Keratin 5 Explained

Keratin 5, also known as KRT5, K5, or CK5, is a protein that is encoded in humans by the KRT5 gene.[1] [2] [3] It dimerizes with keratin 14 and forms the intermediate filaments (IF) that make up the cytoskeleton of basal epithelial cells.[4] [5] This protein is involved in several diseases including epidermolysis bullosa simplex and breast and lung cancers.[6] [7]

Structure

Keratin 5, like other members of the keratin family, is an intermediate filament protein. These polypeptides are characterized by a 310 residue central rod domain that consists of four alpha helix segments (helix 1A, 1B, 2A, and 2B) connected by three short linker regions (L1, L1-2, and L2). The ends of the central rod domain, which are called the helix initiation motif (HIM) and the helix termination motif (HTM), are highly conserved. They are especially important for helix stabilization, heterodimer formation, and filament formation.[8] Lying on either side of the central rod are variable, non-helical head and tail regions which protrude from the IF surface and provide specificity to different IF polypeptides.

IF central rods contain heptad repeats (repeating seven residue patterns) of hydrophobic resides that allow two different IF proteins to intertwine into a coiled-coil formation via hydrophobic interactions. These heterodimers are formed between specific pairs of type I (acidic) and type II (basic) keratin. K5, a type II keratin, pairs with the type I keratin K14.[9] The coiled-coil dimers undergo stepwise assembly and combine in an antiparallel manner, forming end-to-end interactions with other coiled-coils to form large 10 nm intermediate filaments.[10]

Function

Keratin 5 (and K14) are expressed primarily in basal keratinocytes in the epidermis, specifically in the stratified epithelium lining the skin and digestive tract. Keratin intermediate filaments make up the cytoskeletal scaffold within epithelial cells, which contributes to the cell architecture and provides the cells with the ability to withstand mechanical, and non-mechanical, stresses.[11] K5/K14 keratin pairs are able to undergo extensive bundling due to the non-helical tail of K15 acting as a weak cross-linker at the intermediate filament surface. This bundling increases the elasticity, and therefore the mechanical resilience, of the intermediate filaments.

K5/K14 intermediate filaments are anchored to the desmosomes of basal cells via desmoplakin and plakophilin-1, connecting the cells to their neighbours.[12] At the hemidesmosome, plectin and BPAG1 associate with transmembrane proteins α6β4 integrin, a type of cell adhesion molecule, and BP180/collagen XVII, linking K5/K14 filaments in the basal cells to the basal lamina.

Clinical relevance

Epidermolysis bullosa simplex

Epidermolysis bullosa simplex (EBS) is an inherited skin blistering disorder associated with mutations in either K5 or K14.[13] [14] EBS-causing mutations are primarily missense mutations, but a small number of cases arise from insertions or deletions. Their mechanism of action is dominant negative interference, with the mutated keratin proteins interfering with the structure and integrity of the cytoskeleton. This cytoskeletal disorganization also leads to a loss of anchorage to the hemidesmosomes and desmosomes, causing basal cells to lose their linkage with the basal lamina and each other.

The severity of EBS has been observed to be dependent upon the position of the mutation within the protein, as well as the type of keratin (K5 or K14) that contains the mutation. Mutations that occur at either of the two 10-15 residue “hotspot” regions located on either end of the central rod domain (HIM and HTM) tend to coincide with more severe forms of EBS, whereas mutations at other spots usually result in milder symptoms. Since the “hotspot” regions contain the initiation and termination sequences of the alpha-helical rod, mutations at these spots usually have a larger effect on helix stabilization and heterodimer formation. Additionally, mutations in K5 tend to result in more severe symptoms than mutations in K14, possibly due to greater steric interference.

Cancer

Keratin 5 serves as a biomarker for several different types of cancer, including breast and lung cancers. It is often tested in conjunction with keratin 6, using CK5/6 antibodies, which target both keratin forms.[15]

Basal-like breast cancers tend to have poorer outcomes than other types of breast cancer due to a lack of targeted therapies.[16] [17] These breast cancers do not express human epidermal growth factor receptor-2 or receptors for estrogen or progesterone, making them immune to Trastuzumab/Herceptin and hormonal therapies, which are very effective against other breast cancer types. Due to the fact that K5 expression is only seen in basal cells, it serves as an important biomarker for screening patients with basal-like breast cancers to ensure that they are not receiving ineffective treatment.

Studies on lung cancer have also shown that squamous cell carcinomas give rise to tumors with elevated K5 levels, and that they are more likely to arise from stem cells expressing K5 than from those cells without K5 expression. K5 also serves as a marker of mesothelioma, and can be used to distinguish mesothelioma from pulmonary adenocarcinoma.[18] Similarly, it can be used to distinguish papilloma, which is positive for K5, from papillary carcinoma, which is K5 negative.[19] It can also serve as a marker of basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, and thymoma.

