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

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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; Estall, Jennifer L.; Higgins, Rachel; Drucker, Daniel J.

In: Gastroenterology, Vol. 137, No. 3, 01.01.2009, p. 986-996.

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Harvard

Yusta, B, Holland, D, Koehler, JA, Maziarz, M, Estall, JL, Higgins, R & Drucker, DJ 2009, 'ErbB Signaling Is Required for the Proliferative Actions of GLP-2 in the Murine Gut', Gastroenterology, vol. 137, no. 3, pp. 986-996. https://doi.org/10.1053/j.gastro.2009.05.057

APA

Yusta, B., Holland, D., Koehler, J. A., Maziarz, M., Estall, J. L., Higgins, R., & Drucker, D. J. (2009). ErbB Signaling Is Required for the Proliferative Actions of GLP-2 in the Murine Gut. Gastroenterology, 137(3), 986-996. https://doi.org/10.1053/j.gastro.2009.05.057

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Yusta, Bernardo ; Holland, Dianne ; Koehler, Jacqueline A. ; Maziarz, Marlena ; Estall, Jennifer L. ; Higgins, Rachel ; Drucker, Daniel J. / ErbB Signaling Is Required for the Proliferative Actions of GLP-2 in the Murine Gut. In: Gastroenterology. 2009 ; Vol. 137, No. 3. pp. 986-996.

RIS

TY - JOUR

T1 - ErbB Signaling Is Required for the Proliferative Actions of GLP-2 in the Murine Gut

AU - Yusta, Bernardo

AU - Holland, Dianne

AU - Koehler, Jacqueline A.

AU - Maziarz, Marlena

AU - Estall, Jennifer L.

AU - Higgins, Rachel

AU - Drucker, Daniel J.

PY - 2009/1/1

Y1 - 2009/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=69249138379&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2009.05.057

DO - 10.1053/j.gastro.2009.05.057

M3 - Article

VL - 137

SP - 986

EP - 996

JO - Gastroenterology

JF - Gastroenterology

SN - 1528-0012

IS - 3

ER -