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{{Infobox_gene}}
{{PBB_Controls
'''Keratin 5''', also known as '''KRT5''', '''K5''', or '''CK5''', is a [[protein]] that is encoded in humans by the ''KRT5'' [[gene]].<ref name = "entrez">{{Cite web| title = Entrez Gene: KRT5 keratin 5 (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3852| accessdate = }}</ref><ref name="pmid2447486">{{cite journal | vauthors = Lersch R, Fuchs E | title = Sequence and expression of a type II keratin, K5, in human epidermal cells | journal = Molecular and Cellular Biology | volume = 8 | issue = 1 | pages = 486–93 | date = Jan 1988 | pmid = 2447486 | pmc = 363157 | doi =  10.1128/mcb.8.1.486}}</ref><ref name="pmid2456903">{{cite journal | vauthors = Eckert RL, Rorke EA | title = The sequence of the human epidermal 58-kD (#5) type II keratin reveals an absence of 5' upstream sequence conservation between coexpressed epidermal keratins | journal = Dna | volume = 7 | issue = 5 | pages = 337–45 | date = Jun 1988 | pmid = 2456903 | doi = 10.1089/dna.1.1988.7.337 }}</ref> It [[protein dimer|dimerizes]] with [[keratin 14]] and forms the [[intermediate filaments]] (IF) that make up the [[cytoskeleton]] of [[Stratum basale|basal]] [[epithelial cells]].<ref name="Chan">{{cite journal | vauthors = Chan YM, Yu QC, LeBlanc-Straceski J, Christiano A, Pulkkinen L, Kucherlapati RS, Uitto J, Fuchs E | title = Mutations in the non-helical linker segment L1-2 of keratin 5 in patients with Weber-Cockayne epidermolysis bullosa simplex | journal = Journal of Cell Science | volume = 107 | date = Apr 1994 | pmid = 7520042 | issue=4 | pages=765–74}}</ref><ref name = "Atkinson">{{cite journal | vauthors = Atkinson SD, McGilligan VE, Liao H, Szeverenyi I, Smith FJ, Moore CB, McLean WH | title = Development of allele-specific therapeutic siRNA for keratin 5 mutations in epidermolysis bullosa simplex | journal = The Journal of Investigative Dermatology | volume = 131 | issue = 10 | date = Oct 2011 | pmid = 21716320 | doi = 10.1038/jid.2011.169 | pages=2079–86}}</ref> This protein is involved in several diseases including [[epidermolysis bullosa simplex]] and breast and lung cancers.<ref name="Atkinson" /><ref name="Mulvihill">{{cite journal | vauthors = Mulvihill MS, Kratz JR, Pham P, Jablons DM, He B | title = The role of stem cells in airway repair: implications for the origins of lung cancer | journal = Chinese Journal of Cancer | volume = 32 | issue = 2 | date = Feb 2013 | pmid = 23114089 | doi = 10.5732/cjc.012.10097 | pmc=3845611}}</ref><ref name="Van">{{cite journal | vauthors = 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 | title = Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome | journal = The American Journal of Pathology | volume = 161 | issue = 6 | date = Dec 2002 | pmid = 12466114 | doi = 10.1016/S0002-9440(10)64476-8 | pmc=1850928 | pages=1991–1996}}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =  
| Name = Keratin 5 (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types)
| HGNCid = 6442
| Symbol = KRT5
| AltSymbols =; CK5; DDD; EBS2; K5; KRT5A
| OMIM = 148040
| ECnumber = 
| Homologene = 55461
| MGIid = 96702
| GeneAtlas_image1 = PBB_GE_KRT5_201820_at_tn.png
| Function = {{GNF_GO|id=GO:0005198 |text = structural molecule activity}} {{GNF_GO|id=GO:0005200 |text = structural constituent of cytoskeleton}} {{GNF_GO|id=GO:0005515 |text = protein binding}}
| Component = {{GNF_GO|id=GO:0005882 |text = intermediate filament}}
| Process = {{GNF_GO|id=GO:0008544 |text = epidermis development}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 3852
    | Hs_Ensembl = ENSG00000186081
    | Hs_RefseqProtein = NP_000415
    | Hs_RefseqmRNA = NM_000424
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 12
    | Hs_GenLoc_start = 51194628
    | Hs_GenLoc_end = 51200347
    | Hs_Uniprot = P13647
    | Mm_EntrezGene = 110308
    | Mm_Ensembl = ENSMUSG00000061527
    | Mm_RefseqmRNA = NM_027011
    | Mm_RefseqProtein = NP_081287
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 15
    | Mm_GenLoc_start = 101535104
    | Mm_GenLoc_end = 101540925
    | Mm_Uniprot = Q32P04
  }}
}}
'''Keratin 5''' is a [[keratin]] protein often paired with [[keratin 14]].


