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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / pathology*
  • Enterocytes / enzymology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Homeostasis
  • Humans
  • Ileum / pathology
  • Ileum / ultrastructure
  • Integrases / metabolism
  • MAP Kinase Signaling System*
  • Malabsorption Syndromes / enzymology
  • Malabsorption Syndromes / pathology
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 7 / metabolism*
  • Models, Biological
  • Organoids / metabolism
  • Wasting Syndrome

Substances

  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 7
  • Cre recombinase
  • Integrases