Keratin 5

Last updated
KRT5
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases KRT5 , CK5, DDD, DDD1, EBS2, K5, KRT5A, keratin 5, EBS2E, EBS2B, EBS2C, EBS1, EBS2A, EBS2F, EBS2D
External IDs OMIM: 148040 MGI: 96702 HomoloGene: 55461 GeneCards: KRT5
Orthologs
SpeciesHumanMouse
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: 52.51 – 52.52 Mb Chr 15: 101.62 – 101.62 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Keratin 5, also known as KRT5, K5, or CK5, is a protein that is encoded in humans by the KRT5 gene. [5] [6] [7] It dimerizes with keratin 14 and forms the intermediate filaments (IF) that make up the cytoskeleton of basal epithelial cells. [8] [9] This protein is involved in several diseases including epidermolysis bullosa simplex and breast and lung cancers. [9] [10] [11]

Contents

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). [8] 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. [12] 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. [8]

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. [8] 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. [13] 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. [8] [14]

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. [9] [13] 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. [9] [14] [15] 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. [15]

K5/K14 intermediate filaments are anchored to the desmosomes of basal cells via desmoplakin and plakophilin-1, connecting the cells to their neighbours. [16] 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. [14]

Clinical relevance

Epidermolysis bullosa simplex

Epidermolysis bullosa simplex (EBS) is an inherited skin blistering disorder associated with mutations in either K5 or K14. [9] [17] [18] 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. [9] 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. [14] [16]

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. [12] [17] Additionally, mutations in K5 tend to result in more severe symptoms than mutations in K14, possibly due to greater steric interference. [17]

Cancer

Keratin 5 serves as a biomarker for several different types of cancer, including breast and lung cancers. [10] [11] It is often tested in conjunction with keratin 6, using CK5/6 antibodies, which target both keratin forms. [19]

Basal-like breast cancers tend to have poorer outcomes than other types of breast cancer due to a lack of targeted therapies. [11] [20] [21] 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. [20]

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. [10] K5 also serves as a marker of mesothelioma, and can be used to distinguish mesothelioma from pulmonary adenocarcinoma. [22] Similarly, it can be used to distinguish papilloma, which is positive for K5, from papillary carcinoma, which is K5 negative. [23] It can also serve as a marker of basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, and thymoma. [22]

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. [24]

See also

Related Research Articles

<span class="mw-page-title-main">Keratin</span> Structural fibrous protein

Keratin is one of a family of structural fibrous proteins also known as scleroproteins. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up scales, hair, nails, feathers, horns, claws, hooves, and the outer layer of skin among vertebrates. Keratin also protects epithelial cells from damage or stress. Keratin is extremely insoluble in water and organic solvents. Keratin monomers assemble into bundles to form intermediate filaments, which are tough and form strong unmineralized epidermal appendages found in reptiles, birds, amphibians, and mammals. Excessive keratinization participate in fortification of certain tissues such as in horns of cattle and rhinos, and armadillos' osteoderm. The only other biological matter known to approximate the toughness of keratinized tissue is chitin. Keratin comes in two types, the primitive, softer forms found in all vertebrates and harder, derived forms found only among sauropsids.

<span class="mw-page-title-main">Epidermolysis bullosa</span> Rare medical conditions that result in easy blistering of the skin and mucous membranes

Epidermolysis bullosa (EB) is a group of rare medical conditions that result in easy blistering of the skin and mucous membranes. Blisters occur with minor trauma or friction and are painful. Its severity can range from mild to fatal. Inherited EB is a rare disease with a prevalence in the United States of 8.2 per million live births. Those with mild cases may not develop symptoms until they start to crawl or walk. Complications may include esophageal narrowing, squamous cell skin cancer, and the need for amputations.

<span class="mw-page-title-main">Keratin 1</span>

Keratin 1 is a Type II intermediate filament (IFs) of the intracytoplasmatic cytoskeleton. Is co-expressed with and binds to Keratin 10, a Type I keratin, to form a coiled coil heterotypic keratin chain. Keratin 1 and Keratin 10 are specifically expressed in the spinous and granular layers of the epidermis. In contrast, basal layer keratinocytes express little to no Keratin 1. Mutations in KRT1, the gene encoding Keratin 1, have been associated with variants of the disease bullous congenital ichthyosiform erythroderma in which the palms and soles of the feet are affected. Mutations in KRT10 have also been associated with bullous congenital ichthyosiform erythroderma; however, in patients with KRT10 mutations the palms and soles are spared. This difference is likely due to Keratin 9, rather than Keratin 10, being the major binding partner of Keratin 1 in acral keratinocytes.

<span class="mw-page-title-main">Keratin 7</span>

Keratin, type II cytoskeletal 7 also known as cytokeratin-7 (CK-7) or keratin-7 (K7) or sarcolectin (SCL) is a protein that in humans is encoded by the KRT7 gene. Keratin 7 is a type II keratin. It is specifically expressed in the simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels.

