TY - JOUR
T1 - ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation
AU - De Jong, Petrus R.
AU - Taniguchi, Koji
AU - Harris, Alexandra R.
AU - Bertin, Samuel
AU - Takahashi, Naoki
AU - Duong, Jen
AU - Campos, Alejandro D.
AU - Powis, Garth
AU - Corr, Maripat
AU - Karin, Michael
AU - Raz, Eyal
N1 - Funding Information:
We thank M. Scholl and S. Herdman for animal breeding. We thank L. Deng and S. Shenouda for tissue processing. We thank Professor N. Varki from the Department of Pathology (UCSD) for the histological evaluations. We thank M. Mashore from the Microimaging Core Facility (VA San Diego Healthcare System) for his assistance with transmission electron microscopy. We thank J. Santini for assistance in confocal imaging at the University of California at San Diego Neuroscience Microscopy Shared Facility, funded by NIH Grant P30 NS047101 through the NINDS. We thank Dr B. James from the SBP Genomics Shared Resource for cell line authentication, supported by the Sanford Burnham Prebys NCI Cancer Center Support Grant P30 CA030199. We thank Dr S. Grivennikov (Fox Chase Cancer Center) for his comments. This study was supported by grants from the Crohn's and Colitis Foundation of America (CCFA) to P.R.d.J. (Research Fellowship Award #2927), E.R. (Senior Research Award #330251) and S.B. (Career Development Award #381862); the Japan Society for the Promotion of Science (JSPS) to N.T.; a postdoctoral fellowship for Research Abroad, Research Fellowship for Young Scientists and the Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation from the Japan Society for the Promotion of Science (JSPS), and a Uehara Memorial Foundation Fellowship to K.T.; the NIH AI095623 and DK035108 to E.R.; the NIH CA160398 to G.P.; and the NIH AI043477 to M.K., who is an American Cancer Society Research Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.
Publisher Copyright:
© 2016, Nature Publishing Group. All rights reserved.
PY - 2016/5/17
Y1 - 2016/5/17
N2 - 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.
AB - 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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U2 - 10.1038/ncomms11551
DO - 10.1038/ncomms11551
M3 - Article
C2 - 27187615
AN - SCOPUS:84968763638
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 11551
ER -
