ZFIN ID: ZDB-PUB-160401-18
Epidermal growth factor suppresses intestinal epithelial cell shedding via a MAPK dependent pathway
Miguel, J.C., Maxwell, A.A., Hsieh, J.J., Harnisch, L.C., Al Alam, D., Polk, D.B., Lien, C.L., Watson, A.J., Frey, M.R.
Date: 2017
Source: Journal of Cell Science   130(1): 90-96 (Journal)
Registered Authors: Lien, Ching-Ling (Ellen), Maxwell, Adrienne
Keywords: Intestinal epithelium, Inflammatory bowel disease, Epidermal growth factor receptor, EGFR, MAP kinases, MAPKs, Epithelial cell, Cell shedding
MeSH Terms:
  • Animals
  • Caspase Inhibitors/pharmacology
  • Caspases/metabolism
  • Dogs
  • Epidermal Growth Factor/pharmacology*
  • Epithelial Cells/drug effects
  • Epithelial Cells/metabolism*
  • Intestines/cytology*
  • MAP Kinase Signaling System/drug effects*
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases/metabolism
  • Protein Kinase Inhibitors/pharmacology
  • Zebrafish
  • rho GTP-Binding Proteins/metabolism
PubMed: 27026527 Full text @ J. Cell Sci.
Cell shedding from the intestinal villus is a key element of tissue turnover, essential to maintain health and homeostasis. However, the signals regulating this process are not well understood. We asked whether shedding is controlled by epidermal growth factor receptor (EGFR), an important driver of intestinal growth and differentiation. In 3D ileal enteroid culture and cell culture models (MDCK, IEC-6, IPEC-J2 cells), extrusion events were suppressed by EGF, as determined by direct counting of released cells or rhodamine-phalloidin labeling of condensed actin rings. Blockade of MEK/ERK, but not other downstream pathways such as PI3K or PKC, reversed EGF inhibition of shedding. These effects were not due to a change in cell viability. Furthermore, EGF-driven MAPK signaling inhibited both caspase-independent and -dependent shedding pathways. Similar results were foundin vivo,in a novel zebrafish model for intestinal epithelial shedding. Together, the data show that EGF suppresses cell shedding in the intestinal epithelium through a selective, MAPK dependent pathway affecting multiple extrusion mechanisms. EGFR signaling may be a therapeutic target for disorders featuring excessive cell turnover, such as inflammatory bowel diseases.