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ErbB Signaling Is Required for the Proliferative Actions of GLP-2 in the Murine Gut

Yusta, Bernardo ; Holland, Dianne ; Koehler, Jacqueline A. ; Maziarz, Marlena LU ; Estall, Jennifer L. ; Higgins, Rachel and Drucker, Daniel J. (2009) In Gastroenterology 137(3). p.986-996
Abstract

Background & Aims: 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 Egfrwa2 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... (More)

Background & Aims: 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 Egfrwa2 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 Egfrwa2 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.

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type
Contribution to journal
publication status
published
subject
in
Gastroenterology
volume
137
issue
3
pages
11 pages
publisher
Elsevier
external identifiers
  • pmid:19523469
  • scopus:69249138379
ISSN
0016-5085
DOI
10.1053/j.gastro.2009.05.057
language
English
LU publication?
yes
id
fc78caa0-6650-49ce-b98f-55739a0d3d65
date added to LUP
2019-08-05 13:18:25
date last changed
2021-09-08 01:52:35
@article{fc78caa0-6650-49ce-b98f-55739a0d3d65,
  abstract     = {<p>Background &amp; Aims: 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<sup>-/-</sup> mice and in Egfr<sup>wa2</sup> 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<sup>-/-</sup> 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<sup>wa2</sup> 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.</p>},
  author       = {Yusta, Bernardo and Holland, Dianne and Koehler, Jacqueline A. and Maziarz, Marlena and Estall, Jennifer L. and Higgins, Rachel and Drucker, Daniel J.},
  issn         = {0016-5085},
  language     = {eng},
  month        = {01},
  number       = {3},
  pages        = {986--996},
  publisher    = {Elsevier},
  series       = {Gastroenterology},
  title        = {ErbB Signaling Is Required for the Proliferative Actions of GLP-2 in the Murine Gut},
  url          = {http://dx.doi.org/10.1053/j.gastro.2009.05.057},
  doi          = {10.1053/j.gastro.2009.05.057},
  volume       = {137},
  year         = {2009},
}