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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth hormone (GH) and 1alpha,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) are regulators of bone growth and bone metabolism. In target cells, GH activates several signaling pathways, among them the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. GH mainly activates JAK2 and STAT5a and b. The effects of 1,25-(OH)(2)D(3) are mediated via a nuclear receptor, the vitamin D receptor, which, when bound by 1,25-(OH)(2)D(3), activates the transcription of target genes. In earlier studies (Morel, G., Chavassieux, P., Barenton, B., Dubois, P. M., Meunier, P. J., and Boivin, G. (1993) Cell Tissue Res. 273, 279-286) synergistic interaction between 1,25-(OH)(2)D(3) and GH regarding expression of osteoblastic markers has been described. The UMR 106 cell line is a rat osteosarcoma cell line with osteoblast-like properties. We have recently shown (Morales, O., Lindgren, U., and Haldosen, L. A. (2000) J. Bone Miner. Res. 15, 2284-2290) that UMR 106 cells express a GH-responsive JAK2/STAT5 signaling system. These cells also express the vitamin D receptor and respond to 1,25-(OH)(2)D(3). In the present study we have investigated whether 1,25-(OH)(2)D(3) influences GH signaling via the JAK2/STAT5 pathway in UMR 106 cells. We found that 1,25-(OH)(2)D(3) prolonged GH signaling via the JAK2/STAT5 pathway. Pretreatment of cells with 1,25-(OH)(2)D(3) was also necessary in order to detect GH-induced STAT5 transcriptional response. Furthermore, the pretreatment of cells with 1,25-(OH)(2)D(3) rendered to the cells the capacity to respond to repetitive GH-stimulation. In UMR 106 cells, GH induced the expression of the JAK/STAT negative regulatory proteins SOCS-3 and CIS. Interestingly, pretreatment with 1,25-(OH)(2)D(3) inhibited GH-induced expression of these proteins. From these results we propose that 1,25-(OH)(2)D(3) has an inhibitory effect on negative regulatory pathways acting on JAK2 and/or STAT5 in UMR 106 cells and that this, in all or partly, explains the effects of 1,25-(OH)(2)D(3) on GH-signaling via the JAK/STAT pathway.
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PMID:1Alpha,25-dihydroxyvitamin D3 inhibits GH-induced expression of SOCS-3 and CIS and prolongs growth hormone signaling via the Janus kinase (JAK2)/signal transducers and activators of transcription (STAT5) system in osteoblast-like cells. 1210 79

Growth hormone (GH) secretion is regulated by indirect negative feedback mechanisms. To address whether GH has direct actions on pituitary cells, lipid signaling in GH(4)ZR(7) somatomammotroph cells was examined. GH (EC(50) = 5 nm) stimulated diacylglycerol (DAG) and ceramide formation in parallel by over 10-fold within 15 min and persisting for >3 h. GH-induced DAG/ceramide formation was blocked by pertussis toxin (PTX) implicating G(i)/G(o) proteins and was potentiated 1.5-fold by activation of G(i)/G(o)-coupled dopamine-D2S receptors, which had no effect alone. Following PTX pretreatment, only PTX-resistant Galpha(i)3, not Galpha(o) or Galpha(i)2, rescued GH-induced DAG/ceramide signaling. GH-induced DAG/ceramide formation was also blocked in cells expressing Gbetagamma blocker GRK-ct. In GH(4)ZR(7) cells, GH induced phosphorylation of JAK2 and STAT5, which was blocked by PTX and mimicked by ceramide analogue C2-ceramide or sphingomyelinase treatment to increase endogenous ceramide. We conclude that in GH(4) pituitary cells, GH induces formation of DAG/ceramide via a novel Galpha(i)3/Gbetagamma-dependent pathway. This novel pathway suggests a mechanism for autocrine feedback regulation by GH of pituitary function.
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PMID:Growth hormone-induced diacylglycerol and ceramide formation via Galpha i3 and Gbeta gamma in GH4 pituitary cells. Potentiation by dopamine-D2 receptor activation. 1237 52

