title: Growth hormone-induced differential desensitization of STAT5, ERK, and Akt phosphorylation.
abstract: Secretion of growth hormone (GH) in adult male rats is characterized by high peak and undetectable trough levels, both of which are required for male-specific pattern of liver gene expression and GH-induced phosphorylation of STAT5. The present study suggests that regulation of GH receptor (GHR) levels in rat hepatoma cells by repeated GH stimulation determines GH responsiveness via the JAK2/STAT5 pathway. A short exposure to GH rapidly reduced GHR levels which resulted in an equal desensitization of the JAK2/STAT5 pathway. Recovery of GH-induced STAT5 phosphorylation correlated with the time-dependent recovery of GHR levels during incubation in the absence of GH. Acute GH also induced phosphorylation of ERK1/2 and Akt, and this induction was also inhibited by prior exposure to GH. However, unlike the JAK2/STAT5 pathway, the effect of GH to activate the MEK/ERK and phosphatidylinositol 3-kinase/Akt pathways did not recover following prolonged incubation in the absence of GH. Thus, GH administration desensitizes the JAK2/STAT5 pathway, possibly because of down-regulation of GHR, whereas an additional post-receptor mechanism is required for the prolonged refractoriness of the MEK/ERK and phosphatidylinositol 3-kinase/Akt pathways toward a second GH stimulation. Our study suggests that both receptor and post-receptor mechanisms are important in GH-induced homologous desensitization.
authors.affiliation: Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, and the Birmingham Veterans Affairs Medical Center, Birmingham, Alabama 35294, USA.
authors.forename: Shaonin
authors.initials: S
authors.lastname: Ji
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Frank
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Messina
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003720:Densitometry; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D013006:Growth Hormone / Q000494:pharmacology*; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology; D053614:Janus Kinase 2; D007700:Kinetics; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D013006:Growth Hormone; D007328:Insulin; D053614:Janus Kinase 2; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C507927:Jak2 protein, rat; C494920:Akt1 protein, rat