Growth hormone, STAT activation

Cytokine receptors that couple to the JAK-STAT Pathway decode the signaling though hematopoietic cytokines (erythropoietin, thrombopoietin, colony-stimulating factors), prolactin, growth hormone, the a-, (3- and y- interferons, and a number of immunomodulatory interleukins [3], They form homodimetic or heterodimeric receptor complexes, which after ligandbinding recruit and activate isotypes of Janus kinases (JAKs). Activated JAKs in turn... 

FIGURE 4.3 Growth hormone receptor. Monomeric GH associates with two receptor monomers. Activated JAK2 kinases /ram-phosphorylatc JAK2 and GH receptors, and STAT transcription factors are phosphorylated by JAK2. 

STAT1 is activated by various ligands including cytokines, IFN-a, IFN-y, IL-4, IL-5, IL-13, growth factors and hormones. It has four conserved domains N-terminal, C-terminal, SH2 domain and DNA-binding domain, which is typical of all STAT family members. The SH2 domain is distinct for each STAT and a stable SH2-phosphotyrosine bond is formed after the SH2 domain binds to its specific phosphotyrosine domain. This SH2-pTyr bond is responsible for STAT activation... 

Not all receptors may be expressed in the same cell. A case in question is the restricted, cell-specific expression of receptors for IL-2, erythropoietin, thrombo-poietin, prolactin, and growth hormone, all of which activate the same STAT. 

The mutated hormone would bind to the growth-hormone receptor but would not favor receptor dimerization. Thus, it would not stimulate the JAK-STAT signaling pathway. Such a mutated hormone might be useful as a competitive inhibitor for growth hormone. It would block the activity of native growth hormone. 

Growth hormone activation of Stat 1, Stat 3, and Stat 5 in rat liver. Differential kinetics of hormone desensitization and growth hormone stimulation of both tyrosine phosphorylation and serine/threonine phosphorylation. J. Biol. Chem. 271, 5929-5940. 

CYP cytochrome P450 GH growth hormone GHR GH receptor HNF hepatocyte nuclear factor 3MC 3-methylcholanthrene MSG monosodium glutamate SOCS suppressor of cytokine signaling protein STAT signal transducer and activator of transcription. 

Fig. 11.9 Sex-diSerential binding of signal transducer and activator of transcription 5 STAT5) to liver chromatin in male and female liver. The male plasma growth hormone GH) profile aetivates a male-specific pattern of STATS binding to liver ehromatin at sites that are more accessible in male than female liver ( male-biased DHS ), as determined by DNase hypersensitivity site DHS) anal-...

Lahuna O, Rastegar M, Maiter D, Thissen JP, Le-maigre FP, Rousseau GG (2000) Involvement of STATS (signal transducer and activator of transcription 5) and HNF-4 (hepatocyte nuclear factor 4) in the transcriptional control of the hnf6 gene by growth hormone. Mol Endocrinol 14 285-294... 

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