Growth hormone (GH) promotes signaling by causing activation of the non-receptor tyrosine kinase, JAK2, which associates with the GH receptor. GH causes phosphorylation of epidermal growth factor receptor (EGFR; ErbB-1) and its family member, ErbB-2. For EGFR, JAK2-mediated GH-induced tyrosine phosphorylation may allow EGFR to serve as a scaffold for GH signaling. For ErbB-2, GH induces serine/threonine phosphorylation that dampens basal and EGF-induced ErbB-2 kinase activation. We now further explore GH-induced EGFR phosphorylation in 3T3-F442A, a preadipocytic fibroblast cell line that expresses endogenous GH receptor, EGFR, and ErbB-2. Using a monoclonal antibody that recognizes ERK consensus site phosphorylation (PTP101), we found that GH caused PTP101-reactive phosphorylation of EGFR. This GH-induced EGFR phosphorylation was prevented by MEK1 inhibitors but not by a protein kinase C inhibitor. Although GH did not discernibly affect EGF-induced EGFR tyrosine phosphorylation, we observed by immunoblotting a substantial decrease of EGF-induced EGFR degradation in the presence of GH. Fluorescence microscopy studies indicated that EGF-induced intracellular redistribution of an EGFR-cyan fluorescent protein chimera was markedly reduced by GH cotreatment, in support of the immunoblotting results. Notably, protection from EGF-induced degradation and inhibition of EGF-induced intracellular redistribution afforded by GH were both prevented by a MEK1 inhibitor, suggesting a role for GH-induced ERK activation in regulating the trafficking itinerary of the EGF-stimulated EGFR. Finally, we observed augmentation of early aspects of EGF signaling (EGF-induced ERK2 activation and EGF-induced Cbl tyrosine phosphorylation) by GH cotreatment; the GH effect on EGF-induced Cbl tyrosine phosphorylation was also prevented by MEK1 inhibition. These data indicate that GH, by activating ERKs, can modulate EGF-induced EGFR trafficking and signaling and expand our understanding of mechanisms of cross-talk between the GH and EGF signaling systems.
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PMID:Growth hormone-induced phosphorylation of epidermal growth factor (EGF) receptor in 3T3-F442A cells. Modulation of EGF-induced trafficking and signaling. 1264 95

Growth hormone (GH) and insulin-like growth factor (IGF)-I are potent regulators of muscle mass in health and disease. This somatomedin axis is markedly deranged in various catabolic conditions in which circulating and tissue levels of inflammatory cytokines are elevated. The plasma concentration of IGF-I, which is primarily determined by hepatic synthesis and secretion of the peptide hormone, is dramatically decreased during catabolic and inflammatory conditions. Moreover, many of these conditions are also associated with an inability of GH to stimulate hepatic IGF-I synthesis. This defect results from an impaired phosphorylation and activation of the traditional JAK2/STAT5 signal transduction pathway. Numerous lines of evidence support the role of tumor necrosis factor (TNF)-alpha as a prominent but probably not the sole mediator of the sepsis-induced impairment in basal and GH-stimulated IGF-I synthesis in liver. Additionally, catabolic conditions produce comparable alterations in skeletal muscle. However, in contrast to liver, the GH resistance in muscle is not mediated by a defect in STAT5 phosphorylation. Muscle is now recognized to respond to infectious stimuli with the production of numerous inflammatory cytokines, including TNF-alpha. Furthermore, myocytes cultured with TNF-alpha are GH resistant and this defect appears mediated via a STAT5-independent but JNK-dependent mechanism. Collectively, these changes act to limit IGF-I availability in muscle, which disturbs protein balance and results in the loss of protein stores in catabolic and inflammatory conditions.
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PMID:Cytokine inhibition of JAK-STAT signaling: a new mechanism of growth hormone resistance. 1554 17

Growth hormone (GH) exerts many effects in addition to its ability to stimulate growth. The metabolic effects are either chronic diabetogenic or acute insulin-like. The latter effects are only seen in cells that have been deprived of the hormone for a few hours. After exposure to GH the ability of the cells to respond with insulin-like effects disappears within a couple of hours, a negative feedback loop, which is a part of the chronic effects of the hormone. The insulin-like effects are mediated by the cytosolic tyrosine kinase Janus kinase 2 (JAK2) upon GH-GH receptor interaction, resulting in tyrosine phosphorylation of downstream targets including the GH receptor itself and insulin receptor substrate-1 (IRS-1) and IRS-2. Analogous to the post-receptor events for insulin this results in recruitment of phosphatidylinositol-3 kinase (PI3-kinase) to the IRS-proteins. Downstream PI3-kinase protein kinase B/Akt participates in the activation of glucose transporters (GLUT4) and increased glucose uptake as well as activation of phosphodiesterase 3B and hydrolysis of cAMP leading to a net dephosphorylation of the hormone sensitive lipase and inhibition of lipolysis. Simultaneously, JAK2 phosphorylates STAT-family transcription factors that move into the nucleus and activate the transcription of, among others, genes coding for negatively regulatory proteins called Suppressors of cytokine signalling (SOCS). The turnover of SOCS is rapid and in their presence JAK2 will still activate STAT-proteins (and the diabetogenic effects), but no longer phosphorylate the IRS-proteins (and induce insulin-like effects), closing the loop of yet another classical hormonal negative feedback loop.
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PMID:Signaling mechanism for the insulin-like effects of growth hormone--another example of a classical hormonal negative feedback loop. 1577 7

