Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resistance to growth hormone (GH)-mediated induction of insulin-like growth factor I (IGF-I) is a common complication of catabolic diseases, including critical illness and post-surgical conditions. This resistance to GH is believed to be permissive to the development of protein catabolism, cachexia and wasting, which are associated with an increased mortality rate. Data from in vitro studies and animal models suggest that increased levels of inflammatory cytokines can induce cachexia and might inhibit the effects of GH on target tissues. The molecular mechanisms involved are unclear, although an effect of cytokines on GH receptor signalling has been suggested. The GH-activated pathways that mediate the increase in IGF-I levels are not well understood, thereby impeding the elucidation of the effect of inflammatory cytokines. Several signalling cascades, like the JAK-STAT and MAP kinase pathways, have been shown to be activated by GH and some inflammatory cytokines, hence raising the possibility of crosstalk on this level. Our data, however, indicate that inflammatory cytokines have little or no effect on GH-mediated JAK-STAT signalling. In this review, we discuss these results and the possibility that secondary changes in the structure of chromatin are likely to be involved in the induction of IGF-I gene transcription by GH.
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PMID:Inflammatory cytokines and acquired growth hormone resistance. 1098 47

Growth hormone (GH) has long been known to be a primary determinant of body height and an important regulator of body metabolism, yet the cellular and molecular bases for these effects of GH are only beginning to be understood. In 1993, GH receptor (GHR) was first observed to bind to the tyrosine kinase JAK2. GH increased JAK2's affinity for GHR, potently activated JAK2, and stimulated the phosphorylation of tyrosines within JAK2 and the cytoplasmic domain of GHR. In the intervening six years, a variety of signaling molecules have been identified that are tyrosyl phosphorylated in response to GH, presumably by the activated JAK2. These signaling molecules include 1) the latent cytoplasmic transcription factors--designated signal transducers and activators of transcription (Stats)--that have been implicated in the regulation of a variety of GH-dependent genes; 2) Shc proteins that lead to activation of the Ras-MAP kinase pathway: and 3) insulin receptor substrate (IRS) proteins that bind and thereby activate phosphatidylinositol 3' kinase and presumably other proteins. Recently, we have identified two additional signaling molecules for GH that bind to JAK2 and are phosphorylated on tyrosines in response to GH: SH2-B and signal regulated protein (SIRP). Based upon amino acid sequence analysis, SH2-B is presumed to be a cytoplasmic adapter protein. It binds with high affinity via its SH2 domain to phosphorylated tyrosines within JAK2. GH-induced binding of SH2-B to JAK2 via this site potently activates JAK2, leading to enhanced tyrosyl phosphorylation of Stat proteins and other cellular proteins. Because of its other potential protein-protein interaction domains and its recruitment and phosphorylation by kinases that are not activated by SH2-B, SH2-B is thought likely to mediate other, more-specific actions of GH, as yet to be determined. SIRP is a transmembrane protein that is now known to bind to integrin-associated protein. It appears to bind directly to JAK2 by a process that does not require tyrosyl phosphorylation, although is itself highly phosphorylated on tyrosines in response to GH. The phosphorylated SIRP recruits one or more molecules of the tyrosine phosphatase SHP2 that, in turn, de-phosphorylates SIRP and most likely JAK2. Thus, SIRP is predicted to be a negative regulator of GH action. It seems likely that the diverse actions of GH will be found to require coordinated interaction of all of these signaling proteins with each other as well as with other signaling molecules that are activated by GH and the numerous other ligands that are present at cells during a response to GH.
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PMID:SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone. 1103 42

Insulin modulates the biological actions of GH, but little is known about its effect on human hepatic GH receptors (GHRs). Using the human hepatoma cell line HuH7 as a model, we investigated insulin regulation of total, intracellular, and cell surface GHRs and receptor biosynthesis and turnover. Insulin up-regulated total and intracellular GHRs in a concentration-dependent manner. It increased surface GHRs in a biphasic manner, with a peak response at 10 nmol/L, and modulated GH-induced Janus kinase-2 phosphorylation in parallel with expression of surface GHRs. The abundance of GHR messenger ribonucleic acid and protein, as assessed by RT-PCR and Western analysis, respectively, markedly increased with insulin treatment. To examine whether insulin regulates GHRs at the posttranslational level, its effects on receptor surface translocation and internalization were investigated. Insulin suppressed surface translocation in a concentration-dependent manner, whereas internalization was unaffected. Moreover, insulin actions on total GHRs and surface translocation were inhibited by PD98059 and wortmannin, respectively. In conclusion, insulin regulates hepatic GHR biosynthesis and surface translocation in a reciprocal manner, with surface receptor availability the net result of the divergent effects. The divergent actions of insulin appear to be mediated by the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways, respectively.
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PMID:Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. 1113 33

