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Nat Commun. 2016 May 17;7:11551. doi: 10.1038/ncomms11551.

ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation.

Author information

1
Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
2
Sanford Burnham Prebys Medical Discovery Institute, NCI-Designated Cancer Center, La Jolla, California 92037, USA.
3
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, California 92093, USA.
4
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
5
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.
6
Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8514, Japan.

Abstract

The ERK1/2 MAPK signalling module integrates extracellular cues that induce proliferation and differentiation of epithelial lineages, and is an established oncogenic driver, particularly in the intestine. However, the interrelation of the ERK1/2 module relative to other signalling pathways in intestinal epithelial cells and colorectal cancer (CRC) is unclear. Here we show that loss of Erk1/2 in intestinal epithelial cells results in defects in nutrient absorption, epithelial cell migration and secretory cell differentiation. However, intestinal epithelial cell proliferation is not impeded, implying compensatory mechanisms. Genetic deletion of Erk1/2 or pharmacological targeting of MEK1/2 results in supraphysiological activity of the ERK5 pathway. Furthermore, targeting both pathways causes a more effective suppression of cell proliferation in murine intestinal organoids and human CRC lines. These results suggest that ERK5 provides a common bypass route in intestinal epithelial cells, which rescues cell proliferation upon abrogation of ERK1/2 signalling, with therapeutic implications in CRC.

PMID:
27187615
PMCID:
PMC4873670
DOI:
10.1038/ncomms11551
[Indexed for MEDLINE]
Free PMC Article

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