Growth hormone (GH) is known to stimulate luteinizing hormone (LH) release via paracrine interactions between somatotrophs and gonadotrophs. However, it is unclear if LH can exert a reciprocal effect to modulate somatotroph functions. Here we examined the paracrine effects of LH on GH gene expression using grass carp pituitary cells as a cell model. LH receptors were identified in grass carp somatotrophs and their activation by human chorionic gonadotropin (hCG) increased 'steady-state' GH mRNA levels. Removal of endogenous LH by immunoneutralization using LH antiserum inhibited GH release and GH mRNA expression. GH secretagogues, including gonadotrophin releasing hormone (GnRH), pituitary adenylate cyclase-activating polypeptide (PACAP) and apomorphine, were effective in elevating GH mRNA levels but these stimulatory actions were blocked by LH antiserum. In pituitary cells pretreated with actinomycin D, the half-life of GH mRNA was not affected by hCG but was enhanced by LH immunoneutralization. Treatment with LH antiserum also suppressed basal levels of mature GH mRNA and primary transcripts. hCG increased cAMP synthesis in carp pituitary cells and hCG-induced GH mRNA expression was mimicked by forskolin but suppressed by inhibiting adenylate cyclase and protein kinase A. Similarly, the stimulatory actions of hCG and forskolin on GH mRNA expression were blocked by inhibiting Janus kinase 2 (JAK2) and MAP kinase (MAPK), including P42/44(MAPK) and P38 (MAPK). These results suggest that LH is essential for the maintenance of GH release, GH gene expression, and somatotroph responsiveness to GH-releasing factors. The paracrine actions of LH on GH mRNA expression are mediated by a concurrent increase in GH gene transcription and GH mRNA turnover, probably through JAK2/MAPK coupled to the cAMP-dependent pathway.
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PMID:Paracrine regulation of growth hormone gene expression by gonadotrophin release in grass carp pituitary cells: functional implications, molecular mechanisms and signal transduction. 1582 Nov 7

Growth hormone (GH) is a key factor controlling postnatal growth and development. Despite growth-promoting effects in mammals, GH is not associated with muscle growth in the chicken. Janus kinase 2 (JAK2) has been identified as the first intracellular step in GH receptor (GHR) signaling in many species, however, there is limited knowledge regarding the GH signaling pathway in the chicken. In this study, GH-responsive, JAK2 immunoreactive proteins were first assessed in an avian hepatoma cell line (LMH). Tyrosine phosphorylation of a 120-122 kDa JAK2 immunoreactive protein was GH dose-dependent. In addition to in vitro studies, the timecourse of JAK2 activation in liver and skeletal muscle (Pectoralis superficialis) in response to a single intravenous (i.v.) injection of chicken GH (cGH), and the effect of chronic exposure to GH in a physiologically relevant pattern on JAK2 protein expression and tyrosine phosphorylation in vivo were assessed. At a dose of GH that was previously demonstrated to elicit a maximal metabolic response (6.25 microg/kg BW), maximum tyrosine phosphorylation of JAK2 appeared at 10 min post-GH administration in the pectoralis muscle, but was not detectable in liver. To assess whether chronic enhancement of GH would alter expression of JAK2, we utilized a dynamic model of pulsatile GH infusion that mimicked the early pattern of circulating GH expressed in younger, rapidly growing birds (high amplitude peaks with an inter-peak interval of 90 min). A 120-122 kDa protein in liver and muscle, and a dominant 130-136 kDa protein in the muscle, that was phosphorylated in response to GH, were specifically recognized by the JAK2 antibody. Chronic, pulsatile infusion of cGH into 8-week-old chickens was associated with increased abundance and tyrosine phosphorylation of JAK2 protein in both liver and muscle (P < 0.05), which were GH dose-dependent, and mirrored previously reported biological responses for the same birds [Vasilatos-Younken, R., Zhou, Y., Wang, X., McMurtry, J.P., Rosebrough, R.W., Decuypere, E., Buys, N., Darras, V.M., Van Der Geyten, S., Tomas, F., 2000. Altered chicken thyroid hormone metabolism with chronic GH enhancement in vivo: Consequences for skeletal muscle growth. Journal of Endocrinology 166, 609-620.]. In summary (1) JAK2 immunoreactive proteins that associate with the GHR and are tyrosine phosphorylated in response to GH were identified in an avian hepatoma cell line and expressed in both GH responsive (liver) and "non-responsive" (skeletal muscle) tissues; (2) tyrosine phosphorylation of JAK2 occurred within minutes of exposure to a single i.v. injection of GH in vivo in muscle but not liver of 8-week-old birds; and 3) there were GH dose-dependent increases in abundance of JAK2 protein and tyrosine phosphorylation in both tissues when chronically exposed to GH in a physiologically relevant pattern, that mirrored dose-dependent biological responses, including alterations in the pathway of thyroid hormone metabolism, previously reported. Enhanced JAK2 suggests one possible mechanism whereby chronic, physiologically appropriate exposure to the ligand enhances GH biological action via increased abundance of a key upstream component of the signal transduction pathway.
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PMID:Regulation of JAK2 protein expression by chronic, pulsatile GH administration in vivo: a possible mechanism for ligand enhancement of signal transduction. 1599 10

