title: GnRH-(1-5) transactivates EGFR in Ishikawa human endometrial cells via an orphan G protein-coupled receptor.
abstract: The decapeptide GnRH is known for its central role in the regulation of the hypothalamo-pituitary-gonadal axis. In addition, it is also known to have local effects within peripheral tissues. The zinc metalloendopeptidase, EC 3.4.24.15 (EP24.15), can cleave GnRH at the Tyr(5)-Gly(6) bond to form the pentapeptide, GnRH-(1-5). The central and peripheral effect of GnRH-(1-5) is different from its parent peptide, GnRH. In the current study, we examined the effect of GnRH-(1-5) on epidermal growth factor receptor (EGFR) phosphorylation and cellular migration. Using the Ishikawa cell line as a model of endometrial cancer, we demonstrate that GnRH-(1-5) stimulates epidermal growth factor release, increases the phosphorylation of EGFR (P < .05) at three tyrosine sites (992, 1045, 1068), and promotes cellular migration. In addition, we also demonstrate that these actions of GnRH-(1-5) are mediated by the orphan G protein-coupled receptor 101 (GPR101). Down-regulation of GPR101 expression blocked the GnRH-(1-5)-mediated release of epidermal growth factor and the subsequent phosphorylation of EGFR and cellular migration. These results suggest that GPR101 is a critical requirement for GnRH-(1-5) transactivation of EGFR in Ishikawa cells.
authors.affiliation: Department of Obstetrics and Gynecology (T.J.W., M.C., F.V.) and the Program in Molecular and Cellular Biology (D.O.L., T.J.W.), Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814; and Departments of Molecular and Cellular Biology and Neuroscience (S.K.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Madelaine
authors.initials: M
authors.lastname: Cho-Clark
authors.forename: Darwin O
authors.initials: DO
authors.lastname: Larco
authors.forename: Nina N
authors.initials: NN
authors.lastname: Semsarzadeh
authors.forename: Florencia
authors.initials: F
authors.lastname: Vasta
authors.forename: Shaila K
authors.initials: SK
authors.lastname: Mani
authors.forename: T John
authors.initials: TJ
authors.lastname: Wu
mesh_terms: D020013:Calcium Signaling; D045744:Cell Line, Tumor; D002465:Cell Movement; D016889:Endometrial Neoplasms; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D009842:Oligopeptides / Q000502:physiology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000502:physiology*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D011799:Quinazolines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011966:Receptors, LHRH; D013876:Thiophenes / Q000494:pharmacology; D015533:Transcriptional Activation; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C554449:ADGRF1 protein, human; C090711:GPAnt-2; C000594175:GPR101 protein, human; C495201:LHRH (1-5); D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D015513:Oncogene Proteins; D010446:Peptide Fragments; D011799:Quinazolines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011966:Receptors, LHRH; D013876:Thiophenes; D020032:Tyrphostins; C101044:RTKI cpd; D007987:Gonadotropin-Releasing Hormone; D010649:Phenylalanine; D004815:Epidermal Growth Factor; C080985:batimastat; C512478:EGFR protein, human; D066246:ErbB Receptors; D011761:Pyrrolidonecarboxylic Acid