title: Ghrelin promotes intestinal epithelial cell proliferation through PI3K/Akt pathway and EGFR trans-activation both converging to ERK 1/2 phosphorylation.
abstract: Little is known about ghrelin's effects on intestinal epithelial cells even though it is known to be a mitogen for a variety of other cell types. Because ghrelin is released in close proximity to the proliferative compartment of the intestinal tract, we hypothesized that ghrelin may have potent pro-proliferative effect on intestinal epithelial cells as well. To test this hypothesis, we characterized the effects of ghrelin on FHs74Int and Caco-2 intestinal epithelial cell lines in vitro. We found that ghrelin has potent dose dependent proliferative effects in both cell lines through a yet to be characterized G protein coupled growth hormone secretagogue receptor (GHS-R) subtype. Consistent with above findings, cell cycle flowcytometric analyses demonstrated that ghrelin shifts cells from the G1 to S phase and thereby promotes cell cycle progression. Further characterization of subcellular events, suggested that ghrelin mediates its pro-proliferative effect through Adenylate cyclase (AC)-independent epidermal growth factor receptor (EGFR) trans-activation and PI3K-Akt phosphorylation. Both these pathways converge to stimulate MAPK, ERK 1/2 downstream. The role of ghrelin in states where intestinal mucosal injury and rapid mucosal repair occur warrants further investigation.
authors.affiliation: Department of Surgery, Brigham & Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States.
authors.forename: Talat
authors.initials: T
authors.lastname: Waseem
authors.affiliation: Department of Surgery, Brigham & Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Duxbury
authors.affiliation: Department of Surgery, Brigham & Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States.
authors.forename: Stanley W
authors.initials: SW
authors.lastname: Ashley
authors.affiliation: Department of Surgery, Brigham & Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States. Electronic address: mkrobinson@partners.org.
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Robinson
mesh_terms: D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects*; D054439:Ghrelin / Q000494:pharmacology*; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D054439:Ghrelin; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Ghrelin; Intestinal cells; Proliferation; Signaling