Growth hormone is believed to activate the growth hormone receptor (GHR) by dimerizing two identical receptor subunits, leading to activation of JAK2 kinase associated with the cytoplasmic domain. However, we have reported previously that dimerization alone is insufficient to activate full-length GHR. By comparing the crystal structure of the liganded and unliganded human GHR extracellular domain, we show here that there is no substantial change in its conformation on ligand binding. However, the receptor can be activated by rotation without ligand by inserting a defined number of alanine residues within the transmembrane domain. Fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET) and coimmunoprecipitation studies suggest that receptor subunits undergo specific transmembrane interactions independent of hormone binding. We propose an activation mechanism involving a relative rotation of subunits within a dimeric receptor as a result of asymmetric placement of the receptor-binding sites on the ligand.
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PMID:Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. 1611 38

Growth hormone (GH) plays an important role in growth and metabolism by signaling via at least three major pathways, including STATs, ERK1/2, and phosphatidylinositol 3-kinase/Akt. Physiological concentrations of insulin promote growth probably by modulating liver GH receptor (GHR) levels in vivo, but the possible effects of insulin on GH-induced post-GHR signaling have yet to be studied. We hypothesized that short-term insulin, similar to the fluctuations that occur following feeding, affects GH-induced post-GHR signaling. Our present studies suggest that, in rat H4IIE hepatoma cells, insulin (4 h or less) selectively enhanced GH-induced phosphorylation of MEK1/2 and ERK1/2, but not GH-induced activation of STAT5 and Akt. Although insulin pretreatment altered GH-induced formation of Shc.Grb2.SOS complex, it did not significantly affect GH-induced activation of other signaling intermediates upstream of MEK/ERK, including JAK2, Ras, and Raf-1. Immunofluorescent staining indicated that insulin pretreatment facilitated GH-induced cell membrane translocation of MEK1/2. Insulin pretreatment also increased the amount of MEK association with its scaffolding protein, KSR. In summary, short-term insulin treatment of cultured, liver-derived cells selectively sensitized GH-induced MEK/ERK phosphorylation independent of JAK2, Ras, and Raf-1, but likely resulted from increased cell membrane translocation of MEK1/2. These findings suggest that insulin may be necessary for sensitization of cells to GH-induced ERK1/2 activation and provides a potential cellular mechanism by which insulin promotes growth.
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PMID:Insulin enhances growth hormone induction of the MEK/ERK signaling pathway. 1627 59

Growth hormone (GH) stimulates STAT5 phosphorylation by JAK2, which activates IGF-I and serine protease inhibitor 2.1 (Spi 2.1) transcription, whereas STAT5 dephosphorylation by protein tyrosine phosphatases (PTPs) terminates this signal. We hypothesized that the inhibitory effects of TNF on GH signaling and gene transcription were responsible for hepatic GH resistance. CWSV-1 hepatocytes were treated with TNF, pervanadate (a PTP inhibitor), or both, before GH stimulation. Total and tyrosine-phosphorylated JAK2, STAT5, ERK1/2, SHP-1 and SHP-2, IGF-I, and Spi 2.1 mRNA levels were measured. GH stimulated STAT5 and ERK1/2 phosphorylation, IGF-I, and Spi 2.1 mRNA expression. TNF attenuated JAK2/STAT5 and ERK1/2 phosphorylation and IGF-I and Spi 2.1 mRNA expression following GH stimulation. SHP-1 and SHP-2 protein levels were unaltered by TNF or GH, and the GH-induced increase in SHP-1 PTP activity was not further increased by TNF. In TNF-treated cells, pervanadate restored STAT5 and ERK1/2 phosphorylation to control levels following GH stimulation but did not restore IGF-I or Spi 2.1 mRNA induction. Cells transfected with a Spi 2.1 promoter-luciferase vector demonstrate a 50-fold induction in luciferase activity following GH stimulation or cotransfection with a constitutively active STAT5 vector. TNF prevented the induction of Spi 2.1 promoter activity by GH and the STAT5 construct. We conclude that TNF does not inhibit GH activity by inducing SHP-1 or -2 expression and that correction of GH signaling defects in TNF-treated cells by pervanadate does not restore GH-induced gene expression. The inhibitory effects of TNF on GH-mediated gene transcription appear independent of STAT5 activity and previously identified abnormalities in JAK2/STAT5 signaling.
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PMID:Tumor necrosis factor inhibits growth hormone-mediated gene expression in hepatocytes. 1657 84


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