title: Growth hormone-stimulated insulin-like growth factor-1 expression in rainbow trout (Oncorhynchus mykiss) hepatocytes is mediated by ERK, PI3K-AKT, and JAK-STAT.
abstract: Growth hormone (GH) initiates many of its growth-promoting actions by binding to GH receptors (GHR) and stimulating the synthesis and secretion of insulin-like growth factor-1 (IGF-1) from the liver and other sites. In this study, we used hepatocytes isolated from rainbow trout as a model system in which to determine the molecular signaling events of GH in fish. GH directly stimulated the phosphorylation of ERK, protein kinase B (Akt), a downstream target of phosphatidylinositol 3-kinase (PI3K), JAK2, and STAT5 in hepatocytes incubated in vitro. Activation of ERK, Akt, JAK2, and STAT5 was rapid, occurring within 5-10 min, and was concentration dependent. GH-induced ERK activation was completely blocked by the ERK pathway inhibitor, U0126, and the JAK2 inhibitor, 1,2,3,4,5,6-hexabromocyclohexane (Hex), and was partially blocked by the PI3K inhibitor LY294002. GH-stimulated Akt activation was completely blocked by LY294002 and Hex, but was not affected by U0126; whereas, STAT5 activation by GH was blocked only by Hex, and was not affected by either U0126 or LY294002. GH stimulated hepatic expression of IGF-1 mRNA as well as the secretion of IGF-1, effects that were partially or completely blocked by U0126, LY294002, and Hex. These results indicate that GHR linkage to the ERK, PI3K/Akt, or STAT pathways in trout liver cells requires activation of JAK2, and that GH-stimulated IGF-1 synthesis and secretion is mediated through the ERK, PI3K/Akt, and JAK-STAT pathways.
authors.affiliation: Dept. of Biological Sciences, North Dakota State University, Fargo, ND 58108-6050, USA.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Reindl
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Kittilson
authors.forename: Heather E
authors.initials: HE
authors.lastname: Bergan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sheridan
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D013006:Growth Hormone / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D017686:Oncorhynchus mykiss; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D002070:Butadienes; D002867:Chromones; D003510:Cyclohexanes; D048049:Extracellular Signal-Regulated MAP Kinases; D013006:Growth Hormone; D007334:Insulin-Like Growth Factor I; D053612:Janus Kinases; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D050791:STAT Transcription Factors; C500162:1,2,3,4,5,6-hexabromocyclohexane; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one