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 and Eyal Raz
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Petrus R. de Jong: University of California, San Diego
Koji Taniguchi: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego
Alexandra R. Harris: University of California, San Diego
Samuel Bertin: University of California, San Diego
Naoki Takahashi: University of California, San Diego
Jen Duong: University of California, San Diego
Alejandro D. Campos: Sanford Burnham Prebys Medical Discovery Institute, NCI-Designated Cancer Center
Garth Powis: Sanford Burnham Prebys Medical Discovery Institute, NCI-Designated Cancer Center
Maripat Corr: University of California, San Diego
Michael Karin: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego
Eyal Raz: University of California, San Diego

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11551

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