Abstract
After receptor binding, growth hormone (GH) induces GH receptors (GHR) dimerization and JAK2 is activated after its association with a dimerized GHR, stimulating the tyrosyl phosphorylation of insulin receptor substrate-1 (IRS-1), IRS-2 and Shc proteins. G120K-PEG, a GH antagonist is produced by a mutation that blocks GH action by preventing the GHR dimerization. This study shows that the inhibitory effect of G120K-PEG was maximal with a GH:G120K-PEG ratio of 1:100, as no increase in JAK2 tyrosyl phosphorylation was observed with this dose of GH. When the dose of GH was increased and with a GH:G120K-PEG ratio of 1:10 some tyrosyl phosphorylation of JAK2 could be observed. Additionally, GH-induced IRS-1, IRS-2 and SHC tyrosyl phosphorylation was inhibited approximately 50% at equimolar concentrations of the antagonist of GH and almost abolished with a GH:G120K-PEG ratio of 1:100. The results clearly show that G120K-PEG inhibits GH signal transduction in mouse liver.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adaptor Proteins, Vesicular Transport*
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Animals
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Dimerization
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Dose-Response Relationship, Drug
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Hormone Antagonists / pharmacology*
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Human Growth Hormone / antagonists & inhibitors*
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Human Growth Hormone / pharmacology
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Humans
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Janus Kinase 2
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Liver / drug effects*
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Liver / metabolism
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Male
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Mice
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Phosphotyrosine / analysis
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Polyethylene Glycols / pharmacology*
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Prolactin / pharmacology
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Protein Processing, Post-Translational / drug effects
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Protein-Tyrosine Kinases / metabolism
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Proteins / metabolism
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Proto-Oncogene Proteins*
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Receptors, Somatotropin / chemistry
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Receptors, Somatotropin / drug effects
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Shc Signaling Adaptor Proteins
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Signal Transduction / drug effects*
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Src Homology 2 Domain-Containing, Transforming Protein 1
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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G120K-PEG
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Hormone Antagonists
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IRS1 protein, human
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IRS2 protein, human
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Irs1 protein, mouse
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Irs2 protein, mouse
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Phosphoproteins
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Proteins
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Proto-Oncogene Proteins
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Receptors, Somatotropin
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SHC1 protein, human
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Shc Signaling Adaptor Proteins
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Shc1 protein, mouse
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Human Growth Hormone
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Phosphotyrosine
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Polyethylene Glycols
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Prolactin
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Jak2 protein, mouse
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Janus Kinase 2