{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T08:42:09Z","timestamp":1768898529269,"version":"3.49.0"},"reference-count":43,"publisher":"The Endocrine Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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\u2212\/\u2212 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\u2212\/\u2212 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.<\/jats:p>","DOI":"10.1210\/me.2009-0233","type":"journal-article","created":{"date-parts":[[2009,11,3]],"date-time":"2009-11-03T03:05:03Z","timestamp":1257217503000},"page":"204-217","source":"Crossref","is-referenced-by-count":62,"title":["In Vivo Targeting of the Growth Hormone Receptor (GHR) Box1 Sequence Demonstrates that the GHR Does Not Signal Exclusively through JAK2"],"prefix":"10.1210","volume":"24","author":[{"given":"Johanna L.","family":"Barclay","sequence":"first","affiliation":[{"name":"Institute for Molecular Bioscience (J.L.B., L.M.K., L.A., C.N.N., E.M.d.A., M.J.W.), St. Lucia, Australia 4072"}]},{"given":"Linda M.","family":"Kerr","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience (J.L.B., L.M.K., L.A., C.N.N., E.M.d.A., M.J.W.), St. Lucia, Australia 4072"}]},{"given":"Leela","family":"Arthur","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience (J.L.B., L.M.K., L.A., C.N.N., E.M.d.A., M.J.W.), St. Lucia, Australia 4072"}]},{"given":"Jennifer E.","family":"Rowland","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences (J.E.R., M.W., P.G.N.), University of Queensland, St. Lucia, Australia 4072"},{"name":"Instituto Gulbenkian de Ciencia (J.E.R.), 2780 Oeiras, Portugal"}]},{"given":"Caroline N.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience (J.L.B., L.M.K., L.A., C.N.N., E.M.d.A., M.J.W.), St. Lucia, Australia 4072"}]},{"given":"Mayumi","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (M.I.), Toho University School of Medicine, Tokyo 143-8540, Japan"}]},{"given":"Elisabetta M.","family":"d'Aniello","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience (J.L.B., L.M.K., L.A., C.N.N., E.M.d.A., M.J.W.), St. Lucia, Australia 4072"}]},{"given":"Mary","family":"White","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences (J.E.R., M.W., P.G.N.), University of Queensland, St. Lucia, Australia 4072"}]},{"given":"Peter G.","family":"Noakes","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences (J.E.R., M.W., P.G.N.), University of Queensland, St. Lucia, Australia 4072"}]},{"given":"Michael J.","family":"Waters","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience (J.L.B., L.M.K., L.A., C.N.N., E.M.d.A., M.J.W.), St. Lucia, Australia 4072"}]}],"member":"80","reference":[{"key":"2020071614083372500_R1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0092-8674(93)90415-M","article-title":"Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase.","volume":"74","author":"Argetsinger","year":"1993","journal-title":"Cell"},{"key":"2020071614083372500_R2","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.1210\/endo.135.5.7956946","article-title":"Interaction of the GH receptor cytoplasmic domain with the JAK2 tyrosine kinase.","volume":"135","author":"Frank","year":"1994","journal-title":"Endocrinology"},{"key":"2020071614083372500_R3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1677\/jme.1.01933","article-title":"New insights into growth hormone action.","volume":"36","author":"Waters","year":"2006","journal-title":"J Mol Endocrinol"},{"key":"2020071614083372500_R4","author":"Smit"},{"key":"2020071614083372500_R5","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/j.1651-2227.1999.tb14382.x","article-title":"Signal transduction defects in growth hormone insensitivity.","volume":"88","author":"Clayton","year":"1999","journal-title":"Acta Paediatr Suppl"},{"key":"2020071614083372500_R6","doi-asserted-by":"crossref","first-page":"45592","DOI":"10.1074\/jbc.M201385200","article-title":"Identification of a JAK2-independent pathway regulating growth hormone (GH)-stimulated p44\/42 mitogen-activated protein kinase activity. GH activation of Ral and phospholipase D is Src-dependent.","volume":"277","author":"Zhu","year":"2002","journal-title":"J Biol Chem"},{"key":"2020071614083372500_R7","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/ncb1737","article-title":"An agonist-induced conformational change in the growth hormone receptor determines the choice of signaling pathway.","volume":"10","author":"Rowlinson","year":"2008","journal-title":"Nat Cell Biol"},{"key":"2020071614083372500_R8","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1042\/0264-6021:3450017","article-title":"Stimulation of c-Src by prolactin is independent of Jak2.","volume":"345","author":"Fresno Vara","year":"2000","journal-title":"Biochem J"},{"key":"2020071614083372500_R9","doi-asserted-by":"crossref","first-page":"33282","DOI":"10.1074\/jbc.M102924200","article-title":"CrkL is recruited through its SH2 domain to the erythropoietin receptor and plays a role in Lyn-mediated receptor 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