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

Petrus R. De Jong, Koji Taniguchi, Alexandra R. Harris, Samuel Bertin, Naoki Takahashi, Jen Duong, Alejandro D. Campos, Garth Powis, Maripat Corr, Michael Karin, Eyal Raz

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32 Citations (Scopus)

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.

Original languageEnglish
Article number11551
JournalNature communications
Volume7
DOIs
Publication statusPublished - 2016 May 17

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    De Jong, P. R., Taniguchi, K., Harris, A. R., Bertin, S., Takahashi, N., Duong, J., Campos, A. D., Powis, G., Corr, M., Karin, M., & Raz, E. (2016). ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation. Nature communications, 7, [11551]. https://doi.org/10.1038/ncomms11551