title: In vivo targeting of the growth hormone receptor (GHR) Box1 sequence demonstrates that the GHR does not signal exclusively through JAK2.
abstract: 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.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia 4072, Australia. j.barclay@uq.edu.au
authors.forename: Johanna L
authors.initials: JL
authors.lastname: Barclay
authors.forename: Linda M
authors.initials: LM
authors.lastname: Kerr
authors.forename: Leela
authors.initials: L
authors.lastname: Arthur
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Rowland
authors.forename: Caroline N
authors.initials: CN
authors.lastname: Nelson
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Elisabetta M
authors.initials: EM
authors.lastname: d'Aniello
authors.forename: Mary
authors.initials: M
authors.lastname: White
authors.forename: Peter G
authors.initials: PG
authors.lastname: Noakes
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Waters
mesh_terms: D000375:Aging; D000818:Animals; D001837:Body Weights and Measures; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D055879:Gene Knock-In Techniques; D013006:Growth Hormone / Q000494:pharmacology; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics* / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D011986:Receptors, Somatotropin; D050791:STAT Transcription Factors; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases