Keratins in colorectal epithelial function and disease

Abstract

Keratins are the largest subgroup of intermediate filament proteins, which are an important constituent of the cellular cytoskeleton. The principally expressed keratins (K) of the intestinal epithelium are K8, K18 and K19. The specific keratin profile of a particular epithelium provides it with strength and integrity. In the colon, keratins have been shown to regulate electrolyte transport, likely by targeting ion transporters to their correct location in the colonocytes. Keratins are highly dynamic and are subject to post-translational modifications including phosphorylation, acetylation and glycosylation. These affect the filament dynamics and hence solubility of keratins and may contribute to protection against degradation. Keratin null mice (K8(-/-) ) develop colitis, and abnormal keratin mutations have been shown to be associated with inflammatory bowel disease (IBD). Abnormal expression of K7 and K20 has been noted in colitis-associated dysplasia and cancers. In sporadic colorectal cancers (CRCs) may be useful in predicting tumour prognosis; a low K20 expression is noted in CRCs with high microsatellite instability; and keratins have been noted as dysregulated in peri-adenomatous fields. Caspase-cleaved fragment of K18 (M30) in the serum of patients with CRC has been used as a marker of cancer load and to assess response to therapy. These data suggest an emerging importance of keratins in maintaining normal function of the gastrointestinal epithelium as well as being a marker of various colorectal diseases. This review will primarily focus on the biology of these proteins, physiological functions and alterations in IBD and CRCs.

Figure 1

Organization and distribution of keratin 8 in colorectal cells. (Panel a) Representative images of immunocytochemical staining of keratin 8 in HCT116 cells. K8 (green) forms filaments, which radiate throughout the cell. (Panel b) Immunohistochemical staining of keratin 8 (i) and 18 (ii) staining in normal colon crypt.

Figure 2

Similarities between members of the type I and type II keratin subfamilies. Panel a shows alignment between human type I keratins and panel b shows type II keratins. A star beneath the alignment indicates identical residue at a position, sequences accessed from Uniprot on 28.02.12 and alignment undertaken using Blast through Uniprot.

Figure 3

Summary of post-translational modifications of keratin 8 (Panel a), keratin 18 (Panel b) and keratin 19 (Panel c) (accessed from phosphosite.org, 21 February 2012). p, Phosphorylation; a, acetylation; m, methylation; m1, mono-methylation; m2, di-methylation; m3, tri-methylation; u, ubiquitination; S, sumoylation; n, neddylation; g, O-GlcNAc; h, palmitoylation; ad, adenylylation; sn, S-nitrosylation; ca, caspase cleavage.

Figure 4

Protein–protein interaction network view summarizing the network of predicted associations for keratins 8, 18 and 19 (data accessed from STRING 9.0 (http://string-db.org/). The network nodes represent proteins, and edges demonstrate predicted functional associations between them. The colour of the node for the protein analysed is indicated in red; other nodes are coloured to indicate a direct link with the protein. Seven different coloured lines indicate the edges representing the seven types of evidence used in predicting the associations. The lines indicate the following evidences: red line – fusion; green line – neighbourhood; blue line – co-occurrence; purple line – experimental; yellow line – text-mining; light blue line – database; black line – co-expression.