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

---

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

Although the ability of growth hormone (GH) to stimulate body growth and regulate metabolism has been recognized for many years, only recently has insight been gained into the molecular mechanisms by which binding of GH to its receptor (GHR) elicits its diverse effects. This review provides an overview of what is currently known about the molecular mechanisms of GH action. The model presented is one in which GH binding to two GHRs causes dimerization of GHR, activation of the GHR-associated JAK2 tyrosine kinase, and tyrosyl phosphorylation of both JAK2 and GHR. These events recruit and/or activate a variety of signaling molecules, including MAP kinases, insulin receptor substrates, phosphatidylinositol 3' phosphate kinase, diacylglycerol, protein kinase C, intracellular calcium, and Stat transcription factors. These signaling molecules contribute to the GH-induced changes in enzymatic activity, transport function, and gene expression that ultimately culminate in changes in growth and metabolism.
...
PMID:Molecular mechanism of growth hormone action. 881 91

The growth hormone (GH) receptor belongs to the superfamily of transmembrane proteins that includes the prolactin (PRL) receptor and a number of cytokine receptors. Two forms exist for the GH receptor: the membrane-bound form is a protein of 620 amino acid residues with a unique transmembrane domain; the GH-binding protein (GHBP), which is a soluble short form, is identical to the extracellular domain of the membrane receptor. In man and many other species, GHBP is believed to result from proteolytic cleavage of the membrane receptor; in human tissues, only one mRNA form of 4.5 kb encoding the full-length receptor has been detected. In rodents, GHBP is encoded by a specific mRNA of 1.2kb. Binding of GH to its receptor results in dimerization of the receptor, phosphorylation of the tyrosine kinase JAK2 and of the receptor, followed by a cascade of protein phosphorylations. Transcription factors belonging to the signal transducers and activators of transcription (STAT) family are involved in the effects of GH on the transcription of genes such as c-fos, serine protease inhibitor Spi 2.1 and beta-casein. GH is able to activate several STAT proteins including STAT1, 3 and 5. The JAK-STAT pathway is a main pathway for GH effects on gene transcription. Other signalling molecules are involved in GH action through different pathways: GH is able to activate mitogen activated protein (MAP) kinases; the hormone can utilize insulin receptor substrate-1 (IRS-1) and induces the association of phosphatidylinositol 3-kinase with IRS-1. Two main functional regions have been defined in the cytoplasmic domain of the GH receptor by testing the activity of mutant forms of the receptor in several systems: Box 1, a proline-rich sequence in the membrane proximal part, is necessary for all GH effects and is probably the region of association with JAK2; the C-terminal region is required for the induction of specific genes. Other molecules involved in the mechanisms of action of GH remain to be identified. As the same signalling pathways are used by many ligands, explanations for the specificity of the cellular effects have to be determined.
...
PMID:Growth hormone receptor signalling. 885 42

Dopaminergic system seems to influence the regulation of insulin secretion, although in man conflicting data are reported. Furthermore, bromocriptine (BRC), a dopaminergic agonist, has been recently found to inhibit the seasonally occurring hyperinsulinemia and the increase in body weight in the hamster. On this basis, we investigated the effect of BRC on spontaneous and stimulated insulin secretion in human obesity. Six obese (BMI: 33.2 +/- 1.6 Kg/m2) underwent the administration of: 1) arginine (ARG, 0.5 g/Kg iv in 30 min), 2) BRC (2.5 mg po), 3) ARG+BRC. In each test plasma glucose and serum insulin, growth hormone (GH) and prolactin levels were determined. BRC did not significantly reduce spontaneous and ARG-induced insulin release. Baseline and stimulated glucose levels were also unchanged. BRC determined an increase in GH levels (3.7 +/- 1.3 vs 0.5 +/- 0.3 microgram/l, p < 0.05), but failed to modify the somatotrope responsiveness to ARG. On the other hand, both spontaneous and stimulated PRL secretion were reduced by BRC (2.5 +/- 0.4 vs 6.7 +/- 1.1 micrograms/l, p < 0.05 and 0.8 +/- 1.9 vs 11.0 +/- 2.1 micrograms/l, p < 0.05, respectively). Our results show that in obese patients the acute activation of dopaminergic receptors by bromocriptine fails to modify both basal and ARG-induced insulin release, while inhibits spontaneous and stimulated PRL secretion. Our data also show that the low GH response to arginine in obesity is not improved by the coadministration of bromocriptine, in agreement with the hypothesis that both substances act by the same mechanism, i.e. inhibition of endogenous somatostatin release.
...
PMID:Effect of bromocriptine on insulin, growth hormone and prolactin responses to arginine in obesity. 886 1

