title: ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation.
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.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.|Sanford Burnham Prebys Medical Discovery Institute, NCI-Designated Cancer Center, La Jolla, California 92037, USA.
authors.forename: Petrus R
authors.initials: PR
authors.lastname: de Jong
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, California 92093, USA.|Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.|Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Harris
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Bertin
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.|Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8514, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Jen
authors.initials: J
authors.lastname: Duong
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, NCI-Designated Cancer Center, La Jolla, California 92037, USA.
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Campos
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, NCI-Designated Cancer Center, La Jolla, California 92037, USA.
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000473:pathology*; D020895:Enterocytes / Q000201:enzymology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007082:Ileum / Q000473:pathology / Q000648:ultrastructure; D019426:Integrases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008286:Malabsorption Syndromes / Q000201:enzymology / Q000473:pathology; D008810:Mice, Inbred C57BL; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D008954:Models, Biological; D009940:Organoids / Q000378:metabolism; D019282:Wasting Syndrome
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D048054:Mitogen-Activated Protein Kinase 7; C045073:Cre recombinase; D019426:Integrases