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Gene Review

KRT4  -  keratin 4, type II

Homo sapiens

Synonyms: CK-4, CK4, CYK4, Cytokeratin-4, K4, ...
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Disease relevance of KRT4


High impact information on KRT4


Chemical compound and disease context of KRT4


Biological context of KRT4

  • Mutation analysis revealed a heterozygous missense mutation 1345G-->A in KRT4, predicting an amino acid change, E449K, in the 2B domain of the K4 polypeptide [12].
  • Allelic variations of human keratins K4 and K5 provide polymorphic markers within the type II keratin gene cluster on chromosome 12 [13].
  • The genes for human cytokeratins 4 and 15 (KRT4 and 15) are assigned to the p11.2----q12 region of chromosome 12 (cytokeratin 4) and to the q21----q23 region of chromosome 17 (cytokeratin 15), respectively [14].
  • A panel of K4 promoter deletions were found in transient transfection assays to be predominantly active in esophageal and corneal cell lines [15].
  • The extended substrate specificity profiles are in good agreement with known substrate cleavage sites but also in accord with experimentally solved (hK4, hK6, and hK7) or modeled structures [16].

Anatomical context of KRT4


Associations of KRT4 with chemical compounds

  • Of all known proteins, the context of the K8 S73 motif (LLS/TPL) is unique to type II keratins and is conserved in epidermal K5/K6, esophageal K4, and type II hair keratins, except that serine is replaced by threonine [22].
  • Starting from the X-ray crystallographic structure of HPg K4 and the intermolecular 1H-NMR NOE data, two models of the K2 lysine binding site complexed to 6-AHA have been derived which differ mainly in the extent of electrostatic pairing between the K2 Arg56 and Glu57 side chains [23].
  • Reverse transcription-polymerase chain reaction experiments showed that the K4 expression was the one most overtly induced by 2 wk of open treatment with 0.05% of retinoic acid and tazarotene [24].
  • Finally, a dose-response study showed that the de novo appearance of K4 can be utilized as a sensitive test for retinoid bioactivity in epidermis in vivo [24].
  • As is the case for the HPg K1, K4, and K5, among the tested ligands, AMCHA is the one which interacts most firmly with r-K2 (Ka approximately 7.3 mM-1) while the aromatic ligands BASA, benzylamine, and benzamidine exhibit Ka values of approximately 4.0, approximately 0.04, and approximately 0.03 mM-1, respectively [23].

Regulatory relationships of KRT4


Other interactions of KRT4

  • OBJECTIVES: To search for possible mutations in KRT4 and KRT13 [12].
  • In order to understand transcriptional regulatory mechanisms mediated by ELF3, we investigated its effect on the human keratin 4 gene promoter based upon the role of keratin 4 in early differentiation of the esophageal squamous epithelium [27].
  • CK4 and CK16 were not found in the placenta [28].
  • These cells were also immunoreactive with K 4 and K 10 MoAbs [29].
  • Using real-time quantitative polymerase chain reaction (TaqMan) and normalization of the mRNA values to beta-actin, the increase in K4 was found to be 100-1000-fold [24].

Analytical, diagnostic and therapeutic context of KRT4

  • Subchromosomal localization of two human cytokeratin genes (KRT4 and KRT15) by in situ hybridization [14].
  • Sequence analysis revealed a 3 bp (ACA) heterozygous insertion localized in the helix initiation motif of the 1A alpha helical domain of K4 [1].
  • Extraction, two-dimensional electrophoresis and western blotting showed that this transitional JE during eruption also contained CK 6, 16 and perhaps CK 4 [30].
  • In addition to detailed mapping of the KLK4 mRNA 5' end by RT-PCR, this conclusion is supported by predominantly nuclear localization of the hK4 protein in the cell, documented by both immunofluorescence and cell fractionation experiments [9].
  • The binding of alpha-, omega-amino acids, which are important effectors of human plasminogen activation, to the isolated kringle 4 (K4) peptide region of this protein has been investigated by high sensitivity titration calorimetry [31].