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
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).<ref name="Chan" /> 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 [[Alpha helix#Stability|helix stabilization]], heterodimer formation, and filament formation.<ref name="Shinkuma">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.</ref> 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.<ref name="Chan" />
{{PBB_Summary
| section_title =
| summary_text = The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the basal layer of the epidermis with family member KRT14. Mutations in these genes have been associated with a complex of diseases termed epidermolysis bullosa simplex. The type II cytokeratins are clustered in a region of chromosome 12q12-q13.<ref>{{cite web | title = Entrez Gene: KRT5 keratin 5 (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3852| accessdate = }}</ref>
}}


==See also==
IF central rods contain [[heptad repeat]]s (repeating seven residue patterns) of [[hydrophobic]] resides that allow two different IF proteins to intertwine into a [[coiled-coil]] formation via [[hydrophobic interaction]]s.<ref name="Chan" /> 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.<ref name="Ramirez">{{cite journal | vauthors = Ramírez A, Bravo A, Jorcano JL, Vidal M | title = 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 | journal = Differentiation; Research in Biological Diversity | volume = 58 | issue = 1 | date = Nov 1994 | pmid = 7532601 | doi = 10.1046/j.1432-0436.1994.5810053.x | pages=53–64}}</ref> The coiled-coil dimers undergo [[stepwise reaction|stepwise assembly]] and combine in an [[antiparallel (biochemistry)|antiparallel]] manner, forming end-to-end interactions with other coiled-coils to form large 10&nbsp;nm intermediate filaments.<ref name="Chan" /><ref name="Bouameur">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.</ref>
 
== Function ==
 
Keratin 5 (and K14) are expressed primarily in basal [[keratinocyte]]s in the [[epidermis]], specifically in the [[stratified squamous epithelium|stratified epithelium]] lining the skin and digestive tract.<ref name="Atkinson" /><ref name="Ramirez" /> 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, [[stress (mechanics)|stresses]].<ref name="Atkinson" /><ref name="Bouameur" /><ref name = "Coulombe">{{cite journal | vauthors = Coulombe PA, Omary MB | title = 'Hard' and 'soft' principles defining the structure, function and regulation of keratin intermediate filaments | journal = Current Opinion in Cell Biology | volume = 14 | issue = 1 | date = Feb 2002 | pmid = 11792552 | doi=10.1016/S0955-0674(01)00301-5 | pages=110–22}}</ref> K5/K14 keratin pairs are able to undergo extensive bundling due to the non-helical tail of K15 acting as a weak [[cross-link]]er at the intermediate filament surface. This bundling increases the [[elasticity (physics)|elasticity]], and therefore the mechanical resilience, of the intermediate filaments.<ref name="Coulombe" />
 
K5/K14 intermediate filaments are anchored to the [[desmosomes]] of basal cells via [[desmoplakin]] and [[plakophilin| plakophilin-1]], connecting the cells to their neighbours.<ref name="Intong">Intong, Lizbeth RA, and Dédée F. Murrell. "Inherited epidermolysis bullosa: new diagnostic criteria and classification." Clinics in dermatology 30.1 (2012): 70-77.</ref> At the [[hemidesmosome]], plectin and BPAG1 associate with transmembrane proteins α6β4 [[integrin]], a type of [[cell adhesion molecule]], and [[Collagen, type XVII, alpha 1|BP180/collagen XVII]], linking K5/K14 filaments in the basal cells to the [[basal lamina]].<ref name="Bouameur" />
 