IRS-1 has been found to relay the signals from the receptors for insulin, insulin-like growth factor-1, growth hormone, and many cytokines for the downstream effects in the various cell types tested. For interleukin 4 signaling, most studies were performed on hematopoietic cells and cell lines transfected with rat liver IRS-1 cDNA. In a liver cell lineage, IRS-1 expression has been found to be increased in hepatoma cells and hepatocytes in regenerating liver. To elucidate the possible function and the signal transduction pathway for interleukin 4, in comparison with insulin, in liver cells, we used the Hep 3B hepatoma cell line as a model system. Following insulin and interleukin 4 stimulation, rapid tyrosyl phosphorylation of IRS-1 occurred. Interleukin 4, but not insulin, stimulated the tyrosine phosphorylation of JAK1 and, to a lesser extent, JAK2. In contrast to the other cell types, the association of IRS-1 and Grb2 through the SH2 of Grb2 was demonstrated after IL-4 and insulin stimulation of the Hep3B hepatoma cells. Both insulin and interleukin 4 stimulated tyrosine phosphorylation and the enzyme activity of Erk1 kinase. Our results indicate that interleukin 4 and insulin might modulate hepatic cell growth and differentiation through many different or common pathways for the activation of JAK kinases and the usage of IRS-1 as a docking protein. The binding of IRS-1 with Grb2 after IL-4 as well as insulin stimulation may lead to MAP kinase activation, probably through the Grb2/sos/p21ras pathway.
...
PMID:Signal transduction pathways for interleukin 4 and insulin in human hepatoma cells. 886 52

In this report, we demonstrate that insulin receptor substrate-2 (IRS-2) is tyrosyl-phosphorylated following stimulation of 3T3-F442A fibroblasts with growth hormone (GH), leukemia inhibitory factor and interferon-gamma. In response to GH and leukemia inhibitory factor, IRS-2 is immediately phosphorylated, with maximal phosphorylation detected at 15 min; the signal is substantially diminished by 60 min. In response to interferon-gamma, tyrosine phosphorylation of IRS-2 was prolonged, with substantial signal still detected at 60 min. Characterization of the mechanism of signaling utilized by GH indicated that tyrosine residues in GH receptor are not necessary for tyrosyl phosphorylation of IRS-2; however, the regions of GH receptor necessary for IRS-2 tyrosyl phosphorylation are the same as those required for JAK2 association and tyrosyl phosphorylation. The role of IRS-2 as a signaling molecule for GH is further demonstrated by the finding that GH stimulates association of IRS-2 with the 85-kDa regulatory subunit of phosphatidylinositol 3'-kinase and with the protein-tyrosine phosphatase SHP2. These results are consistent with the possibility that IRS-2 is a downstream signaling partner of multiple members of the cytokine family of receptors that activate JAK kinases.
...
PMID:Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling. 891 Jun 7

This study investigated the effects of a roasted soybean (RSB)-supplemented diet and an estrogen implant (SYN; Synovex-S ear implant, 20 mg estradiol benzoate plus 200 mg progesterone) in young crossbred beef steers on their performance and plasma growth hormone (GH) response to challenge injections of thyrotropin-releasing hormone (TRH) + GH-releasing hormone (GHRH). Twenty individually fed steers (body weight 255 +/- 5 kg) were assigned to the following treatments: 1) no SYN and fed a soybean meal-supplemented diet, 2) no SYN and fed the RSB-supplemented diet, 3) plus SYN and soybean meal, and 4) plus SYN and RSB. Steers were fed 1.13 MJ metabolizable energy/kg metabolic body weight daily of an 18% protein diet. After a 5-wk growth period, all steers were challenged (intravenous injection) over a 3-wk period with three levels of a combination of TRH + GHRH (0.1 + 0.01, 1.0 + 0.1, 2.5 + 0.25 microg/kg body weight, respectively). After an additional 3 wk, steers were reimplanted and a second 5-wk growth period was followed by a single challenge of the 1.0 + 0.1 TRH + GHRH dose level. Plasma nonesterified fatty acid concentration was greater when steers were fed the RSB compared with soybean meal (265 vs. 205 micromol/L; P < 0.01; SEM = 9.5). Body weight gains for treatments 1, 2, 3 and 4 were 1.35, 1.21, 1.47 and 1.38 kg/d, respectively (RSB, P < 0.10; SYN, P < 0.07; SEM = 0.06). Gain/dry matter intake (g/kg) means were 184, 167, 197 and 184 (RSB, P< 0.04; SYN, P < 0.07; SEM = 7.5). Feeding roasted soybeans results in depressed area under the GH response curve [907, 555, 827 and 989 microg/(L*min) (SYN x RSB, P < 0.03; SEM = 117)] and depressed peak response (37.2, 26.6, 33.5 and 41.1 microg/L [SYN x RSB, P < 0.05; SEM = 4.5]), an effect alleviated by estrogen for young growing steers (Period 1) but not for heavier steers (Period 2).
...
PMID:Roasted soybeans and an estrogenic growth promoter affect growth hormone status and performance of beef steers. 891 61