  1. A glutamine insertion in the 1A alpha helical domain of the keratin 4 gene in a familial case of white sponge nevus. Terrinoni, A., Candi, E., Oddi, S., Gobello, T., Camaione, D.B., Mazzanti, C., Zambruno, G., Knight, R., Melino, G. J. Invest. Dermatol. (2000) [Pubmed]
  2. Cytokeratin subsets for distinguishing Barrett's esophagus from intestinal metaplasia in the cardia using endoscopic biopsy specimens. El-Zimaity, H.M., Graham, D.Y. Am. J. Gastroenterol. (2001) [Pubmed]
  3. Sinonasal undifferentiated carcinoma, nasopharyngeal-type undifferentiated carcinoma, and keratinizing and nonkeratinizing squamous cell carcinoma express different cytokeratin patterns. Franchi, A., Moroni, M., Massi, D., Paglierani, M., Santucci, M. Am. J. Surg. Pathol. (2002) [Pubmed]
  4. The cytokeratin profile of medullary carcinoma of the breast. Tot, T. Histopathology (2000) [Pubmed]
  5. Differential expression of the keratin-4, -13, -14, -17 and transglutaminase 3 genes during the development of oral squamous cell carcinoma from leukoplakia. Ohkura, S., Kondoh, N., Hada, A., Arai, M., Yamazaki, Y., Sindoh, M., Takahashi, M., Matsumoto, I., Yamamoto, M. Oral Oncol. (2005) [Pubmed]
  6. A mutation in the mucosal keratin K4 is associated with oral white sponge nevus. Rugg, E.L., McLean, W.H., Allison, W.E., Lunny, D.P., Macleod, R.I., Felix, D.H., Lane, E.B., Munro, C.S. Nat. Genet. (1995) [Pubmed]
  7. An ECT2-centralspindlin complex regulates the localization and function of RhoA. Yüce, O., Piekny, A., Glotzer, M. J. Cell Biol. (2005) [Pubmed]
  8. CYK-4: A Rho family gtpase activating protein (GAP) required for central spindle formation and cytokinesis. Jantsch-Plunger, V., Gönczy, P., Romano, A., Schnabel, H., Hamill, D., Schnabel, R., Hyman, A.A., Glotzer, M. J. Cell Biol. (2000) [Pubmed]
  9. Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer. Xi, Z., Klokk, T.I., Korkmaz, K., Kurys, P., Elbi, C., Risberg, B., Danielsen, H., Loda, M., Saatcioglu, F. Cancer Res. (2004) [Pubmed]
  10. Marker profile of different phases in the transition of normal human ovarian epithelium to ovarian carcinomas. van Niekerk, C.C., Boerman, O.C., Ramaekers, F.C., Poels, L.G. Am. J. Pathol. (1991) [Pubmed]
  11. Human kallikrein 4 (KLK4) is highly expressed in serous ovarian carcinomas. Dong, Y., Kaushal, A., Bui, L., Chu, S., Fuller, P.J., Nicklin, J., Samaratunga, H., Clements, J.A. Clin. Cancer Res. (2001) [Pubmed]
  12. A novel mutation in the keratin 4 gene causing white sponge naevus. Chao, S.C., Tsai, Y.M., Yang, M.H., Lee, J.Y. Br. J. Dermatol. (2003) [Pubmed]
  13. Allelic variations of human keratins K4 and K5 provide polymorphic markers within the type II keratin gene cluster on chromosome 12. Wanner, R., Förster, H.H., Tilmans, I., Mischke, D. J. Invest. Dermatol. (1993) [Pubmed]
  14. Subchromosomal localization of two human cytokeratin genes (KRT4 and KRT15) by in situ hybridization. Barletta, C., Batticane, N., Ragusa, R.M., Leube, R., Peschle, C., Romano, V. Cytogenet. Cell Genet. (1990) [Pubmed]
  15. Transcriptional regulation of the differentiation-linked human K4 promoter is dependent upon esophageal-specific nuclear factors. Opitz, O.G., Jenkins, T.D., Rustgi, A.K. J. Biol. Chem. (1998) [Pubmed]