== Clinical relevance ==
 
=== Epidermolysis bullosa simplex ===
 
Epidermolysis bullosa simplex (EBS) is an inherited skin blistering disorder associated with mutations in either K5 or K14.<ref name="Atkinson" /><ref name="Liovic">{{cite journal | vauthors = Liovic M, Stojan J, Bowden PE, Gibbs D, Vahlquist A, Lane EB, Komel R | title = A novel keratin 5 mutation (K5V186L) in a family with EBS-K: a conservative substitution can lead to development of different disease phenotypes | journal = The Journal of Investigative Dermatology | volume = 116 | issue = 6 | date = Jun 2001 | pmid = 11407988 | doi = 10.1046/j.1523-1747.2001.01334.x | pages=964–9}}.</ref> EBS-causing mutations are primarily [[missense mutation]]s, but a small number of cases arise from [[insertion (genetics)|insertions]] or [[deletion (genetics)|deletions]].  Their mechanism of action is [[mutation#By effect on function|dominant negative interference]], with the mutated keratin proteins interfering with the structure and integrity of the cytoskeleton.<ref name="Atkinson" /> 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.<ref name="Bouameur" /><ref name="Intong" />
 
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.<ref name="Shinkuma" /><ref name="Liovic" /> Additionally, mutations in K5 tend to result in more severe symptoms than mutations in K14, possibly due to greater [[Steric effects#Steric hindrance|steric interference]].<ref name="Liovic" />
 
=== Cancer ===
 
Keratin 5 serves as a [[biomarker]] for several different types of cancer, including breast and lung cancers.<ref name="Mulvihill" /><ref name="Van" />
 
[[Basal-like carcinoma|Basal-like breast cancers]] tend to have poorer outcomes than other types of breast cancer due to a lack of targeted therapies.<ref name="Van" /><ref name="Cheang 1">{{cite journal | vauthors = Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, Perou CM, Nielsen TO | title = Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype | journal = Clinical Cancer Research | volume = 14 | issue = 5 | date = Mar 2008 | pmid = 18316557 | doi = 10.1158/1078-0432.CCR-07-1658 | pages=1368–76}}</ref><ref name="Cheang 2">{{cite journal | vauthors = Cheang MC, van de Rijn M, Nielsen TO | title = Gene expression profiling of breast cancer | journal = Annual Review of Pathology | volume = 3 | pmid = 18039137 | doi = 10.1146/annurev.pathmechdis.3.121806.151505 | year=2008 | pages=67–97}}</ref> These breast cancers do not express [[HER2/neu|human epidermal growth factor receptor-2]] or [[receptor (biochemistry)|receptors]] for [[estrogen]] or [[progesterone]], making them immune to [[trastuzumab| Trastuzumab/Herceptin]] and [[hormone therapy|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 (medicine)|screening]] patients with basal-like breast cancers to ensure that they are not receiving ineffective treatment.<ref name="Cheang 1" />
 
Studies on lung cancer have also shown that [[squamous cell carcinoma]]s 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.<ref name="Mulvihill" /> K5 also serves as a marker of [[mesothelioma]], and can be used to distinguish mesothelioma from [[pulmonary]] [[adenocarcinoma]].<ref name="Chu">{{cite journal | vauthors = Chu PG, Weiss LM | title = Expression of cytokeratin 5/6 in epithelial neoplasms: an immunohistochemical study of 509 cases | journal = Modern Pathology | volume = 15 | issue = 1 | date = Jan 2002 | pmid = 11796835 | doi = 10.1038/modpathol.3880483 | pages=6–10}}</ref> Similarly, it can be used to distinguish [[papilloma]], which is positive for K5, from [[papillary carcinoma]], which is K5 negative.<ref>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).</ref> It can also serve as a marker of [[basal cell carcinoma]], [[transitional cell carcinoma]], salivary gland tumors, and [[thymoma]].<ref name="Chu" />
 
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.<ref>{{cite journal | vauthors = Savagner P | title = The epithelial-mesenchymal transition (EMT) phenomenon | journal = Annals of Oncology | volume = 21 Suppl 7 | date = Oct 2010 | pmid = 20943648 | doi = 10.1093/annonc/mdq292 | pmc=3379967 | pages=vii89–vii92}}</ref>
 
