ERK5 Signalling Rescues Intestinal Epithelial Turnover and Tumour Cell Proliferation Upon ERK1/2 Abrogation

Overview

Journal Nat Commun

Specialty Biology

Date 2016 May 18

PMID 27187615

Citations 40

Authors

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

Affiliations

Soon will be listed here.

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.

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