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.
Highlights
The extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogenactivated protein kinases (MAPKs) signalling module integrates extracellular cues that induce proliferation and differentiation of epithelial lineages, and is an established oncogenic driver, in the intestine
The ERK1/2 pathway is likely activated by autocrine and paracrine factors downstream of receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR)[10], and by exogenous microbialderived substrates that signal through the Toll-like receptor (TLR)/MyD88 pathway[11]
Here we show that ERK1/2 signalling in mouse intestinal epithelium is dispensable for cell proliferation, while it resulted in abnormal differentiation of enterocytes, wasting disease and lethality (Fig. 1)
Summary
The ERK1/2 MAPK signalling module integrates extracellular cues that induce proliferation and differentiation of epithelial lineages, and is an established oncogenic driver, in the intestine. Genetic deletion of Erk1/2 in primary IEC or treatment of colorectal cancer (CRC) cell lines with MEK1/2 inhibitors results in compensatory activation of the ERK5 pathway. Immunofluorescent staining of small intestine and colon confirmed IEC-specific deletion of ERK1/2; ERK2-positive immunoreactivity in DIEC mice was observed only in lamina propria cells and intraepithelial lymphocytes (Fig. 1a).
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