== See also ==
* [[Intermediate filament]]
* [[Keratin]]
* [[Keratin 14]]
* [[Cytoskeleton]]
* [[Epidermolysis bullosa simplex]]
* [[Epidermolysis bullosa simplex]]
* [[Basal-like carcinoma]]


==References==
== References ==
{{reflist|2}}
{{Reflist|33em}}
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal  | author=Schuilenga-Hut PH, Vlies P, Jonkman MF, ''et al.'' |title=Mutation analysis of the entire keratin 5 and 14 genes in patients with epidermolysis bullosa simplex and identification of novel mutations. |journal=Hum. Mutat. |volume=21 |issue= 4 |pages= 447 |year= 2003 |pmid= 12655565 |doi= 10.1002/humu.9124 }}
*{{cite journal  | author=Seibert JA, Boone JM |title=X-ray imaging physics for nuclear medicine technologists. Part 2: X-ray interactions and image formation. |journal=Journal of nuclear medicine technology |volume=33 |issue= 1 |pages= 3-18 |year= 2005 |pmid= 15731015 |doi=  }}
*{{cite journal  | author=Ohtsuki M, Tomic-Canic M, Freedberg IM, Blumenberg M |title=Regulation of epidermal keratin expression by retinoic acid and thyroid hormone. |journal=J. Dermatol. |volume=19 |issue= 11 |pages= 774-80 |year= 1993 |pmid= 1284070 |doi=  }}
*{{cite journal  | author=Lane EB, Rugg EL, Navsaria H, ''et al.'' |title=A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. |journal=Nature |volume=356 |issue= 6366 |pages= 244-6 |year= 1992 |pmid= 1372711 |doi= 10.1038/356244a0 }}
*{{cite journal  | author=Tavakkol A, Griffiths CE, Keane KM, ''et al.'' |title=Cellular localization of mRNA for cellular retinoic acid-binding protein II and nuclear retinoic acid receptor-gamma 1 in retinoic acid-treated human skin. |journal=J. Invest. Dermatol. |volume=99 |issue= 2 |pages= 146-50 |year= 1992 |pmid= 1378478 |doi=  }}
*{{cite journal  | author=Rosenberg M, Fuchs E, Le Beau MM, ''et al.'' |title=Three epidermal and one simple epithelial type II keratin genes map to human chromosome 12. |journal=Cytogenet. Cell Genet. |volume=57 |issue= 1 |pages= 33-8 |year= 1991 |pmid= 1713141 |doi=  }}
*{{cite journal  | author=Ryynänen M, Knowlton RG, Uitto J |title=Mapping of epidermolysis bullosa simplex mutation to chromosome 12. |journal=Am. J. Hum. Genet. |volume=49 |issue= 5 |pages= 978-84 |year= 1991 |pmid= 1718160 |doi=  }}
*{{cite journal  | author=Bonifas JM, Rothman AL, Epstein EH |title=Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities. |journal=Science |volume=254 |issue= 5035 |pages= 1202-5 |year= 1991 |pmid= 1720261 |doi=  }}
*{{cite journal  | author=Lersch R, Fuchs E |title=Sequence and expression of a type II keratin, K5, in human epidermal cells. |journal=Mol. Cell. Biol. |volume=8 |issue= 1 |pages= 486-93 |year= 1988 |pmid= 2447486 |doi=  }}
*{{cite journal  | author=Galup C, Darmon MY |title=Isolation and characterization of a cDNA clone coding for human epidermal keratin K5. Sequence of the carboxyterminal half of this keratin. |journal=J. Invest. Dermatol. |volume=91 |issue= 1 |pages= 39-42 |year= 1988 |pmid= 2455002 |doi=  }}
*{{cite journal  | author=Eckert RL, Rorke EA |title=The sequence of the human epidermal 58-kD (#5) type II keratin reveals an absence of 5' upstream sequence conservation between coexpressed epidermal keratins. |journal=DNA |volume=7 |issue= 5 |pages= 337-45 |year= 1988 |pmid= 2456903 |doi=  }}
*{{cite journal  | author=Lersch R, Stellmach V, Stocks C, ''et al.'' |title=Isolation, sequence, and expression of a human keratin K5 gene: transcriptional regulation of keratins and insights into pairwise control. |journal=Mol. Cell. Biol. |volume=9 |issue= 9 |pages= 3685-97 |year= 1989 |pmid= 2476664 |doi=  }}
*{{cite journal  | author=Rugg EL, Morley SM, Smith FJ, ''et al.'' |title=Missing links: Weber-Cockayne keratin mutations implicate the L12 linker domain in effective cytoskeleton function. |journal=Nat. Genet. |volume=5 |issue= 3 |pages= 294-300 |year= 1994 |pmid= 7506097 |doi= 10.1038/ng1193-294 }}
*{{cite journal  | author=Chan YM, Yu QC, LeBlanc-Straceski J, ''et al.'' |title=Mutations in the non-helical linker segment L1-2 of keratin 5 in patients with Weber-Cockayne epidermolysis bullosa simplex. |journal=J. Cell. Sci. |volume=107 ( Pt 4) |issue=  |pages= 765-74 |year= 1994 |pmid= 7520042 |doi=  }}
*{{cite journal  | author=Kouklis PD, Hutton E, Fuchs E |title=Making a connection: direct binding between keratin intermediate filaments and desmosomal proteins. |journal=J. Cell Biol. |volume=127 |issue= 4 |pages= 1049-60 |year= 1994 |pmid= 7525601 |doi=  }}
*{{cite journal  | author=Stephens K, Zlotogorski A, Smith L, ''et al.'' |title=Epidermolysis bullosa simplex: a keratin 5 mutation is a fully dominant allele in epidermal cytoskeleton function. |journal=Am. J. Hum. Genet. |volume=56 |issue= 3 |pages= 577-85 |year= 1995 |pmid= 7534039 |doi=  }}
*{{cite journal  | author=Ehrlich P, Sybert VP, Spencer A, Stephens K |title=A common keratin 5 gene mutation in epidermolysis bullosa simplex--Weber-Cockayne. |journal=J. Invest. Dermatol. |volume=104 |issue= 5 |pages= 877-9 |year= 1995 |pmid= 7537780 |doi=  }}
*{{cite journal  | author=Wanner R, Förster HH, Tilmans I, Mischke D |title=Allelic variations of human keratins K4 and K5 provide polymorphic markers within the type II keratin gene cluster on chromosome 12. |journal=J. Invest. Dermatol. |volume=100 |issue= 6 |pages= 735-41 |year= 1993 |pmid= 7684424 |doi=  }}
*{{cite journal  | author=Dong W, Ryynänen M, Uitto J |title=Identification of a leucine-to-proline mutation in the keratin 5 gene in a family with the generalized Köbner type of epidermolysis bullosa simplex. |journal=Hum. Mutat. |volume=2 |issue= 2 |pages= 94-102 |year= 1993 |pmid= 7686424 |doi= 10.1002/humu.1380020206 }}
*{{cite journal  | author=Chan YM, Yu QC, Fine JD, Fuchs E |title=The genetic basis of Weber-Cockayne epidermolysis bullosa simplex. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue= 15 |pages= 7414-8 |year= 1993 |pmid= 7688477 |doi=  }}
}}
{{refend}}


