Keratin 19 Explained

Keratin, type I cytoskeletal 19 (Keratin-19)) also known as cytokeratin-19 (CK-19) is a 40 kDa protein that in humans is encoded by the KRT19 gene.^{[1] [2]} Keratin-19 is a type I keratin.

Function

Keratin-19 is a member of the keratin family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins.

Keratin-19 is a type I keratin. The type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains. Unlike its related family members, this smallest known acidic cytokeratin is not paired with a basic cytokeratin in epithelial cells. It is specifically found in the embryonic periderm, the transiently superficial layer that envelops the developing epidermis. The type I cytokeratins are clustered in a region of chromosome 17 (q12-q21).

Use as biomarker

CYFRA 21-1, a soluble fragment of KRT19, is a tumor marker of various types of cancer, including lung, breast, stomach, pancreas, ovary. KRT19 is commonly expressed in carcinomas of these organs and CYFRA 21-1 is produced when KRT19 is cleaved during cell apoptosis.^{[3] [4]}

Due to its high sensitivity, KRT19 is the most used marker for the RT-PCR-mediated detection of tumor cells disseminated in lymph nodes, peripheral blood, and bone marrow of breast cancer patients. Depending on the assays, KRT19 has been shown to be both a specific and a non-specific marker.

False positivity in CYFRA 21-1 / KRT19 RT-PCR studies include:

• illegitimate transcription (expression of small amounts of KRT19 mRNA by tissues in which it has no real physiological role)
• haematological disorders (KRT19 induction in peripheral blood cells by cytokines and growth factors, which circulate at higher concentrations in inflammatory conditions and neutropenia)
• the presence of pseudogenes (two KRT19 pseudogenes, KRT19a and KRT19b, have been identified, which have significant sequence homology to KRT19 mRNA. Subsequently, attempts to detect the expression of the authentic KRT19 may result in the detection of either or both of these pseudogenes)
• sample contamination (introduction of contaminating epithelial cells during peripheral blood sampling for subsequent RT-PCR analysis).^[5]
• trauma and stress (such as shear stress, heat shock, toxins, infection, aging and oxidative stress such as from smoking), which increase KRT19 expression and cell apoptosis^[3]
• weight loss and muscle wasting/apoptosis (KRT19 is expressed in muscle)^[3]

Moreover, Ck-19 is widely applied as post-operative diagnostic marker of papillary thyroid carcinoma.^[6]

Keratin-19 is often used together with keratin 8 and keratin 18 to differentiate cells of epithelial origin from hematopoietic cells in tests that enumerate circulating tumor cells in blood.^[7]

Interactions

Keratin-19 has been shown to interact with Pinin.^[8]

