In vivo targeting of the growth hormone receptor (GHR) Box1 sequence demonstrates that the GHR does not signal exclusively through JAK2

Barclay, Johanna L., Kerr, Linda M., Arthur, Leela, Rowland, Jennifer E., Nelson, Caroline N., Ishikawa, Mayumi, d'Aniello, Elisabetta M., White, Mary, Noakes, Peter G. and Waters, Michael J. (2010) In vivo targeting of the growth hormone receptor (GHR) Box1 sequence demonstrates that the GHR does not signal exclusively through JAK2. Molecular Endocrinology, 24 1: 204-217. doi:10.1210/me.2009-0233


Author Barclay, Johanna L.
Kerr, Linda M.
Arthur, Leela
Rowland, Jennifer E.
Nelson, Caroline N.
Ishikawa, Mayumi
d'Aniello, Elisabetta M.
White, Mary
Noakes, Peter G.
Waters, Michael J.
Title In vivo targeting of the growth hormone receptor (GHR) Box1 sequence demonstrates that the GHR does not signal exclusively through JAK2
Journal name Molecular Endocrinology   Check publisher's open access policy
ISSN 0888-8809
1944-9917
Publication date 2010
Year available 2009
Sub-type Article (original research)
DOI 10.1210/me.2009-0233
Volume 24
Issue 1
Start page 204
End page 217
Total pages 14
Editor D. B. DeFranco
Place of publication MD, USA
Publisher The Endocrine Society
Collection year 2010
Language eng
Subject C1
92 Health
920106 Endocrine Organs and Diseases (excl. Diabetes)
06 Biological Sciences
0604 Genetics
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.
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Sun, 10 Jan 2010, 00:03:18 EST