Twenty crossbred beef steers (initial BW 182 +/- 1.8 kg) were used in a 2 x 2 factorial to determine the effects of implantation with Synovex-S (SYN; 20 mg 17-beta estradiol benzoate + 200 mg progesterone, ear implant) and administration of recombinant bovine growth hormone (Somavubove SbV, .1 mg.kgBW-1.d-1, i.m.) on the morphology of six muscles (longissimus, psoas major, supraspinatus, triceps brachii, semitendinosus, rectus femoris) of growing steers. Implantation with SYN decreased the percentage distribution of FOG fibers and increased FG fibers in the supraspinatus and rectus femoris muscles (P < .05). Steers treated with SYN had a larger area of SO and FG fibers in the psoas major muscle (P < .05). The administration of SbV decreased the percentage distribution of FOG fibers and increased FG fibers in the rectus femoris muscle (P < .05). Steers administered SbV had larger SO, FOG, and FG fibers in the psoas major muscle and SO fibers in the supraspinatus and semitendinosus muscles (P < .05). The combined administration of SYN and SbV had minimal, if any, effect on the percentage distribution of fiber types (P > .05) but increased (P < .05) the fiber areas of all muscles (18.5 to 54.8%) except the rectus femoris (P > .05). Proximate composition of the muscles was generally not affected (P > .05) by any of the treatments. The only observations were decreases in fat content for psoas major and rectus femoris muscles as a result of the combined administration of SYN and SbV. These results indicate that both growth-promoting agents, SYN and SbV, have potential to increase muscle fiber size, but muscles respond differently to the administrations of SYN and SbV. However, when SYN and SbV are administered in combination, the combined effects result in an additive increase in muscle fiber hypertrophic response.
...
PMID:Effects of Synovex-S and recombinant bovine growth hormone (Somavubove) on growth responses of steers: II. Muscle morphology and proximate composition of muscles. 899 6

Growth hormone (GH) plays a significant role in normal growth and development. Signaling to the cell is believed to require growth hormone receptor (GHR) dimerization, which occurs following binding of a single growth hormone molecule to each of two receptors. We have developed human growth hormone receptor-specific monoclonal antibodies, one of which was used here to characterize hormone/receptor interactions. This antibody, GHR05, is directed against the hinge spanning subdomains I and II of the receptor's extracellular region. Antibody binding to the cell surface receptor increases upon receptor binding to growth hormone, but not when it binds a mutant form, hGHG120R, which does not trigger receptor activation. Growth hormone binding thus appears to lead to a conformational change in the receptor epitope recognized by GHR05, giving rise to the active dimer configuration, necessary for signal transduction. Using a chimeric receptor-expressing, growth hormone-dependent murine cell line, we find that GHR05 binds to the receptor in the absence of human GH and delivers a signal leading to cell proliferation. Finally, GHR05 treatment of IM-9 cells, a human cell line expressing a functional human GHR, leads to cell proliferation mediated by the generation of GH-specific signals, including phosphorylation of the JAK2 tyrosine kinase and activation of STAT5.
...
PMID:Conformational changes required in the human growth hormone receptor for growth hormone signaling. 908 50

The signal transduction mechanism involved in human placental lactogen (hPL) was studied. We have identified that hPL rapidly stimulated the tyrosine phosphorylation of at least 7 proteins including Janus Kinases (JAK1 and JAK2) and a signal transducer and activator of transcription protein (Stat3). This is the first evidence that the JAK-STAT pathway is involved in the hPL signaling. Moreover, two unknown proteins which were different from STAT proteins (Stat1, 3 and 5) in sizes were predominantly tyrosine-phosphorylated. Because human growth hormone (hGH) activates Stat1, 3, 5 and human prolactin (hPRL) activates Stat5, these results show that hPL uses a unique signal transduction pathway which is different from hGH and hPRL.
...
PMID:Participation of JAK, STAT and unknown proteins in human placental lactogen-induced signaling: a unique signaling pathway different from prolactin and growth hormone. 913 82

The interaction of prolactin (PRL) with its receptor leads to activation of the tyrosine kinase, Janus kinase 2 (JAK2). In the cytoplasmic juxtamembrane region, a short segment (Box 1) which is conserved in other receptors of the PRL/growth hormone (GH)/cytokine receptor family, is required for signal transduction. To assess the contribution of the different amino acids of Box 1, individual alanine substitutions of all residues, grouped substitution of four prolines (4PA mutant) and individual leucine replacement of the two last prolines (P248L and P250L mutants) were introduced. Here we show that P250L and 4PA (i) inhibit PRL-induced transactivation of a luciferase reporter governed by a beta-caseine gene promoter; (ii) decrease in JAK2 tyrosine kinase activity in biotinylated-PRL precipitates; (iii) impair the interaction between PRLR and JAK2, as evidenced by lack of co-immunoprecipitation, (iv) and prevent the activation of signal transducer and activator of transcription (Stat) as determined by absence of tyrosine phosphorylation of Stat5. Our data suggest that the Box 1 region of the PRL receptor and particularly the last proline is critical for JAK2 association and subsequent activation. These results support the notion that the tyrosine kinase JAK2 is implicated in activation of downstream protein effectors such as Stat5, which are involved in transcription of PRL-responsive genes.
...
PMID:The last proline of Box 1 is essential for association with JAK2 and functional activation of the prolactin receptor. 920 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---