Further reading

• Otsuka Y, Ichikawa Y, Kunisaki C, Matsuda G, Akiyama H, Nomura M, Togo S, Hayashizaki Y, Shimada H . Correlating purity by microdissection with gene expression in gastric cancer tissue . Scandinavian Journal of Clinical and Laboratory Investigation . 67 . 4 . 367–79 . 2007 . 17558891 . 10.1080/00365510601046334 . 36635804 .
• Rasmussen HH, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J . Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes . Electrophoresis . 13 . 12 . 960–9 . December 1992 . 1286667 . 10.1002/elps.11501301199 . 41855774 .
• Bader BL, Magin TM, Hatzfeld M, Franke WW . Amino acid sequence and gene organization of cytokeratin no. 19, an exceptional tail-less intermediate filament protein . The EMBO Journal . 5 . 8 . 1865–75 . August 1986 . 2428612 . 1167052 . 10.1002/j.1460-2075.1986.tb04438.x.
• Stasiak PC, Lane EB . Sequence of cDNA coding for human keratin 19 . Nucleic Acids Research . 15 . 23 . 10058 . December 1987 . 2447559 . 306562 . 10.1093/nar/15.23.10058 .
• Eckert RL . Sequence of the human 40-kDa keratin reveals an unusual structure with very high sequence identity to the corresponding bovine keratin . Proceedings of the National Academy of Sciences of the United States of America . 85 . 4 . 1114–8 . February 1988 . 2448790 . 279716 . 10.1073/pnas.85.4.1114 . 1988PNAS...85.1114E . free .
• Blumenberg M . Concerted gene duplications in the two keratin gene families . Journal of Molecular Evolution . 27 . 3 . 203–11 . 1988 . 2458477 . 10.1007/BF02100075 . 1988JMolE..27..203B . 5606956 .
• Bader BL, Jahn L, Franke WW . Low level expression of cytokeratins 8, 18 and 19 in vascular smooth muscle cells of human umbilical cord and in cultured cells derived therefrom, with an analysis of the chromosomal locus containing the cytokeratin 19 gene . European Journal of Cell Biology . 47 . 2 . 300–19 . December 1988 . 2468493 .
• Stasiak PC, Purkis PE, Leigh IM, Lane EB . Keratin 19: predicted amino acid sequence and broad tissue distribution suggest it evolved from keratinocyte keratins . The Journal of Investigative Dermatology . 92 . 5 . 707–16 . May 1989 . 2469734 . 10.1111/1523-1747.ep12721500 .
• Shezen E, Okon E, Ben-Hur H, Abramsky O . Cytokeratin expression in human thymus: immunohistochemical mapping . Cell and Tissue Research . 279 . 1 . 221–31 . Jan 1995 . 7534649 . 10.1007/BF00300707 . 23434233 .
• Milisavljevic V, Freedberg IM, Blumenberg M . Close linkage of the two keratin gene clusters in the human genome . Genomics . 34 . 1 . 134–8 . May 1996 . 8661035 . 10.1006/geno.1996.0252 . free .
• Ceratto N, Dobkin C, Carter M, Jenkins E, Yao XL, Cassiman JJ, Aly MS, Bosco P, Leube R, Langbein L, Feo S, Romano V . Human type I cytokeratin genes are a compact cluster . Cytogenetics and Cell Genetics . 77 . 3–4 . 169–74 . 1997 . 9284906 . 10.1159/000134566 .
• Kucharzik T, Lügering N, Schmid KW, Schmidt MA, Stoll R, Domschke W . Human intestinal M cells exhibit enterocyte-like intermediate filaments . Gut . 42 . 1 . 54–62 . Jan 1998 . 9505886 . 1726964 . 10.1136/gut.42.1.54 .
• Yang GP, Ross DT, Kuang WW, Brown PO, Weigel RJ . Combining SSH and cDNA microarrays for rapid identification of differentially expressed genes . Nucleic Acids Research . 27 . 6 . 1517–23 . March 1999 . 10037815 . 148347 . 10.1093/nar/27.6.1517 .
• Zhou X, Liao J, Hu L, Feng L, Omary MB . Characterization of the major physiologic phosphorylation site of human keratin 19 and its role in filament organization . The Journal of Biological Chemistry . 274 . 18 . 12861–6 . April 1999 . 10212274 . 10.1074/jbc.274.18.12861 . free.
• Salas PJ . Insoluble gamma-tubulin-containing structures are anchored to the apical network of intermediate filaments in polarized CACO-2 epithelial cells . The Journal of Cell Biology . 146 . 3 . 645–58 . August 1999 . 10444072 . 2150552 . 10.1083/jcb.146.3.645 .
• Whittock NV, Eady RA, McGrath JA . Genomic organization and amplification of the human keratin 15 and keratin 19 genes . Biochemical and Biophysical Research Communications . 267 . 1 . 462–5 . Jan 2000 . 10623642 . 10.1006/bbrc.1999.1966 .
• Shi J, Sugrue SP . Dissection of protein linkage between keratins and pinin, a protein with dual location at desmosome-intermediate filament complex and in the nucleus . The Journal of Biological Chemistry . 275 . 20 . 14910–5 . May 2000 . 10809736 . 10.1074/jbc.275.20.14910 . free.
• Brembeck FH, Rustgi AK . The tissue-dependent keratin 19 gene transcription is regulated by GKLF/KLF4 and Sp1 . The Journal of Biological Chemistry . 275 . 36 . 28230–9 . September 2000 . 10859317 . 10.1074/jbc.M004013200 . free .
• Kagaya M, Kaneko S, Ohno H, Inamura K, Kobayashi K . Cloning and characterization of the 5'-flanking region of human cytokeratin 19 gene in human cholangiocarcinoma cell line . Journal of Hepatology . 35 . 4 . 504–11 . October 2001 . 11682035 . 10.1016/S0168-8278(01)00167-2 . 2297/15681 . free .

Notes and References

1. Schweizer J, Bowden PE, Coulombe PA, Langbein L, Lane EB, Magin TM, Maltais L, Omary MB, Parry DA, Rogers MA, Wright MW . New consensus nomenclature for mammalian keratins . The Journal of Cell Biology . 174 . 2 . 169–74 . July 2006 . 16831889 . 2064177 . 10.1083/jcb.200603161 .
2. Web site: Entrez Gene: KRT19 keratin 19.
3. Variability of serum CYFRA 21 − 1 and its susceptibility to clinical characteristics in individuals without cancer: a 4-year retrospective analysis . BMC Pulm Med . 2023 . 10.1186/s12890-023-02650-x. free . 10500899 . 23 . 1 . 344 . 37705035 . Minamibata A, Kono Y, Arimoto T, Marunaka Y, Takayama K .
4. Serum CYFRA 21-1 (cytokeratin-19 fragments) is a useful tumour marker for detecting disease relapse and assessing treatment efficacy in breast cancer . 15280913 . 10.1038/sj.bjc.6602074 . 91 . 5 . 2409884 . Br J Cancer . 873–8 . Nakata B, Takashima T, Ogawa Y, Ishikawa T, Hirakawa K. 2004 .
5. Lacroix M . Significance, detection and markers of disseminated breast cancer cells . Endocrine-Related Cancer . 13 . 4 . 1033–67 . December 2006 . 17158753 . 10.1677/ERC-06-0001 . 10708900 .
6. Dinets A, Pernemalm M, Kjellin H, Sviatoha V, Sofiadis A, Juhlin CC, Zedenius J, Larsson C, Lehtiö J, Höög A . Differential protein expression profiles of cyst fluid from papillary thyroid carcinoma and benign thyroid lesions . PLOS ONE . 10 . 5 . e0126472 . May 2015 . 25978681 . 10.1371/journal.pone.0126472 . 4433121. 2015PLoSO..1026472D . free .
7. Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, Tibbe AG, Uhr JW, Terstappen LW . Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases . Clinical Cancer Research . 10 . 20 . 6897–904 . October 2004 . 15501967 . 10.1158/1078-0432.CCR-04-0378 . free .
8. Shi J, Sugrue SP . Dissection of protein linkage between keratins and pinin, a protein with dual location at desmosome-intermediate filament complex and in the nucleus . The Journal of Biological Chemistry . 275 . 20 . 14910–5 . May 2000 . 10809736 . 10.1074/jbc.275.20.14910 . free.