==External links==
== Further reading ==
{{Refbegin|33em}}
* {{cite journal | vauthors = Schuilenga-Hut PH, van der Vlies P, Jonkman MF, Waanders E, Buys CH, Scheffer H | title = Mutation analysis of the entire keratin 5 and 14 genes in patients with epidermolysis bullosa simplex and identification of novel mutations | journal = Human Mutation | volume = 21 | issue = 4 | pages = 447 | date = Apr 2003 | pmid = 12655565 | doi = 10.1002/humu.9124 }}
* {{cite journal | vauthors = Seibert JA, Boone JM | title = X-ray imaging physics for nuclear medicine technologists. Part 2: X-ray interactions and image formation | journal = Journal of Nuclear Medicine Technology | volume = 33 | issue = 1 | pages = 3–18 | date = Mar 2005 | pmid = 15731015 | doi =  }}
* {{cite journal | vauthors = Ohtsuki M, Tomic-Canic M, Freedberg IM, Blumenberg M | title = Regulation of epidermal keratin expression by retinoic acid and thyroid hormone | journal = The Journal of Dermatology | volume = 19 | issue = 11 | pages = 774–80 | date = Nov 1992 | pmid = 1284070 | doi =  10.1111/j.1346-8138.1992.tb03779.x}}
* {{cite journal | vauthors = Lane EB, Rugg EL, Navsaria H, Leigh IM, Heagerty AH, Ishida-Yamamoto A, Eady RA | title = A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering | journal = Nature | volume = 356 | issue = 6366 | pages = 244–6 | date = Mar 1992 | pmid = 1372711 | doi = 10.1038/356244a0 }}
* {{cite journal | vauthors = Tavakkol A, Griffiths CE, Keane KM, Palmer RD, Voorhees JJ | title = Cellular localization of mRNA for cellular retinoic acid-binding protein II and nuclear retinoic acid receptor-gamma 1 in retinoic acid-treated human skin | journal = The Journal of Investigative Dermatology | volume = 99 | issue = 2 | pages = 146–50 | date = Aug 1992 | pmid = 1378478 | doi = 10.1111/1523-1747.ep12616781 }}
* {{cite journal | vauthors = Rosenberg M, Fuchs E, Le Beau MM, Eddy RL, Shows TB | title = Three epidermal and one simple epithelial type II keratin genes map to human chromosome 12 | journal = Cytogenetics and Cell Genetics | volume = 57 | issue = 1 | pages = 33–8 | year = 1991 | pmid = 1713141 | doi = 10.1159/000133109 }}
* {{cite journal | vauthors = Ryynänen M, Knowlton RG, Uitto J | title = Mapping of epidermolysis bullosa simplex mutation to chromosome 12 | journal = American Journal of Human Genetics | volume = 49 | issue = 5 | pages = 978–84 | date = Nov 1991 | pmid = 1718160 | pmc = 1683248 | doi =  }}
* {{cite journal | vauthors = Bonifas JM, Rothman AL, Epstein EH | title = Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities | journal = Science | volume = 254 | issue = 5035 | pages = 1202–5 | date = Nov 1991 | pmid = 1720261 | doi = 10.1126/science.1720261 }}
* {{cite journal | vauthors = Lersch R, Fuchs E | title = Sequence and expression of a type II keratin, K5, in human epidermal cells | journal = Molecular and Cellular Biology | volume = 8 | issue = 1 | pages = 486–93 | date = Jan 1988 | pmid = 2447486 | pmc = 363157 | doi =  10.1128/mcb.8.1.486}}
* {{cite journal | vauthors = Galup C, Darmon MY | title = Isolation and characterization of a cDNA clone coding for human epidermal keratin K5. Sequence of the carboxyterminal half of this keratin | journal = The Journal of Investigative Dermatology | volume = 91 | issue = 1 | pages = 39–42 | date = Jul 1988 | pmid = 2455002 | doi = 10.1111/1523-1747.ep12463286 }}