The expression of K5 is linked to the intermediate phenotype of cells undergoing the epithelial-mesenchymal transition (EMT). This process has a large role in tumor progression and metastasis since it helps enable tumor cells to travel throughout the body and colonize distant sites. K5 may therefore be useful in the identification of basal cell metastases.[20]

See also

Further reading

External links

Notes and References

  1. Web site: Entrez Gene: KRT5 keratin 5 (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types).
  2. Lersch R, Fuchs E . Sequence and expression of a type II keratin, K5, in human epidermal cells . Molecular and Cellular Biology . 8 . 1 . 486–93 . Jan 1988 . 2447486 . 363157 . 10.1128/mcb.8.1.486.
  3. Eckert RL, Rorke EA . The sequence of the human epidermal 58-kD (#5) type II keratin reveals an absence of 5' upstream sequence conservation between coexpressed epidermal keratins . DNA . 7 . 5 . 337–45 . Jun 1988 . 2456903 . 10.1089/dna.1.1988.7.337 .
  4. Chan YM, Yu QC, LeBlanc-Straceski J, Christiano A, Pulkkinen L, Kucherlapati RS, Uitto J, Fuchs E . Mutations in the non-helical linker segment L1-2 of keratin 5 in patients with Weber-Cockayne epidermolysis bullosa simplex . Journal of Cell Science . 107 . Apr 1994 . 7520042 . 4 . 765–74. 10.1242/jcs.107.4.765 .
  5. Atkinson SD, McGilligan VE, Liao H, Szeverenyi I, Smith FJ, Moore CB, McLean WH . Development of allele-specific therapeutic siRNA for keratin 5 mutations in epidermolysis bullosa simplex . The Journal of Investigative Dermatology . 131 . 10 . Oct 2011 . 21716320 . 10.1038/jid.2011.169 . 2079–86. free .
  6. Mulvihill MS, Kratz JR, Pham P, Jablons DM, He B . The role of stem cells in airway repair: implications for the origins of lung cancer . Chinese Journal of Cancer . 32 . 2 . 71–4 . Feb 2013 . 23114089 . 10.5732/cjc.012.10097 . 2024-04-03 . 3845611.
  7. van de Rijn M, Perou CM, Tibshirani R, Haas P, Kallioniemi O, Kononen J, Torhorst J, Sauter G, Zuber M, Köchli OR, Mross F, Dieterich H, Seitz R, Ross D, Botstein D, Brown P . Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome . The American Journal of Pathology . 161 . 6 . Dec 2002 . 12466114 . 10.1016/S0002-9440(10)64476-8 . 1850928 . 1991–1996.
  8. Shinkuma, Satoru, et al. "A Novel Keratin 5 Mutation in an African Family with Epidermolysis Bullosa Simplex Indicates the Importance of the Amino Acid Located at the Boundary Site Between the H1 and Coil 1A Domains." Acta Dermato-Venereologica 93.5 (2013): 585-587.
  9. Ramírez A, Bravo A, Jorcano JL, Vidal M . Sequences 5' of the bovine keratin 5 gene direct tissue- and cell-type-specific expression of a lacZ gene in the adult and during development . Differentiation; Research in Biological Diversity . 58 . 1 . Nov 1994 . 7532601 . 10.1046/j.1432-0436.1994.5810053.x . 53–64.
  10. Bouameur, Jamal-Eddine, et al. "Interaction of plectin with keratins 5 and 14: dependence on several plectin domains and keratin quaternary structure." Journal of Investigative Dermatology 134.11 (2014): 2776-2783.
  11. Coulombe PA, Omary MB . 'Hard' and 'soft' principles defining the structure, function and regulation of keratin intermediate filaments . Current Opinion in Cell Biology . 14 . 1 . Feb 2002 . 11792552 . 10.1016/S0955-0674(01)00301-5 . 110–22.
  12. Intong, Lizbeth RA, and Dédée F. Murrell. "Inherited epidermolysis bullosa: new diagnostic criteria and classification." Clinics in Dermatology 30.1 (2012): 70-77.
  13. Liovic M, Stojan J, Bowden PE, Gibbs D, Vahlquist A, Lane EB, Komel R . A novel keratin 5 mutation (K5V186L) in a family with EBS-K: a conservative substitution can lead to development of different disease phenotypes . The Journal of Investigative Dermatology . 116 . 6 . Jun 2001 . 11407988 . 10.1046/j.1523-1747.2001.01334.x . 964–9. free . .
  14. Bardhan. Ajoy. Bruckner-Tuderman. Leena. Chapple. Iain L. C.. Fine. Jo-David. Harper. Natasha. Has. Cristina. Magin. Thomas M.. Marinkovich. M. Peter. Marshall. John F.. McGrath. John A.. Mellerio. Jemima E.. 2020-09-24. Epidermolysis bullosa. Nature Reviews Disease Primers. en. 6. 1. 78. 10.1038/s41572-020-0210-0. 32973163. 221861310. 2056-676X.
  15. Web site: Cytokeratin 5/6. Robert Terlević, Semir Vranić. Topic Completed: 3 June 2019. Revised: 8 December 2019
  16. Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, Perou CM, Nielsen TO . Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype . Clinical Cancer Research . 14 . 5 . Mar 2008 . 18316557 . 10.1158/1078-0432.CCR-07-1658 . 1368–76. free .
  17. Cheang MC, van de Rijn M, Nielsen TO . Gene expression profiling of breast cancer . Annual Review of Pathology . 3 . 18039137 . 10.1146/annurev.pathmechdis.3.121806.151505 . 2008 . 67–97.
  18. Chu PG, Weiss LM . Expression of cytokeratin 5/6 in epithelial neoplasms: an immunohistochemical study of 509 cases . Modern Pathology . 15 . 1 . Jan 2002 . 11796835 . 10.1038/modpathol.3880483 . 6–10. free .
  19. Wang, Yu, et al. "An analysis of Cyclin D1, Cytokeratin 5/6 and Cytokeratin 8/18 expression in breast papillomas and papillary carcinomas." Diagn Pathol 8.8 (2013).
  20. Savagner P . The epithelial-mesenchymal transition (EMT) phenomenon . Annals of Oncology . 21 . Oct 2010 . Suppl 7 . 20943648 . 10.1093/annonc/mdq292 . 3379967 . vii89–vii92.

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