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Cell Death Differ. 2017 Jun;24(6):984-996. doi: 10.1038/cdd.2017.28. Epub 2017 May 5.

Keratins regulate colonic epithelial cell differentiation through the Notch1 signalling pathway.

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Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.
Turku Center of Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Technical University of Eindhoven, Eindhoven, The Netherlands.
Turku Center for Disease Modeling, University of Turku, Turku, Finland.


Keratins (K) are intermediate filament proteins important in stress protection and mechanical support of epithelial tissues. K8, K18 and K19 are the main colonic keratins, and K8-knockout (K8-/-) mice display a keratin dose-dependent hyperproliferation of colonic crypts and a colitis-phenotype. However, the impact of the loss of K8 on intestinal cell differentiation has so far been unknown. Here we show that K8 regulates Notch1 signalling activity and differentiation in the epithelium of the large intestine. Proximity ligation and immunoprecipitation assays demonstrate that K8 and Notch1 co-localize and interact in cell cultures, and in vivo in the colonic epithelial cells. K8 with its heteropolymeric partner K18 enhance Notch1 protein levels and activity in a dose dependent manner. The levels of the full-length Notch1 receptor (FLN), the Notch1 intracellular domain (NICD) and expression of Notch1 downstream target genes are reduced in the absence of K8, and the K8-dependent loss of Notch1 activity can be rescued with re-expression of K8/K18 in K8-knockout CRISPR/Cas9 Caco-2 cells protein levels. In vivo, K8 deletion with subsequent Notch1 downregulation leads to a shift in differentiation towards a goblet cell and enteroendocrine phenotype from an enterocyte cell fate. Furthermore, the K8-/- colonic hyperproliferation results from an increased number of transit amplifying progenitor cells in these mice. K8/K18 thus interact with Notch1 and regulate Notch1 signalling activity during differentiation of the colonic epithelium.

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