* {{cite journal | vauthors = Eckert RL, Rorke EA | title = The sequence of the human epidermal 58-kD (#5) type II keratin reveals an absence of 5' upstream sequence conservation between coexpressed epidermal keratins | journal = Dna | volume = 7 | issue = 5 | pages = 337–45 | date = Jun 1988 | pmid = 2456903 | doi = 10.1089/dna.1.1988.7.337 }}
* {{cite journal | vauthors = Lersch R, Stellmach V, Stocks C, Giudice G, Fuchs E | title = Isolation, sequence, and expression of a human keratin K5 gene: transcriptional regulation of keratins and insights into pairwise control | journal = Molecular and Cellular Biology | volume = 9 | issue = 9 | pages = 3685–97 | date = Sep 1989 | pmid = 2476664 | pmc = 362429 | doi =  10.1128/mcb.9.9.3685}}
* {{cite journal | vauthors = Rugg EL, Morley SM, Smith FJ, Boxer M, Tidman MJ, Navsaria H, Leigh IM, Lane EB | title = Missing links: Weber-Cockayne keratin mutations implicate the L12 linker domain in effective cytoskeleton function | journal = Nature Genetics | volume = 5 | issue = 3 | pages = 294–300 | date = Nov 1993 | pmid = 7506097 | doi = 10.1038/ng1193-294 }}
* {{cite journal | vauthors = Kouklis PD, Hutton E, Fuchs E | title = Making a connection: direct binding between keratin intermediate filaments and desmosomal proteins | journal = The Journal of Cell Biology | volume = 127 | issue = 4 | pages = 1049–60 | date = Nov 1994 | pmid = 7525601 | pmc = 2200061 | doi = 10.1083/jcb.127.4.1049 }}
* {{cite journal | vauthors = Stephens K, Zlotogorski A, Smith L, Ehrlich P, Wijsman E, Livingston RJ, Sybert VP | title = Epidermolysis bullosa simplex: a keratin 5 mutation is a fully dominant allele in epidermal cytoskeleton function | journal = American Journal of Human Genetics | volume = 56 | issue = 3 | pages = 577–85 | date = Mar 1995 | pmid = 7534039 | pmc = 1801159 | doi =  }}
* {{cite journal | vauthors = Ehrlich P, Sybert VP, Spencer A, Stephens K | title = A common keratin 5 gene mutation in epidermolysis bullosa simplex--Weber-Cockayne | journal = The Journal of Investigative Dermatology | volume = 104 | issue = 5 | pages = 877–9 | date = May 1995 | pmid = 7537780 | doi = 10.1111/1523-1747.ep12607050 }}
* {{cite journal | vauthors = Wanner R, Förster HH, Tilmans I, Mischke D | title = Allelic variations of human keratins K4 and K5 provide polymorphic markers within the type II keratin gene cluster on chromosome 12 | journal = The Journal of Investigative Dermatology | volume = 100 | issue = 6 | pages = 735–41 | date = Jun 1993 | pmid = 7684424 | doi = 10.1111/1523-1747.ep12475671 }}
* {{cite journal | vauthors = Dong W, Ryynänen M, Uitto J | title = Identification of a leucine-to-proline mutation in the keratin 5 gene in a family with the generalized Köbner type of epidermolysis bullosa simplex | journal = Human Mutation | volume = 2 | issue = 2 | pages = 94–102 | year = 1993 | pmid = 7686424 | doi = 10.1002/humu.1380020206 }}
* {{cite journal | vauthors = Chan YM, Yu QC, Fine JD, Fuchs E | title = The genetic basis of Weber-Cockayne epidermolysis bullosa simplex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 15 | pages = 7414–8 | date = Aug 1993 | pmid = 7688477 | pmc = 47148 | doi = 10.1073/pnas.90.15.7414 }}
{{Refend}}
 
== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1369/  GeneReviews/NCBI/UW/NIH entry on Epidermolysis Bullosa Simplex]
* {{MeshName|Keratin-5}}
* {{MeshName|Keratin-5}}


{{Fibrous proteins}}
{{Cytoskeletal proteins}}
 
[[Category:Keratins]]
[[Category:Keratins]]
{{WikiDoc Sources}}

Revision as of 10:38, 2 September 2017

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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.[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

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

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

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.[10]

Clinical relevance

Epidermolysis bullosa simplex

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

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

References

  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. doi:10.1128/mcb.8.1.486. 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. ↑ 4.0 4.1 4.2 4.3 4.4 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. PMID 7520042.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 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.
  6. ↑ 6.0 6.1 6.2 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. PMC 3845611. PMID 23114089.
  7. ↑ 7.0 7.1 7.2 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 (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): 1991–1996. doi:10.1016/S0002-9440(10)64476-8. PMC 1850928. PMID 12466114.
  8. ↑ 8.0 8.1 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. ↑ 9.0 9.1 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.
  10. ↑ 10.0 10.1 10.2 10.3 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. ↑ 11.0 11.1 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.
  12. ↑ 12.0 12.1 Intong, Lizbeth RA, and Dédée F. Murrell. "Inherited epidermolysis bullosa: new diagnostic criteria and classification." Clinics in dermatology 30.1 (2012): 70-77.
  13. ↑ 13.0 13.1 13.2 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..
  14. ↑ 14.0 14.1 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.
  15. ↑ 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.
  16. ↑ 16.0 16.1 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.
  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: vii89–vii92. doi:10.1093/annonc/mdq292. PMC 3379967. PMID 20943648.

Further reading

External links

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