GH signals by interacting with GH receptor (GHR). A substantial fraction of circulating GH complexes with GH-binding protein (GHBP), which corresponds to the GHR extracellular domain. GHBP is generated by 1) alternative splicing of a common GHR precursor messenger RNA to encode secreted GHBP (the source of the vast majority of GHBP in rodents); and 2) proteolysis of the cell-associated GHR with shedding of GHBP (a mechanism operative in rabbits and humans). We previously observed that phorbol ester (PMA)-induced activation of protein kinase C (PKC) causes metalloprotease-mediated GHR proteolysis and GHBP shedding in human IM-9 lymphocytes. We now demonstrate that PMA-induced hydroxamate (IC3)-inhibitable GHR proteolysis and GHBP shedding were also detected in murine 3T3-F442A and 3T3-L1 preadipocytes and in Chinese hamster ovary (CHO) cells stably expressing rabbit GHR (rbGHR), although the degree of GHBP shedding was much smaller for murine GHR than for rabbit or human GHRs. PMA-induced GHR proteolysis in 3T3-F442A, 3T3-L1, and CHO-rbGHR cells was significantly reduced by pretreatment with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 inhibitors, suggesting involvement of the mitogen-activated protein kinase pathway in regulating this PKC-dependent effect. In contrast, GHR proteolysis promoted by N-ethylmaleimide, although inhibited by IC3, was unaffected by inhibition of either PKC or mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1. Thus, different pathways leading to metalloprotease-mediated receptor proteolysis are accessed by PMA vs. N-ethylmaleimide. To determine whether other, possibly more physiologically relevant, stimuli induce GHR proteolysis, we tested effects of platelet-derived growth factor (PDGF) and serum. Treatment of serum-deprived cells with PDGF (in 3T3-F442A cells) or serum (in 3T3-F442A and CHO-rbGHR cells) promoted GHR proteolysis, which was inhibited by IC3. Interestingly, PMA-, PDGF-, and serum-induced GHR proteolysis was associated with substantial decreases in GH-induced activation of Janus kinase-2, which were also prevented by IC3. These findings suggest that inducible metalloprotease-mediated GHR proteolysis constitutes an important mechanism of receptor down-regulation and modulation of GH signaling.
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PMID:Phorbol ester- and growth factor-induced growth hormone (GH) receptor proteolysis and GH-binding protein shedding: relationship to GH receptor down-regulation. 1118 29

The cellular and molecular basis of growth hormone (GH) actions on the heart remain poorly defined, and it is unclear whether GH effects on the myocardium are direct or mediated at least in part via insulin-like growth factor (IGF-1). Here, we demonstrate that the cultured neonatal cardiomyocyte is not an appropriate model to study the effects of GH because of artifactual loss of GH receptors (GHRs). To circumvent this problem, rat neonatal cardiomyocytes were infected with a recombinant adenovirus expressing the murine GHR. Functional integrity of GHR was suggested by GH-induced activation of the cognate JAK2/STAT5, MAPK, and Akt intracellular pathways in the cells expressing GHR. Although exposure to GH resulted in a significant increase in the size of the cardiomyocyte and increased expression of c-fos, myosin light chain 2, and skeletal alpha-actin mRNAs, there were no significant changes in IGF-1 or atrial natriuretic factor mRNA levels in response to GH stimulation. In this model, GH increased incorporation of leucine, uptake of palmitic acid, and abundance of fatty acid transport protein mRNA. In contrast, GH decreased uptake of 2-deoxy-d-glucose and levels of Glut1 protein. Thus, in isolated rat neonatal cardiomyocytes expressing GHR, GH induces hypertrophy and causes alterations in cellular metabolic profile in the absence of demonstrable changes in IGF-1 mRNA, suggesting that these effects may be independent of IGF-1.
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PMID:Demonstration of direct effects of growth hormone on neonatal cardiomyocytes. 1130 22

