Molecular Events in Growth Hormone–Receptor Interaction and Signaling

Smit, Lisa S.; Meyer, Debra J.; Argetsinger, Lawrence S.; Schwartz, Jessica; Carter‐Su, Christin

doi:10.1002/cphy.cp070514

Cited by 16 publications

(14 citation statements)

References 374 publications

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“…Cell type specificity was one hypothesis put forward to explain the apparent discrepancy between these two groups regarding the role of Src in Stat5b phosphorylation [28]. Previous studies in IM-9 and CHO cells based upon truncated and mutated GHR and JAK2 inhibitors had suggested that regulation of cellular [Ca 2+ ] by GH may also be JAK2 independent [21], raising the possibility that this function might also be mediated by Src. Although recent inhibitor studies by Zhang et al [29] found that human GH-induced increases in cytosolic free Ca 2+ in and insulin secretion from BRIN-BD11 beta cells appeared to be dependent upon activation of both JAK2 and Src, these actions were not mediated via the GHR but rather the prolactin receptor which can also bind human GH.…”

Section: Gh Signal Transduction Via Src Tyrosine Kinasementioning

confidence: 97%

“…tyrosine 966 [20]) as well as the phosphorylated tyrosines in GHR, are thought to serve as docking sites for signaling molecules containing Src homology 2 (SH2) or phosphotyrosine binding (PTB) domains. Based on mutational studies, seven different tyrosines within the cytoplasmic domain of the GHR have been implicated in at least one downstream GH response (reviewed in [21]). For example, five or six phosphorylated tyrosines in GHR have been hypothesized to bind Stat5a and Stat5b, based upon decreased GH-dependent Stat5 tyrosyl phosphorylation or Stat5-dependent responses in cells expressing mutated or truncated GHR [11,[22][23][24].…”

Section: Gh Signal Transduction Via Jak2mentioning

confidence: 99%

“…Recruitment of these signaling molecules to GHR-JAK2 complexes and their activation allows GH to elicit diverse biological and physiological effects. A number of signaling proteins and pathways are thought to be initiated at least in part as a consequence of binding to activated GHR-JAK2 complexes (reviewed in [21,25]). Examples include Stats 1, 3, 5a and 5b, the MAPK pathway, and the phosphatidylinositol 3′-kinase (PI3K) pathway ( Fig.…”

Section: Gh Signal Transduction Via Jak2mentioning

confidence: 99%

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Recent advances in growth hormone signaling

Lanning

Carter‐Su

2006

Rev Endocr Metab Disord

209

163

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Growth hormone (GH) is a major regulatory factor for overall body growth as evidenced by the height extremes in people with abnormal circulating GH levels or GH receptor (GHR) disruptions. GH also affects metabolism, cardiac and immune function, mental agility and aging. Currently, GH is being used therapeutically for a variety of clinical conditions including promotion of growth in short statured children, treatment of adults with GH deficiency and HIV-associated wasting. To help reveal previous unrecognized functions of GH, better understand the known functions of GH, and avoid adverse consequences that are often associated with exogenous GH administration, careful delineation of the molecular mechanisms whereby GH induces its diverse effects is needed. GH is a peptide hormone that is secreted into the circulation by the anterior pituitary and acts upon various target tissues expressing GHR. GH binding of GHR activates the tyrosine kinase Janus kinase 2 (JAK2), thus initiating a multitude of signaling cascades that result in a variety of biological responses including cellular proliferation, differentiation and migration, prevention of apoptosis, cytoskeletal reorganization and regulation of metabolic pathways. A number of signaling proteins and pathways activated by GH have been identified, including JAKs, signal transducers and activators of transcription (Stats), the mitogen activated protein kinase (MAPK) pathway, and the phosphatidylinositol 3'-kinase (PI3K) pathway. Although these signal transduction pathways have been well characterized, the manner by which GH activates these pathways, the downstream signals induced by these pathways, and the cross-talk with other pathways are not completely understood. Recent findings have added vital information to our understanding of these downstream signals induced by GH and mechanisms that terminate GH signaling, and identified new GH signaling proteins and pathways. This review will highlight some of these findings, many of which are unexpected and some of which challenge previously held beliefs about the mechanisms of GH signaling.

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Section: Gh Signal Transduction Via Src Tyrosine Kinasementioning

confidence: 97%

Section: Gh Signal Transduction Via Jak2mentioning

confidence: 99%

Section: Gh Signal Transduction Via Jak2mentioning

confidence: 99%

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Recent advances in growth hormone signaling

Lanning

Carter‐Su

2006

Rev Endocr Metab Disord

209

163

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“…These responses are initiated by the interaction of GH with the GH receptor, a member of the cytokine receptor superfamily (12,13). Janus kinase 2 (JAK2), a non-receptor tyrosine kinase, associates with dimerized GH receptors (14).…”

Section: Introductionmentioning

confidence: 99%

“…The activated JAK2 phosphorylates itself and the cytoplasmic domain of the GH receptor to initiate downstream signaling. Cytoplasmic signaling molecules, including Signal Transducers and Activators of Transcription (Stats), pathways mediated by Mitogen Activated Protein Kinases (MAPK), and Phosphatidy Inositol 3′ Kinase (PI3K), relay GH signals to the nuclei of target cells to modulate gene transcription (12,13,15,16).…”

Section: Introductionmentioning

confidence: 99%

Multiple mechanisms of growth hormone-regulated gene transcription

Ceseña

Cui

Piwien-Pilipuk³

et al. 2007

Molecular Genetics and Metabolism

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Diverse physiological actions of growth hormone (GH) are mediated by changes in gene transcription. Transcription can be regulated at several levels, including post-translational modification of transcription factors, and formation of multiprotein complexes involving transcription factors, co-regulators and additional nuclear proteins; these serve as targets for regulation by hormones and signaling pathways. Evidence that GH regulates transcription at multiple levels is exemplified by analysis of the proto-oncogene c-fos. Among the GH-regulated transcription factors on c-fos, C/EBPβ appears to be key, since depletion of C/EBPβ by RNA interference blocks the stimulation of c-fos by GH. The phosphorylation state of C/EBPβ and its ability to activate transcription are regulated by GH through MAPK and PI3K/Akt-mediated signaling cascades. The acetylation of C/EBPβ also contributes to its ability to activate c-fos transcription. These and other post-translational modifications of C/EBPβ appear to be integrated for regulation of transcription by GH. The formation of nuclear proteins into complexes associated with DNA-bound transcription factors is also regulated by GH. Both C/EBPβ and the co-activator p300 are recruited to c-fos in response to GH, altering c-fos promoter activation. In addition, GH rapidly induces spatio-temporal relocalization of C/EBPβ within the nucleus. Thus, GH-regulated gene transcription mediated by C/ EBPβ reflects the integration of diverse mechanisms including post-translational modifications, modulation of protein complexes associated with DNA and relocalization of gene regulatory proteins. Similar integration involving other transcription factors, including Stats, appears to be a feature of regulation by GH of other gene targets.

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The Metabolic Actions of Growth Hormone

Goodman

2001

Comprehensive Physiology

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Molecular Events in Growth Hormone–Receptor Interaction and Signaling

Cited by 16 publications

References 374 publications

Recent advances in growth hormone signaling

Recent advances in growth hormone signaling

Multiple mechanisms of growth hormone-regulated gene transcription

The Metabolic Actions of Growth Hormone

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