Magin, T.M., Oshima, R.G. J. Cell Biol. (2000) [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. Activation and enzymatic characterization of recombinant human kallikrein 8. Kishi, T., Cloutier, S.M., Kündig, C., Deperthes, D., Diamandis, E.P. Biol. Chem. (2006) [Pubmed]
  5. 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]
  6. 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]
  7. Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8. Casanova, M.L., Bravo, A., Ramírez, A., Morreale de Escobar, G., Were, F., Merlino, G., Vidal, M., Jorcano, J.L. J. Clin. Invest. (1999) [Pubmed]
  8. A two-amino acid insertion in the Cys146- Cys167 loop of the alphaIIb subunit is associated with a variant of Glanzmann thrombasthenia. Critical role of Asp163 in ligand binding. Honda, S., Tomiyama, Y., Shiraga, M., Tadokoro, S., Takamatsu, J., Saito, H., Kurata, Y., Matsuzawa, Y. J. Clin. Invest. (1998) [Pubmed]
  9. 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]
  10. 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]
  11. Fulvestrant (ICI 182,780)-dependent interacting proteins mediate immobilization and degradation of estrogen receptor-alpha. Long, X., Nephew, K.P. J. Biol. Chem. (2006) [Pubmed]
  12. Monoclonal antibody mapping of keratins 8 and 17 and of vimentin in normal human mammary gland, benign tumors, dysplasias and breast cancer. Guelstein, V.I., Tchypysheva, T.A., Ermilova, V.D., Litvinova, L.V., Troyanovsky, S.M., Bannikov, G.A. Int. J. Cancer (1988) [Pubmed]
  13. Keratin 8 phosphorylation by protein kinase C delta regulates shear stress-mediated disassembly of keratin intermediate filaments in alveolar epithelial cells. Ridge, K.M., Linz, L., Flitney, F.W., Kuczmarski, E.R., Chou, Y.H., Omary, M.B., Sznajder, J.I., Goldman, R.D. J. Biol. Chem. (2005) [Pubmed]
  14. 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]
  15. Oncogenic regulation and function of keratins 8 and 18. Oshima, R.G., Baribault, H., Caulín, C. Cancer Metastasis Rev. (1996) [Pubmed]
  16. Mutation of keratin 8 in patients with liver disease. Schöniger-Hekele, M., Petermann, D., Müller, C. J. Gastroenterol. Hepatol. (2006) [Pubmed]
  17. Lessons from keratin 18 knockout mice: formation of novel keratin filaments, secondary loss of keratin 7 and accumulation of liver-specific keratin 8-positive aggregates. Magin, T.M., Schröder, R., Leitgeb, S., Wanninger, F., Zatloukal, K., Grund, C., Melton, D.W. J. Cell Biol. (1998) [Pubmed]
  18. Posttranslational regulation of keratins: degradation of mouse and human keratins 18 and 8. Kulesh, D.A., Ceceña, G., Darmon, Y.M., Vasseur, M., Oshima, R.G. Mol. Cell. Biol. (1989) [Pubmed]
  19. 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]
  20. Formation of Mallory body-like inclusions and cell death induced by deregulated expression of keratin 18. Nakamichi, I., Hatakeyama, S., Nakayama, K.I. Mol. Biol. Cell (2002) [Pubmed]
  21. Cell differentiation lineage in the prostate. Wang, Y., Hayward, S., Cao, M., Thayer, K., Cunha, G. Differentiation (2001) [Pubmed]
  22. Vimentin, cytokeratin 8 and cytokeratin 18 are not specific markers for M-cells in human palatine tonsils. Koshi, R., Mustafa, Y., Perry, M.E. J. Anat. (2001) [Pubmed]
  23. Pervanadate-mediated tyrosine phosphorylation of keratins 8 and 19 via a p38 mitogen-activated protein kinase-dependent pathway. Feng, L., Zhou, X., Liao, J., Omary, M.B. J. Cell. Sci. (1999) [Pubmed]
  24. Protein phosphatase-2A associates with and dephosphorylates keratin 8 after hyposmotic stress in a site- and cell-specific manner. Tao, G.Z., Toivola, D.M., Zhou, Q., Strnad, P., Xu, B., Michie, S.A., Omary, M.B. J. Cell. Sci. (2006) [Pubmed]
  25. Identification of a novel keratin epitope: evidence for association between non-helical sub-domains L12 during filament assembly. Waseem, A., White, K., Waseem, N.H. Int. J. Biochem. Cell Biol. (1997) [Pubmed]
  26. Characterization of the binding sites for plasminogen and tissue-type plasminogen activator in cytokeratin 8 and cytokeratin 18. Kralovich, K.R., Li, L., Hembrough, T.A., Webb, D.J., Karns, L.R., Gonias, S.L. J. Protein Chem. (1998) [Pubmed]
  27. Association of glucose-regulated protein (grp78) with human keratin 8. Liao, J., Price, D., Omary, M.B. FEBS Lett. (1997) [Pubmed]
  28. Vitamin K3 (menadione)-induced oncosis associated with keratin 8 phosphorylation and histone H3 arylation. Scott, G.K., Atsriku, C., Kaminker, P., Held, J., Gibson, B., Baldwin, M.A., Benz, C.C. Mol. Pharmacol. (2005) [Pubmed]
  29. The intermediate filament protein keratin 8 is a novel cytoplasmic substrate for c-Jun N-terminal kinase. He, T., Stepulak, A., Holmström, T.H., Omary, M.B., Eriksson, J.E. J. Biol. Chem. (2002) [Pubmed]
  30. PKC epsilon-related kinase associates with and phosphorylates cytokeratin 8 and 18. Omary, M.B., Baxter, G.T., Chou, C.F., Riopel, C.L., Lin, W.Y., Strulovici, B. J. Cell Biol. (1992) [Pubmed]
  31. 2A proteinase of human rhinovirus cleaves cytokeratin 8 in infected HeLa cells. Seipelt, J., Liebig, H.D., Sommergruber, W., Gerner, C., Kuechler, E. J. Biol. Chem. (2000) [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. The development of the intrahepatic bile ducts in man: a keratin-immunohistochemical study. Van Eyken, P., Sciot, R., Callea, F., Van der Steen, K., Moerman, P., Desmet, V.J. Hepatology (1988) [Pubmed]
  34. Unique role for the periplakin tail in intermediate filament association: specific binding to keratin 8 and vimentin. Kazerounian, S., Uitto, J., Aho, S. Exp. Dermatol. (2002) [Pubmed]
  35. Identification of trichoplein, a novel keratin filament-binding protein. Nishizawa, M., Izawa, I., Inoko, A., Hayashi, Y., Nagata, K., Yokoyama, T., Usukura, J., Inagaki, M. J. Cell. Sci. (2005) [Pubmed]
  36. 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]
  37. Proteomic profiling of cellular proteins interacting with the hepatitis C virus core protein. Kang, S.M., Shin, M.J., Kim, J.H., Oh, J.W. Proteomics (2005) [Pubmed]
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