Signalling Pathway of GH.

Carter‐Su, Christin; King, Anthony P.; Argetsinger, Lawrence S.; Smit, Lisa S.; VanderKuur, Joyce A.; Campbell, George S.

doi:10.1507/endocrj.43.suppl_s65

Cited by 45 publications

(22 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We show that Jak2 is the kinase that phosphorylates Fpn in response to hepcidin, thereby identifying the molecular basis of Fpn down-regulation. The binding and activation of Jak2 to cytokine and growth factor receptors following ligand administration is well recognized (11,17). Fpn differs from cytokine and growth factor receptors as it is a polytopic membrane protein and not a single transmembrane protein.…”

Section: Discussionmentioning

confidence: 99%

Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2

Domenico

Lo²,

Kaplan³

2009

Proc. Natl. Acad. Sci. U.S.A.

126

111

View full text Add to dashboard Cite

Hepcidin is a hormone secreted in response to iron loading and inflammation. Hepcidin binds to the iron exporter ferroportin, inducing its degradation and thus preventing iron entry into plasma. We determined that hepcidin binding to ferroportin leads to the binding and activation of the protein Janus Kinase2 (Jak2), which is required for phosphorylation of ferroportin. Ferroportin is a dimer and both monomers must be capable of binding hepcidin for Jak2 to bind to ferroportin. Once Jak2 is bound to the ferroportin dimer, both ferroportin monomers must be functionally competent to activate Jak2 and for ferroportin to be phosphorylated. These results show that cooperativity between the ferroportin monomers is required for hepcidin-mediated Jak2 activation and ferroportin down-regulation. These results provide a molecular explanation for the dominant inheritance of hepcidin resistant iron overload disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2

Domenico

Lo²,

Kaplan³

2009

Proc. Natl. Acad. Sci. U.S.A.

126

111

View full text Add to dashboard Cite

show abstract

“…We examined whether the transcription response was mediated by Stat transcription factors, as Jak2 is known to activate Stat transcription factors (6,7,11). Stat3 was coimmunoprecipitated with Fpn in the presence but not in the absence of hepcidin (Figure 2A).…”

Section: Hepcidin Binding To Fpn Induces a Transcriptional Response mentioning

confidence: 99%

“…Studies have shown that activation of Jak2, by growth factor or cytokine receptors, results in receptor phosphorylation as well as the phosphorylation of Stats, which are transcriptional activators (6,7). Here we demonstrate that activation of Jak2, through binding of hepcidin to Fpn, results in Stat3-mediated transcriptional activation of a large number of genes.…”

Section: Introductionmentioning

confidence: 99%

Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice

Domenico¹,

Zhang²,

Koening³

et al. 2010

J. Clin. Invest.

173

118

View full text Add to dashboard Cite

Hepcidin is a peptide hormone that regulates iron homeostasis and acts as an antimicrobial peptide. It is expressed and secreted by a variety of cell types in response to iron loading and inflammation. Hepcidin mediates iron homeostasis by binding to the iron exporter ferroportin, inducing its internalization and degradation via activation of the protein kinase Jak2 and the subsequent phosphorylation of ferroportin. Here we have shown that hepcidin-activated Jak2 also phosphorylates the transcription factor Stat3, resulting in a transcriptional response. Hepcidin treatment of ferroportin-expressing mouse macrophages showed changes in mRNA expression levels of a wide variety of genes. The changes in transcript levels for half of these genes were a direct effect of hepcidin, as shown by cycloheximide insensitivity, and dependent on the presence of Stat3. Hepcidinmediated transcriptional changes modulated LPS-induced transcription in both cultured macrophages and in vivo mouse models, as demonstrated by suppression of IL-6 and TNF-α transcript and secreted protein. Hepcidin-mediated transcription in mice also suppressed toxicity and morbidity due to single doses of LPS, poly(I:C), and turpentine, which is used to model chronic inflammatory disease. Most notably, we demonstrated that hepcidin pretreatment protected mice from a lethal dose of LPS and that hepcidin-knockout mice could be rescued from LPS toxicity by injection of hepcidin. The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses.

show abstract

“…Growth hormone (GH), a multifunctional hormone secreted from somatotrophs of the anterior pituitary, regulates overall body and cell growth, carbohydrate-proteinlipid metabolism, and water-electrolyte balance (10,34). Production and release of GH are controlled tightly but occasionally fall into imbalance; GH excess results in acromegaly and gigantism, whereas its deficiency in children results in impaired growth and short stature.…”

Section: Introductionmentioning

confidence: 99%

Ghrelin: Structure and Function

Kojima

Kangawa²

2005

Physiological Reviews

1,621

1,176

View full text Add to dashboard Cite

Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-R, a G protein-coupled receptor whose ligand has only been discovered recently. Using a reverse pharmacology paradigm with a stable cell line expressing GHS-R, we purified an endogenous ligand for GHS-R from rat stomach and named it “ghrelin,” after a word root (“ghre”) in Proto-Indo-European languages meaning “grow.” Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin's activity. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. In addition, ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Ghrelin is orexigenic; it is secreted from the stomach and circulates in the bloodstream under fasting conditions, indicating that it transmits a hunger signal from the periphery to the central nervous system. Taking into account all these activities, ghrelin plays important roles for maintaining GH release and energy homeostasis in vertebrates.

show abstract

Signalling Pathway of GH.

Cited by 45 publications

References 32 publications

Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2

Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2

Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice

Ghrelin: Structure and Function

Contact Info

Product

Resources

About