  16. Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences. Debela, M., Magdolen, V., Schechter, N., Valachova, M., Lottspeich, F., Craik, C.S., Choe, Y., Bode, W., Goettig, P. J. Biol. Chem. (2006) [Pubmed]
  17. Molecular characterization and expression of the stratification-related cytokeratins 4 and 15. Leube, R.E., Bader, B.L., Bosch, F.X., Zimbelmann, R., Achtstaetter, T., Franke, W.W. J. Cell Biol. (1988) [Pubmed]
  18. The promoter of the HaCaT keratinocyte differentiation-related gene keratin 4 contains a functional AP-2 binding site. Wanner, R., Zhang, J., Dorbic, T., Mischke, D., Henz, B.M., Wittig, B., Rosenbach, T. Arch. Dermatol. Res. (1997) [Pubmed]
  19. In situ hybridization study of cytokeratin 4, 13, 16 and 19 mRNAs in human developing junctional epithelium. Feghali-Assaly, M., Sawaf, M.H., Ouhayoun, J.P. Eur. J. Oral Sci. (1997) [Pubmed]
  20. Allele frequencies and segregation of human polymorphic keratins K4 and K5. Mischke, D., Wille, G., Wild, A.G. Am. J. Hum. Genet. (1990) [Pubmed]
  21. Intermediate filaments as differentiation markers of normal pancreas and pancreas cancer. Schüssler, M.H., Skoudy, A., Ramaekers, F., Real, F.X. Am. J. Pathol. (1992) [Pubmed]
  22. Type II keratins are phosphorylated on a unique motif during stress and mitosis in tissues and cultured cells. Toivola, D.M., Zhou, Q., English, L.S., Omary, M.B. Mol. Biol. Cell (2002) [Pubmed]
  23. Ligand preferences of kringle 2 and homologous domains of human plasminogen: canvassing weak, intermediate, and high-affinity binding sites by 1H-NMR. Marti, D.N., Hu, C.K., An, S.S., von Haller, P., Schaller, J., Llinás, M. Biochemistry (1997) [Pubmed]
  24. Keratin 4 upregulation by retinoic acid in vivo: a sensitive marker for retinoid bioactivity in human epidermis. Virtanen, M., Törmä, H., Vahlquist, A. J. Invest. Dermatol. (2000) [Pubmed]
  25. Multi-layered periodontal pocket epithelium reconstituted in vitro: histology and cytokeratin profiles. Papaioannou, W., Cassiman, J.J., Van den Oord, J., De Vos, R., van Steenberghe, D., Quirynen, M. J. Periodontol. (1999) [Pubmed]
  26. Retinoic acid affects the expression rate of the differentiation-related genes aryl hydrocarbon receptor, ARNT and keratin 4 in proliferative keratinocytes only. Wanner, R., Panteleyev, A., Henz, B.M., Rosenbach, T. Biochim. Biophys. Acta (1996) [Pubmed]
  27. Dual function of the epithelial specific ets transcription factor, ELF3, in modulating differentiation. Brembeck, F.H., Opitz, O.G., Libermann, T.A., Rustgi, A.K. Oncogene (2000) [Pubmed]
  28. Differentiation of human trophoblast populations involves alterations in cytokeratin patterns. Mühlhauser, J., Crescimanno, C., Kasper, M., Zaccheo, D., Castellucci, M. J. Histochem. Cytochem. (1995) [Pubmed]
  29. 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]
  30. Cytokeratin profile of the junctional epithelium in partially erupted teeth. Feghali-Assaly, M., Sawaf, M.H., Serres, G., Forest, N., Ouhayoun, J.P. J. Periodont. Res. (1994) [Pubmed]
  31. Thermodynamic properties of the binding of alpha-, omega-amino acids to the isolated kringle 4 region of human plasminogen as determined by high sensitivity titration calorimetry. Sehl, L.C., Castellino, F.J. J. Biol. Chem. (1990) [Pubmed]
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