The human growth hormone (GH) was shown to modulate leukocyte functions such as stimulating directed migration of human monocytes in vitro. Dimerisation of GH-receptors leads to the activation of various signalling mechanisms. As transduction of GH signals to monocytes is unknown, we investigated GH signalling mechanisms in monocyte migration using a modified Boyden chamber chemotaxis assay. Inhibition of tyrosyl phosphorylation of GH receptor-associated tyrosine kinase by tyrphostin-23 or staurosporine blocked GH-stimulated monocyte migration down to random levels. Furthermore, pre-incubation with effective concentrations of 4B-phorbol-12-myristate-13-acetate (PMA), staurosporine and bisindolylmaleimide I, inhibitors of protein kinase C, significantly decreased GH-induced migration, suggesting that PKC is involved in the signalling cascade. Additionally, phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK) activation seems to be required. This study revealed signalling pathways in monocyte movement toward GH in vitro.
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PMID:Signal transduction pathways in directed migration of human monocytes induced by human growth hormone in vitro. 1146 Mar 15

GH is required for normal postnatal growth and metabolism. GH stimulates postnatal growth through induction of IGF-I gene expression. Although the liver is the major site of GH-regulated IGF-I, recent evidence indicates that GH-regulated IGF-I expression in nonhepatic tissues is sufficient for normal postnatal growth. One potentially important nonhepatic site of GH-stimulated IGF-I expression is skeletal muscle, as injection of GH into animals leads to increased IGF-I mRNA in this tissue. Nevertheless, direct effects of GH in skeletal muscle cells in culture have not been reported. We therefore tested the C2C12 myogenic cell line for its response to GH and demonstrate that C2C12 skeletal muscle cells rapidly respond to physiological levels of GH with increased tyrosine phosphorylation of the GH receptor, Janus kinase 2, signal transducer and activator of transcription-5a and -5b, insulin receptor substrate-1, and activation of MAPKs/ERKs and protein kinase B/Akt. In these cells, GH stimulates the expression of IGF-I and two members of the suppressors of cytokine signaling family, cytokine-inducible SH2-containing protein and suppressor of cytokine signaling-2. Treatment of C2C12 myoblasts with either the MAPK kinase inhibitor PD98059 or the PI3K inhibitor wortmannin results in higher levels of GH-induced IGF-I and suppressor of cytokine signaling-2 mRNA expression, suggesting that activation of MAPK and PI3K pathways has an inhibitory role in IGF-I and suppressor of cytokine signaling-2 gene regulation. Therefore, C2C12 cells provide the first in vitro model system to study various aspects of GH action in skeletal muscle.
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PMID:GH regulation of IGF-I and suppressor of cytokine signaling gene expression in C2C12 skeletal muscle cells. 1151 67

The signal transduction pathways that mediate GH-dependent regulation of IGF-I gene expression remain poorly defined. To establish a GH-responsive in vitro model system to study the effect of GH on the expression of the endogenous IGF-I gene, primary hepatocytes from adult male rats were prepared. These cells expressed both the GH receptor and the IGF-I gene, as demonstrated using a ribonuclease protection assay. Western blot analyses using antibodies directed against the phosphorylated forms of the ERKs, signal transducer and activator of transcription-5, and Akt/protein kinase B, a protein kinase that is downstream of PI3K, demonstrated GH-dependent phosphorylation of these signaling molecules. These signaling molecules are components of the major signal transduction pathways that are activated by GH. To determine whether GH-responsive IGF-I gene expression could be demonstrated in these cells, hepatocytes were treated without or with 50 ng/ml GH for 3--48 h. IGF-I mRNA levels increased within 3 h, and a maximal 2.2-fold increase was observed after 24 h of GH treatment. To determine whether ERK activation contributes to GH-induced IGF-I gene expression, hepatocytes were treated for 12 h without or with 50 ng/ml GH and 50 microM PD98059, an inhibitor of MAPK kinase-1 and -2. Treatment with PD98059 did not have a significant effect on GH-induced IGF-I gene expression. Similar studies were performed using 50 microM LY 294002, an inhibitor of PI3K. These studies demonstrated that treatment with LY 294002 completely abrogated GH-induced IGF-I gene expression. In contrast, PI3K-specific doses of another inhibitor of PI3K, wortmannin, failed to inhibit the GH-induced increase in IGF-I mRNA levels. In summary, rat hepatocytes in primary culture provide a good model system to study GH-induced IGF-I gene expression, and the results of these studies suggest that a signaling pathway inhibited by LY 294002, possibly a PI3K-dependent pathway, is important for GH-stimulated IGF-I gene expression in hepatocytes.
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PMID:LY 294002, an inhibitor of phosphatidylinositol 3-kinase, inhibits GH-mediated expression of the IGF-I gene in rat hepatocytes. 1151 77