<span class="mw-page-title-main">Keratin 2A</span>

Keratin 2A also known as keratin 2E or keratin 2 is a protein that in humans is encoded by the KRT2A gene.

Type II keratins constitutes the Type II intermediate filaments (IFs) of the intracytoplasmatic cytoskeleton, which is present in all mammalian epithelial cells. The type 2 cytokeratins consist of basic or neutral, high molecular weight proteins which in vivo are arranged in pairs of heterotypic Type I and Type II keratin chains, coexpressed during differentiation of simple and stratified epithelial tissues. It has been seen that Type II Keratins are developed before Type 1 keratins during human embryonic development.

<span class="mw-page-title-main">Keratin 14</span> Protein-coding gene in the species Homo sapiens

Keratin 14 is a member of the type I keratin family of intermediate filament proteins. Keratin 14 was the first type I keratin sequence determined. Keratin 14 is also known as cytokeratin-14 (CK-14) or keratin-14 (KRT14). In humans it is encoded by the KRT14 gene.

<span class="mw-page-title-main">Keratin 10</span> Protein-coding gene in the species Homo sapiens

Keratin, type I cytoskeletal 10 also known as cytokeratin-10 (CK-10) or keratin-10 (K10) is a protein that in humans is encoded by the KRT10 gene. Keratin 10 is a type I keratin.

<span class="mw-page-title-main">Keratin 19</span> Protein-coding gene in the species Homo sapiens

Keratin, type I cytoskeletal 19 also known as cytokeratin-19 (CK-19) or keratin-19 (K19) is a 40 kDa protein that in humans is encoded by the KRT19 gene. Keratin 19 is a type I keratin.

<span class="mw-page-title-main">Keratin 18</span>

Keratin 18 is a type I cytokeratin. It is, together with its filament partner keratin 8, perhaps the most commonly found products of the intermediate filament gene family. They are expressed in single layer epithelial tissues of the body. Mutations in this gene have been linked to cryptogenic cirrhosis. Two transcript variants encoding the same protein have been found for this gene.

<span class="mw-page-title-main">Keratin 15</span> Protein-coding gene in the species Homo sapiens

Keratin 15 is a protein that in humans is encoded by the KRT15 gene. It has also been referred to as cytokeratin 15, K1CO and KRTB.

Hair keratin is a type of keratin found in hair and the nails.

<span class="mw-page-title-main">Cytokeratin</span> Keratin protein

Cytokeratins are keratin proteins found in the intracytoplasmic cytoskeleton of epithelial tissue. They are an important component of intermediate filaments, which help cells resist mechanical stress. Expression of these cytokeratins within epithelial cells is largely specific to particular organs or tissues. Thus they are used clinically to identify the cell of origin of various human tumors.

<span class="mw-page-title-main">Hemidesmosome</span>

Hemidesmosomes are very small stud-like structures found in keratinocytes of the epidermis of skin that attach to the extracellular matrix. They are similar in form to desmosomes when visualized by electron microscopy, however, desmosomes attach to adjacent cells. Hemidesmosomes are also comparable to focal adhesions, as they both attach cells to the extracellular matrix. Instead of desmogleins and desmocollins in the extracellular space, hemidesmosomes utilize integrins. Hemidesmosomes are found in epithelial cells connecting the basal epithelial cells to the lamina lucida, which is part of the basal lamina. Hemidesmosomes are also involved in signaling pathways, such as keratinocyte migration or carcinoma cell intrusion.

<span class="mw-page-title-main">Plectin</span> Mammalian protein found in Homo sapiens

Plectin is a giant protein found in nearly all mammalian cells which acts as a link between the three main components of the cytoskeleton: actin microfilaments, microtubules and intermediate filaments. In addition, plectin links the cytoskeleton to junctions found in the plasma membrane that structurally connect different cells. By holding these different networks together, plectin plays an important role in maintaining the mechanical integrity and viscoelastic properties of tissues.

<span class="mw-page-title-main">Epidermolysis bullosa simplex</span> Medical condition

Epidermolysis bullosa simplex (EBS) is a disorder resulting from mutations in the genes encoding keratin 5 or keratin 14.

<span class="mw-page-title-main">Desmoplakin</span> Protein found in humans

Desmoplakin is a protein in humans that is encoded by the DSP gene. Desmoplakin is a critical component of desmosome structures in cardiac muscle and epidermal cells, which function to maintain the structural integrity at adjacent cell contacts. In cardiac muscle, desmoplakin is localized to intercalated discs which mechanically couple cardiac cells to function in a coordinated syncytial structure. Mutations in desmoplakin have been shown to play a role in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, where it may present with acute myocardial injury; striate palmoplantar keratoderma, Carvajal syndrome and paraneoplastic pemphigus.

