Cytokeratin Overview

Cytokeratins are a complex family of proteins that are the key components of the cytoskeleton of epithelial cells, forming the intermediate filaments characteristic of that structure.

There are more than 50 recognised members of the cytokeratin family in humans, although many are restricted to expression in hair follicles and are only recently discovered. This blog won’t include discussion of those, but will instead focus on the more traditional epithelial cell cytokeratin family members that have found so much utility in defining tissue types in IHC applications.

Cytokeratin structure

Cytokeratin structure is not considered in detail here but has been well described by Kumar et al (1). A key feature of cytokeratins is that they always form pairs comprising one Type I and one Type II family member. This pairing occurs by association of their central rod domains in a coiled formation, and the heterodimers then form tetramers that are the basic building blocks of the intermediate filament within cells. Individual cytokerations tend to show restricted expression patterns within tissues and it this that effectively underlies the utility of antibodies that recognise specific cytokeratins to identify certain tissue types.

Cytokeratin 1

CK1 is typically found in combination with CK10, and expression of this pair is often regarded as a marker of keratinocytes and terminal epidermal differentiation. CK1 is not routinely used in tumour diagnosis.   The importance of this pair in maintaining epidermal integrity is highlighted by the fact that mutations in either CK1 or CK10 are associated with the blistering condition epidermolytic hyperkeratosis. CK1 also pairs with CK9 in palmoplantar epidermis.

Cytokeratin 2

CK2 is widely expressed, and also associated with terminally differentiated epidermal keratinocytes. It tends not to be associated with specific type I cytokeratins.

Cytokeratin 3

CK3 is found as a pair with CK12, and this combination is cell type specific, being found in corneal epithelium.

Cytokeratin 4

CK4 is often, but not exclusively, found paired with CK13. This pair are found in mucosally differentiated tissue, especially in the suprabasal compartment of mucosal stratified squamous epithelia. CK4 is frequently expressed in ductal adenocarcinomas of the pancreas and in some invasive ductal breast carcinomas.

Cytokeratin 5

CK5 is an important family member that is often paired with CK14, and the pair are major components of stratified squamous epithelia, being strongly expressed in the basal cell layer. The structural importance of this pair is demonstrated by the fact that mutations lead to the hereditary skin blistering disease epidermolysis bullosa.

CK5 is a valuable marker of tumours, often being used to differentiate tumours of squamous cell origin and differentiating them from histologically similar adenocarcinomas.

Cytokeratin 6

CK6 is most often found as a pair with CK16, and the pair have a broad distribution pattern in stratified epithelia. Of particular interest is the rapid induction of CK6/16 expression at sites of wound healing.

Cytokeratin 7

CK7 is most often found paired with CK19, and is considered to be a “ductal-type” keratin, being found in several simple ductal epithelia including mesothelium and urothelium. It is absent in intestinal epithelium however. In diagnosis CK7 is expressed in almost all carcinomas, but is notably absent in colorectal adenocarcinoma, which can be valuable is assessing the source of secondary tumour growth in some cases.

Cytokeratin 8

CK8 is primarily found in combination with CK18, and this pair are the primary cytokeratin pair of simple epithelial cells. In some tissues, such as in normal hepatocytes, they are the only cytokeratin pair present.  With such a broad distribution it is not surprising that in tumours CK8 is found in almost all carcinomas apart from some differentiated squamous cell carcinomas. CK8 is also found as a piar with CK19 in some tissues such as intestinal epithelium.

Cytokeratin 9

CK9 is a highly specific cytokeratin found only in palmoplantar epidermis, where it is strongly expressed and may be reflective of a role in mechanical strengthening of the skin in these areas. CK9 has no relevance in tumour diagnosis.

Cytokeratin 10

CK10 pairs primarily with CK1 - see above for discussion

Cytokeratin 12

CK12 pairs primarily with CK3 – see above for discussion

Cytokeratin 13

CK13 pairs primarily with CK4 – see above for discussion

Cytokeratin 14

CK14 pairs primarily with CK5 – see above for discussion

Cytokeratin 15

CK15 was identified as a minor component of epidermis, and subsequently shown to be restricted to basal cell layers of stratified squamous epithelium, where it can be found in combination with CK5.

Cytokeratin 16

CK16 pairs primarily with CK6 – see above for discussion

Cytokeratin 17

CK17 has been found to be expressed in basal and myoepithelial cells of complex tissues including respiratory epithelium, urothelium, sweat glands and breast tissue.. CK17 is expressed during the wound healing process, somewhat after CK6/16. In tumours CK17 is broadly expressed in squamous cell carcinomas.

Cytokeratin 18

CK18 is primarily found paired with CK8, so see this for a general discussion. Of particular interest is that fragments of CK18 as detected by specific monoclonal antibodies have been used as markers of apoptosis in peripheral blood, a characteristic that has attracted significant attention in developing assays to distinguish necrosis from apoptosis. More recently new antibodies have implied the ability to use this assay to detect non-alcoholic fatty liver disease (2)

Cytokeratin 19

CK19 pairs primarily with CK7, but in some tissues lacking CK7 it will form pairs with CK8. CK19 has a very broad tissue distribution, and is not widely used in tumour diagnosis due to it’s inability to distinguish adenocarcinoma from squamous cell carcinoma. CK19 fragments have also been found to be useful in serum assays for following response to therapy, especially in squamous cell lung carcinoma (3)

Cytokeratin 20

CK20 is primarily found associated with CK8. It has a very restricted expression pattern, being found in intestinal epithelium, urothelium and Merkel cells in the skin. CK20 detection is widely used in pathology, where it is valuable in identifying the origin of metastatic adenocarcinomas, which if CK20 positive are very likely to be of intestinal or pancreobiliary origin.

Cytokeratin specific antibodies

There are many antibodies available that recognise cytokeratins. Some of these antibodies are highly specific, and will detect just a single cytokeratin, whilst others have a broader reactivity pattern. Immuquest are pleased to offer a range of cytokeratin specific antibodies to support studies of CK expression in different tissues, and to help identify specific tumour types.

References 

1. Kumar, A. et al (2008) J. Oro. Biol.  2:6-11
2. Yamada, M. et al (2021) Reports 11:18187
3. Barak, V. et al (2004) Clin. Biochem. 37:529-540