Alexandros Skouris
PhD student
Rutgers University
EGFR Biased Signaling in Intestinal Inflammation and Epithelial Regeneration
The Epidermal Growth Factor Receptor (EGFR) regulates epithelial regeneration in the intestine during inflammatory bowel disease (IBD). Multiple ligands bind to EGFR, but EREG and EPIGEN induce a unique signaling pattern marked by weak EGFR dimerization and sustained ERK signaling. This phenomenon, in which a single receptor induces distinct signaling depending on the ligand, is termed ‘biased signaling’. EREG, which leads to weak EGFR dimerization, has a unique role in intestinal homeostasis, while a recent study indicated that it contributes to the maintenance of fibrosis in both lung and skin of bleomycin-treated mice, by activating EGFR in fibroblasts. The R84K point mutation in EGFR eliminates biased signaling in vitro. To examine the impact of EGFR biased signaling in vivo, we generated EGFR^R84K/R84K mice, hereafter referred to as R84K. We found that the R84K mice are protected against dextran sodium sulfate (DSS)-induced colitis. Bone marrow transplantation experiments indicate that R84K signaling within the non-hematopoietic cells drives the protection against colitis. Further, assessing the intestinal epithelial regeneration after irradiation showed decreased expression of inflammatory and tuft cell markers in the R84K small intestine. Altogether, our studies aim to provide mechanistic understanding of how EGFR biased signaling impacts intestinal health and may facilitate the development of EGFR-targeted therapeutics that support the repair of the intestinal mucosa.
The Epidermal Growth Factor Receptor (EGFR) regulates epithelial regeneration in the intestine during inflammatory bowel disease (IBD). Multiple ligands bind to EGFR, but EREG and EPIGEN induce a unique signaling pattern marked by weak EGFR dimerization and sustained ERK signaling. This phenomenon, in which a single receptor induces distinct signaling depending on the ligand, is termed ‘biased signaling’. EREG, which leads to weak EGFR dimerization, has a unique role in intestinal homeostasis, while a recent study indicated that it contributes to the maintenance of fibrosis in both lung and skin of bleomycin-treated mice, by activating EGFR in fibroblasts. The R84K point mutation in EGFR eliminates biased signaling in vitro. To examine the impact of EGFR biased signaling in vivo, we generated EGFR^R84K/R84K mice, hereafter referred to as R84K. We found that the R84K mice are protected against dextran sodium sulfate (DSS)-induced colitis. Bone marrow transplantation experiments indicate that R84K signaling within the non-hematopoietic cells drives the protection against colitis. Further, assessing the intestinal epithelial regeneration after irradiation showed decreased expression of inflammatory and tuft cell markers in the R84K small intestine. Altogether, our studies aim to provide mechanistic understanding of how EGFR biased signaling impacts intestinal health and may facilitate the development of EGFR-targeted therapeutics that support the repair of the intestinal mucosa.