<span class="mw-page-title-main">Keratin 8</span>

Keratin, type II cytoskeletal 8 also known as cytokeratin-8 (CK-8) or keratin-8 (K8) is a keratin protein that is encoded in humans by the KRT8 gene. It is often paired with keratin 18.

<span class="mw-page-title-main">Collagen, type XVII, alpha 1</span> Mammalian protein found in humans

Collagen XVII, previously called BP180, is a transmembrane protein which plays a critical role in maintaining the linkage between the intracellular and the extracellular structural elements involved in epidermal adhesion, identified by Diaz and colleagues in 1990.

<span class="mw-page-title-main">Collagen, type VII, alpha 1</span> Protein found in humans

Collagen alpha-1(VII) chain is a protein that in humans is encoded by the COL7A1 gene. It is composed of a triple helical, collagenous domain flanked by two non-collagenous domains, and functions as an anchoring fibril between the dermal-epidermal junction in the basement membrane. Mutations in COL7A1 cause all types of dystrophic epidermolysis bullosa, and the exact mutations vary based on the specific type or subtype. It has been shown that interactions between the NC-1 domain of collagen VII and several other proteins, including laminin-5 and collagen IV, contribute greatly to the overall stability of the basement membrane.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000186081 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000061527 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: KRT5 keratin 5 (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types)".
  6. ↑ 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.
  7. ↑ 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.
  8. 1 2 3 4 5 Chan YM, Yu QC, LeBlanc-Straceski J, Christiano A, Pulkkinen L, Kucherlapati RS, Uitto J, Fuchs E (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 (4): 765–74. doi:10.1242/jcs.107.4.765. PMID   7520042.
  9. 1 2 3 4 5 6 Atkinson SD, McGilligan VE, Liao H, Szeverenyi I, Smith FJ, Moore CB, McLean WH (Oct 2011). "Development of allele-specific therapeutic siRNA for keratin 5 mutations in epidermolysis bullosa simplex". The Journal of Investigative Dermatology. 131 (10): 2079–86. doi: 10.1038/jid.2011.169 . PMID   21716320.
  10. 1 2 3 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): 71–4. doi:10.5732/cjc.012.10097 (inactive 2024-04-03). PMC   3845611 . PMID   23114089.{{cite journal}}: CS1 maint: DOI inactive as of April 2024 (link)
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  12. 1 2 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.
  13. 1 2 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): 53–64. doi:10.1046/j.1432-0436.1994.5810053.x. PMID   7532601.
  14. 1 2 3 4 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.
  15. 1 2 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): 110–22. doi:10.1016/S0955-0674(01)00301-5. PMID   11792552.
  16. 1 2 Intong, Lizbeth RA, and Dédée F. Murrell. "Inherited epidermolysis bullosa: new diagnostic criteria and classification." Clinics in Dermatology 30.1 (2012): 70-77.
  17. 1 2 3 Liovic M, Stojan J, Bowden PE, Gibbs D, Vahlquist A, Lane EB, Komel R (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): 964–9. doi: 10.1046/j.1523-1747.2001.01334.x . PMID   11407988..
  18. ↑ Bardhan A, Bruckner-Tuderman L, Chapple IL, Fine JD, Harper N, Has C, Magin TM, Marinkovich MP, Marshall JF, McGrath JA, Mellerio JE (2020-09-24). "Epidermolysis bullosa". Nature Reviews Disease Primers. 6 (1): 78. doi:10.1038/s41572-020-0210-0. ISSN   2056-676X. PMID   32973163. S2CID   221861310.
  19. ↑ Robert Terlević, Semir Vranić. "Cytokeratin 5/6". Topic Completed: 3 June 2019. Revised: 8 December 2019
  20. 1 2 Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, Perou CM, Nielsen TO (Mar 2008). "Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype". Clinical Cancer Research. 14 (5): 1368–76. doi: 10.1158/1078-0432.CCR-07-1658 . PMID   18316557.
  21. ↑ Cheang MC, van de Rijn M, Nielsen TO (2008). "Gene expression profiling of breast cancer". Annual Review of Pathology. 3: 67–97. doi:10.1146/annurev.pathmechdis.3.121806.151505. PMID   18039137.
  22. 1 2 Chu PG, Weiss LM (Jan 2002). "Expression of cytokeratin 5/6 in epithelial neoplasms: an immunohistochemical study of 509 cases". Modern Pathology. 15 (1): 6–10. doi: 10.1038/modpathol.3880483 . PMID   11796835.
  23. ↑ 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).
  24. ↑ Savagner P (Oct 2010). "The epithelial-mesenchymal transition (EMT) phenomenon". Annals of Oncology. 21 (Suppl 7): vii89–vii92. doi:10.1093/annonc/mdq292. PMC   3379967 . PMID   20943648.

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