ErbB signaling is required for the proliferative actions of GLP-2 in the murine gut.
OBJECTIVE
Glucagon-like peptide-2 (GLP-2) is a 33-amino acid peptide hormone secreted by enteroendocrine cells in response to nutrient ingestion. GLP-2 stimulates crypt cell proliferation leading to expansion of the mucosal epithelium; however, the mechanisms transducing the trophic effects of GLP-2 are incompletely understood.


METHODS
We examined the gene expression profiles and growth-promoting actions of GLP-2 in normal mice in the presence or absence of an inhibitor of ErbB receptor signaling, in Glp2r(-/-) mice and in Egfr(wa2) mice harboring a hypomorphic point mutation in the epidermal growth factor receptor.


RESULTS
Exogenous GLP-2 administration rapidly induced the expression of a subset of ErbB ligands including amphiregulin, epiregulin, and heparin binding (HB)-epidermal growth factor, in association with induction of immediate early gene expression in the small and large bowel. These actions of GLP-2 required a functional GLP-2 receptor because they were eliminated in Glp2r(-/-) mice. In contrast, insulin-like growth factor-I and keratinocyte growth factor, previously identified mediators of GLP-2 action, had no effect on the expression of these ErbB ligands. The GLP-2-mediated induction of ErbB ligand expression was not metalloproteinase inhibitor sensitive but was significantly diminished in Egfr(wa2) mice and completed abrogated in wild-type mice treated with the pan-ErbB inhibitor CI-1033. Furthermore, the stimulatory actions of GLP-2 on crypt cell proliferation and bowel growth were eliminated in the presence of CI-1033.


CONCLUSIONS
These findings identify the ErbB signaling network as a target for GLP-2 action leading to stimulation of growth factor-dependent signal transduction and bowel growth in vivo.
Yusta
Bernardo
B
Department of Medicine, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Holland
Dianne
D
Koehler
Jacqueline A
JA
Maziarz
Marlena
M
Estall
Jennifer L
JL
Higgins
Rachel
R
Drucker
Daniel J
DJ
D066258:Amphiregulin; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism; D066260:Epiregulin; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology*; D006023:Glycoproteins / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007583:Jejunum / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018739:Oncogene Proteins v-erbB / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017354:Point Mutation; D015398:Signal Transduction
D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D066260:Epiregulin; C587881:Ereg protein, mouse; D053767:Glucagon-Like Peptide 2; D006023:Glycoproteins; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D018739:Oncogene Proteins v-erbB; D004815:Epidermal Growth Factor; D066246:ErbB Receptors