GH is generally believed to signal exclusively through Janus tyrosine kinases (JAK), particularly JAK2, leading to activation of signal transducers and activators of transcription (STAT), ERK and phosphatidylinositol 3-kinase pathways, resulting in transcriptional regulation of target genes. Here we report the creation of targeted knock-in mice wherein the Box1 motif required for JAK2 activation by the GH receptor (GHR) has been disabled by four Pro/Ala mutations. These mice are unable to activate hepatic JAK2, STAT3, STAT5, or Akt in response to GH injection but can activate Src and ERK1/2. Their phenotype is identical to that of the GHR(-/-) mouse, emphasizing the key role of JAK2 in postnatal growth and the minimization of obesity in older males. In particular, they show dysregulation of the IGF-I/IGF-binding protein axis at transcript and protein levels and decreased bone length. Because no gross phenotypic differences were evident between GHR(-/-) and Box1 mutants, we undertook transcript profiling in liver from 4-month-old males. We compared their transcript profiles with our 391-GHR truncated mice, which activate JAK2, ERK1/2, and STAT3 in response to GH but not STAT5a/b. This has allowed us for the first time to identify in vivo Src/ERK-regulated transcripts, JAK2-regulated transcripts, and those regulated by the distal part of the GHR, particularly by STAT5.
Pubmed ID: 19884384 RIS Download
Mesh terms: Aging | Animals | Body Weights and Measures | Cell Line | Extracellular Signal-Regulated MAP Kinases | Female | Gene Expression Profiling | Gene Knock-In Techniques | Growth Hormone | Insulin-Like Growth Factor Binding Proteins | Insulin-Like Growth Factor I | Janus Kinase 2 | Liver | Male | Mice | Mice, Inbred C57BL | Mice, Transgenic | Organ Specificity | Protein Interaction Domains and Motifs | Proto-Oncogene Proteins c-akt | Receptors, Somatotropin | STAT Transcription Factors | Sex Characteristics | Signal Transduction | src-Family Kinases
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