Growth hormone (GH) is a major growth-promoting and metabolic regulatory hormone. Interaction of GH with its cell surface GH receptor (GHR), by virtue of receptor dimerization, causes activation of the GHR-associated cytoplasmic tyrosine kinase, JAK2. Several signalling pathways, including the STAT5, PI3 kinase and MAP kinase pathways, are thereby accessed, resulting in various biochemical and biological cellular signalling outcomes which are rapidly becoming deciphered. Various mechanisms probably exist to terminate, modulate and prevent GH signalling. Some of these mechanisms regulate receptor abundance and/or availability while others may alter the responsiveness of downstream signalling molecules to receptor engagement. In this review, recent insights into modulation of GH signalling are discussed. Special emphasis is placed on mechanisms of homologous and heterologous desensitization and on the likelihood that inducible GHR proteolysis, in addition to causing GH binding protein generation, may also serve as an important mechanism of heterologous GHR downregulation.
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PMID:Growth hormone signalling and its regulation: preventing too much of a good thing. 1173 35

GH and IGF-I are critical hormones for the regulation of longitudinal growth and the maintenance of lean body mass in humans. The regulation of IGF-I expression by GH in hepatocytes is well documented; however less is known about the regulation of IGF-I in peripheral tissues such as muscle. We have examined the regulation of IGF-I mRNA by GH and IGF-I in C2C12 myoblasts. GH stimulated the accumulation of IGF-I mRNA dose- and time-dependently. An elevation of IGF-I mRNA was observed with GH doses as low as 0.75 ng/ml and after exposure to GH for as little as 1 h, and the increase required ongoing transcription and translation. GH applied in a pulsatile fashion for 10 min followed by an 8-h interpulse interval increased IGF-I mRNA to a greater extent than continuous exposure. GH stimulated tyrosine phosphorylation of the GH receptor, signal transducer and activator of transcription-3 (Stat3), and Stat5. Stat5 was resistant to additional phosphorylation if cells were given a GH pulse within 2 h of a previous GH exposure. The refractory period lasted for 4 h, and cells could be maximally stimulated again after 6 h. Stat3 phosphorylation was also enhanced in cells that were allowed to recover from a previous application of GH. The tyrosine kinase inhibitors, genistein, PP1, and AG-490, and the MAPK kinase inhibitor, PD98059, did not block Stat3 or Stat5 phosphorylation. In contrast, WHI-P154, a Janus kinase-3 inhibitor, dose-dependently prevented Stat3, but not Stat5, phosphorylation. GH-inducible nuclear transport of Stat3 was likewise inhibited by WHI-P154. Most importantly, GH-dependent IGF-I mRNA expression was inhibited by WHI-P154. In contrast, IGF-I mRNA expression was inhibited by IGF-I peptide, and the effect of IGF-I was dominant over that of GH. IGF-I mRNA was regulated by both PI3K and MAPK signal transduction pathways, but IGF-I peptide signaled predominantly through a wortmannin-sensitive pathway to down-regulate its own mRNA. Our data suggest that Janus kinases (Jak2 or Jak3) and their downstream targets (Stat3 and Stat5) may play important roles in the expression of IGF-I mRNA and the myoblast response to GH. In addition, C2C12 cells appear to be a good model system to examine GH regulation of Janus kinase/Stat signaling and the regulation of IGF-I mRNA.
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PMID:Regulation of IGF-I mRNA and signal transducers and activators of transcription-3 and -5 (Stat-3 and -5) by GH in C2C12 myoblasts. 1179 3


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