Keratin 5

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Keratin 5
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols KRT5 ; CK5; DDD; DDD1; EBS2; K5; KRT5A
External IDs OMIM148040 MGI96702 HomoloGene55461 GeneCards: KRT5 Gene
RNA expression pattern
PBB GE KRT5 201820 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3852 110308
Ensembl ENSG00000186081 ENSMUSG00000061527
UniProt P13647 Q922U2
RefSeq (mRNA) NM_000424 NM_027011
RefSeq (protein) NP_000415 NP_081287
Location (UCSC) Chr 12:
52.91 – 52.91 Mb
Chr 15:
101.71 – 101.71 Mb
PubMed search [1] [2]

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.[5][6][7]

Structure[edit]

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).[4] 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.[4]

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.[4] 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.[4][10]

Function[edit]

Keratin 5 (and K14) are expressed primarily in basal keratinocytes in the epidermis, specifically in the stratified epithelium lining the skin and digestive tract.[9][5] 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.[5][11][10] 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.[11]

K5/K14 intermediate filaments are anchored to the desmosomes of basal cells via desmoplakin and plakophilin-1, connecting the cells to their neighbors. [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. [10]

Clinical relevance[edit]

Epidermolysis bullosa simplex[edit]

Epidermolysis bullosa simplex (EBS) is an inherited skin blistering disorder associated with mutations in either K5 or K14.[5][13] 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.[5] 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. [10][12]

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.[8][13] Additionally, mutations in K5 tend to result in more severe symptoms than mutations in K14, possibly due to greater steric interference.[13]

Cancer[edit]

Keratin 5 serves as a biomarker for several different types of cancer, including breast and lung cancers.[6][7]

Basal-like breast cancers tend to have poorer outcomes than other types of breast cancer due to a lack of targeted therapies.[7][14][15] 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.[14]

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.[6] K5 also serves as a marker of mesothelioma, and can be used to distinguish mesothelioma from pulmonary adenocarcinoma.[16] Similarly, it can be used to distinguish papilloma, which is positive for K5, from papillary carcinoma, which is K5 negative. [17] It can also serve as a marker of basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, and thymoma.[16]

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.[18]

See also[edit]

References[edit]

  1. ^ "Entrez Gene: KRT5 keratin 5 (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types)". 
  2. ^ 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. PMC 363157. PMID 2447486. 
  3. ^ 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. 
  4. ^ a b c d e Chan YM, Yu QC, LeBlanc-Straceski J, Christiano A, Pulkkinen L, Kucherlapati RS et al. (Apr 1994). "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 ( Pt 4). PMID 7520042. 
  5. ^ a b c d e f Atkinson SD, McGilligan VE, Liao H, Szeverenyi I, Smith FJ, Moore CB et al. (Oct 2011). "Development of allele-specific therapeutic siRNA for keratin 5 mutations in epidermolysis bullosa simplex". The Journal of Investigative Dermatology 131 (10). doi:10.1038/jid.2011.169. PMID 21716320. 
  6. ^ a b c Mulvihill MS, Kratz JR, Pham P, Jablons DM, He B (Feb 2013). "The role of stem cells in airway repair: implications for the origins of lung cancer". Chinese Journal of Cancer 32 (2). doi:10.5732/cjc.012.10097. PMID 23114089. 
  7. ^ a b c van de Rijn M, Perou CM, Tibshirani R, Haas P, Kallioniemi O, Kononen J et al. (Dec 2002). "Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome". The American Journal of Pathology 161 (6). doi:10.1016/S0002-9440(10)64476-8. PMID 12466114. 
  8. ^ a b 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. ^ a b Ramírez A, Bravo A, Jorcano JL, Vidal M (Nov 1994). "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). doi:10.1046/j.1432-0436.1994.5810053.x. PMID 7532601. 
  10. ^ a b c d 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. ^ a b Coulombe PA, Omary MB (Feb 2002). "'Hard' and 'soft' principles defining the structure, function and regulation of keratin intermediate filaments". Current Opinion in Cell Biology 14 (1). PMID 11792552. 
  12. ^ a b Intong, Lizbeth RA, and Dédée F. Murrell. "Inherited epidermolysis bullosa: new diagnostic criteria and classification." Clinics in dermatology 30.1 (2012): 70-77.
  13. ^ a b c Liovic M, Stojan J, Bowden PE, Gibbs D, Vahlquist A, Lane EB et al. (Jun 2001). "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). doi:10.1046/j.1523-1747.2001.01334.x. PMID 11407988. .
  14. ^ a b Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK et al. (Mar 2008). "Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype". Clinical Cancer Research 14 (5). doi:10.1158/1078-0432.CCR-07-1658. PMID 18316557. 
  15. ^ Cheang MC, van de Rijn M, Nielsen TO. "Gene expression profiling of breast cancer". Annual Review of Pathology 3. doi:10.1146/annurev.pathmechdis.3.121806.151505. PMID 18039137. 
  16. ^ a b Chu PG, Weiss LM (Jan 2002). "Expression of cytokeratin 5/6 in epithelial neoplasms: an immunohistochemical study of 509 cases". Modern Pathology 15 (1). doi:10.1038/modpathol.3880483. PMID 11796835. 
  17. ^ 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).
  18. ^ Savagner P (Oct 2010). "The epithelial-mesenchymal transition (EMT) phenomenon". Annals of Oncology. 21 Suppl 7. doi:10.1093/annonc/mdq292. PMID 20943648. 

Further reading[edit]

External links[edit]