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

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  • Petrus R. de Jong

    (University of California, San Diego
    Sanford Burnham Prebys Medical Discovery Institute, NCI-Designated Cancer Center)

  • Koji Taniguchi

    (Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego
    Graduate School of Medical Sciences, Kyushu University
    Keio University School of Medicine)

  • Alexandra R. Harris

    (University of California, San Diego
    Present address: Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA)

  • Samuel Bertin

    (University of California, San Diego)

  • Naoki Takahashi

    (University of California, San Diego
    Niigata University Graduate School of Medical and Dental Sciences)

  • 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)

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.

Suggested Citation

  • 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, 2016. "ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation," Nature Communications, Nature, vol. 7(1), pages 1-15, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11551
    DOI: 10.1038/ncomms11551
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