Keratin 5

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

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. 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. 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.

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. 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. 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. 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.

Basal-like breast cancers tend to have poorer outcomes than other types of breast cancer due to a lack of targeted therapies. 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. Similarly, it can be used to distinguish papilloma, which is positive for K5, from papillary carcinoma, which is K5 negative. 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.

See also

• Intermediate filament
• Keratin
• Keratin 14
• Cytoskeleton
• Epidermolysis bullosa simplex
• Basal-like carcinoma

Further reading

• Schuilenga-Hut PH, van der Vlies P, Jonkman MF, Waanders E, Buys CH, Scheffer H (Apr 2003). "Mutation analysis of the entire keratin 5 and 14 genes in patients with epidermolysis bullosa simplex and identification of novel mutations". Human Mutation. 21 (4): 447. doi:10.1002/humu.9124. PMID 12655565.
• Seibert JA, Boone JM (Mar 2005). "X-ray imaging physics for nuclear medicine technologists. Part 2: X-ray interactions and image formation". Journal of Nuclear Medicine Technology. 33 (1): 3–18. PMID 15731015.
• Ohtsuki M, Tomic-Canic M, Freedberg IM, Blumenberg M (Nov 1992). "Regulation of epidermal keratin expression by retinoic acid and thyroid hormone". The Journal of Dermatology. 19 (11): 774–80. doi:10.1111/j.1346-8138.1992.tb03779.x. PMID 1284070.
• Lane EB, Rugg EL, Navsaria H, Leigh IM, Heagerty AH, Ishida-Yamamoto A, Eady RA (Mar 1992). "A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering". Nature. 356 (6366): 244–6. doi:10.1038/356244a0. PMID 1372711.
• Tavakkol A, Griffiths CE, Keane KM, Palmer RD, Voorhees JJ (Aug 1992). "Cellular localization of mRNA for cellular retinoic acid-binding protein II and nuclear retinoic acid receptor-gamma 1 in retinoic acid-treated human skin". The Journal of Investigative Dermatology. 99 (2): 146–50. doi:10.1111/1523-1747.ep12616781. PMID 1378478.
• Rosenberg M, Fuchs E, Le Beau MM, Eddy RL, Shows TB (1991). "Three epidermal and one simple epithelial type II keratin genes map to human chromosome 12". Cytogenetics and Cell Genetics. 57 (1): 33–8. doi:10.1159/000133109. PMID 1713141.
• Ryynänen M, Knowlton RG, Uitto J (Nov 1991). "Mapping of epidermolysis bullosa simplex mutation to chromosome 12". American Journal of Human Genetics. 49 (5): 978–84. PMC 1683248. PMID 1718160.
• Bonifas JM, Rothman AL, Epstein EH (Nov 1991). "Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities". Science. 254 (5035): 1202–5. doi:10.1126/science.1720261. PMID 1720261.
• Lersch R, Fuchs E (Jan 1988). "Sequence and expression of a type II keratin, K5, in human epidermal cells". Molecular and Cellular Biology. 8 (1): 486–93. doi:10.1128/mcb.8.1.486. PMC 363157. PMID 2447486.
• Galup C, Darmon MY (Jul 1988). "Isolation and characterization of a cDNA clone coding for human epidermal keratin K5. Sequence of the carboxyterminal half of this keratin". The Journal of Investigative Dermatology. 91 (1): 39–42. doi:10.1111/1523-1747.ep12463286. PMID 2455002.
• Eckert RL, Rorke EA (Jun 1988). "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. doi:10.1089/dna.1.1988.7.337. PMID 2456903.
• Lersch R, Stellmach V, Stocks C, Giudice G, Fuchs E (Sep 1989). "Isolation, sequence, and expression of a human keratin K5 gene: transcriptional regulation of keratins and insights into pairwise control". Molecular and Cellular Biology. 9 (9): 3685–97. doi:10.1128/mcb.9.9.3685. PMC 362429. PMID 2476664.
• Rugg EL, Morley SM, Smith FJ, Boxer M, Tidman MJ, Navsaria H, Leigh IM, Lane EB (Nov 1993). "Missing links: Weber-Cockayne keratin mutations implicate the L12 linker domain in effective cytoskeleton function". Nature Genetics. 5 (3): 294–300. doi:10.1038/ng1193-294. PMID 7506097.
• Kouklis PD, Hutton E, Fuchs E (Nov 1994). "Making a connection: direct binding between keratin intermediate filaments and desmosomal proteins". The Journal of Cell Biology. 127 (4): 1049–60. doi:10.1083/jcb.127.4.1049. PMC 2200061. PMID 7525601.
• Stephens K, Zlotogorski A, Smith L, Ehrlich P, Wijsman E, Livingston RJ, Sybert VP (Mar 1995). "Epidermolysis bullosa simplex: a keratin 5 mutation is a fully dominant allele in epidermal cytoskeleton function". American Journal of Human Genetics. 56 (3): 577–85. PMC 1801159. PMID 7534039.
• Ehrlich P, Sybert VP, Spencer A, Stephens K (May 1995). "A common keratin 5 gene mutation in epidermolysis bullosa simplex--Weber-Cockayne". The Journal of Investigative Dermatology. 104 (5): 877–9. doi:10.1111/1523-1747.ep12607050. PMID 7537780.
• Wanner R, Förster HH, Tilmans I, Mischke D (Jun 1993). "Allelic variations of human keratins K4 and K5 provide polymorphic markers within the type II keratin gene cluster on chromosome 12". The Journal of Investigative Dermatology. 100 (6): 735–41. doi:10.1111/1523-1747.ep12475671. PMID 7684424.
• Dong W, Ryynänen M, Uitto J (1993). "Identification of a leucine-to-proline mutation in the keratin 5 gene in a family with the generalized Köbner type of epidermolysis bullosa simplex". Human Mutation. 2 (2): 94–102. doi:10.1002/humu.1380020206. PMID 7686424.
• Chan YM, Yu QC, Fine JD, Fuchs E (Aug 1993). "The genetic basis of Weber-Cockayne epidermolysis bullosa simplex". Proceedings of the National Academy of Sciences of the United States of America. 90 (15): 7414–8. doi:10.1073/pnas.90.15.7414. PMC 47148. PMID 7688477.

External links

• GeneReviews/NCBI/UW/NIH entry on Epidermolysis Bullosa Simplex
• Keratin-5 at the US National Library of Medicine Medical Subject Headings (MeSH)