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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of ErbB4 receptor is correlated with the incidence of non-metastatic types of human cancers, whereas the overexpression of other ErbB receptor families (ErbB1/EGFR, ErbB2 and ErbB3) is correlated to the formation of metastatic tumors. However, the molecular mechanism underlying this phenomenon has been unclear. Earlier, we demonstrated that okadaic acid (OA), an inhibitor of a serine/threonine phosphatase PP2A, stimulated the growth hormone-induced ERK phosphorylation in the wild type Chinese hamster ovary (CHO) cells and the cells expressing ErbB1 receptor, but suppressed ERK activation in CHO cells that express ErbB4 receptor. PP2A had been understood as a negative regulator of the growth hormone-stimulated signal transduction pathways, however, this observation suggested that expression of ErbB4 receptor reversed the regulation of PP2A in the ErbB4 signalling pathway. In this study, we found that OA suppressed phosphorylation of Shc at Tyr317, therefore it down-regulated ERK phosphorylation in the ErbB4 expressing CHO cells. Accordingly, basal PP2A contributed to the phosphorylation of Shc Tyr317 in ErbB4 expressing CHO cells, nevertheless it had been reported that PP2A negatively regulates Shc tyrosine phosphorylation in the EGF- or IGF-I-induced signalling pathways. By testing OA for human cancer cell lines that express different types of ErbB receptors, we found that ErbB4 receptor expression was accompanied with positive regulation of PP2A for phosphorylation of Shc Tyr317 and its downstream ERK phosphorylation in MCF-7 and SK-OV-3 cell lines, but not in LNCaP and PC-3 cells. Thus, PP2A regulates the ERK activity in a cell-specific manner, and it is speculated that distinct regulation of PP2A in the ErbB4 receptor signalling pathway may cause a difference in progression of cancer phenotypes.
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PMID:Expression of the ErbB4 receptor causes reversal regulation of PP2A in the Shc signal transduction pathway in human cancer cells. 1647 70

Recent evidence indicates that growth hormone (GH) is involved in liver regeneration. To test whether insulin-like growth factor I (IGF-I) mediates this effect, we studied liver regeneration induced by partial hepatectomy in liver-specific IGF type 1 receptor knockout (LIGFREKO) mice. The absence of IGF-1R caused a significant decrease in hepatocyte proliferation in males (-52%), but not in females, as assessed by Ki67 immunohistochemistry. Cyclin D1 and cyclin A protein levels in the livers of LIGFREKO males were only half those in controls, indicating that cyclin induction during liver regeneration is dependent on IGF-1R signaling. Analyzing the signaling cascade initiated by IGF-1R, we observed a lack of IRS-1 induction in LIGFREKO livers. In contrast, the induction of IRS-2 synthesis was similar in LIGFREKO and control groups, suggesting the existence of differential regulation of IRS synthesis during liver regeneration. Regenerating livers from LIGFREKO animals also showed significantly less activated ERKs than controls. Our findings demonstrate that IGF-1R makes a significant contribution to liver regeneration. Using the LIGFREKO model, we provide new evidence that IGF-1R/IRS-1/ERK signaling may be the intracellular pathway controlling the cell cycle via cyclin D1 and cyclin A in the regenerating liver.
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PMID:Hepatocyte proliferation during liver regeneration is impaired in mice with liver-specific IGF-1R knockout. 1648 30

Blockade of growth hormone (GH), decreased insulin-like growth factor-1 (IGF1) action and increased insulin sensitivity are associated with life extension and an apparent slowing of the aging process. We examined expression of genes involved in insulin action, IR, IRS1, IRS2, IGF1, IGF1R, GLUT4, PPARs and RXRs in the hearts of normal and GHR-/- (KO) mice fed ad libitum or subjected to 30% caloric restriction (CR). CR increased the cardiac expression of IR, IRS1, IGF1, IGF1R and GLUT4 in normal mice and IRS1, GLUT4, PPARalpha and PPARbeta/delta in GHR-KO animals. Expression of IR, IRS1, IRS2, IGF1, GLUT4, PPARgamma and PPARalpha did not differ between GHR-KO and normal mice. These unexpected results suggest that CR may lead to major modifications of insulin action in the heart, but high insulin sensitivity of GHR-KO mice is not associated with alterations in the levels of most of the examined molecules related to intracellular insulin signaling.
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PMID:Caloric restriction and growth hormone receptor knockout: effects on expression of genes involved in insulin action in the heart. 1652 78

Mesenchymal cells are successfully used to create cell-loaded devices in tissue engineering. Molecular properties of the cells and interaction with polymer scaffolds regulate the development of desired tissues. The present study compared the molecular markers in mesenchymal pleuripotent C3H10T1/2 and osteogenic MBA-15 cells. The cells express transcription factors (TF) of chondro-ostegenic pathway (cbfa-1 and c-fos) and MyoD - TF of muscle differentiation pathway, but not myogenin. Analyzed cells expressed receptors for glucocorticoids, growth hormone, prolactin, and PTH, which indicates their potential responsiveness to systemic signals. Analysis of mRNA encoding for receptors of TGFbeta, TNF, and various interleukins revealed differential expression of IL-2r and TGFbeta-1r receptors, which were expressed by MBA-15 but not by C3H10T1/2 cells. Expression of functional genes indicates differences in the stages of cell differentiation: ALK was present in MBA-15 only, while both cell types expressed collagen-I. Furthermore, we evaluated the expression of adhesion proteins that mediate cell-polymer interactions by flow cytometry analysis. Cell adhesion molecules (CAMs) analyzed were integrinalpha-M (CD11b), selectin-E (CD62E), and PECAM-1 (CD31), which have shown differential expression on cells cultured on plastic, poly(L-lactic acid) (PLLA) or poly(DL-lactide-glycolide acid) (PDLGA) polymer films. Detailed molecular characterization of mesenchymal cells will enable optimization of culture conditions for successful creation of implantable cell-loaded constructs.
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PMID:Molecular and cellular characterization of mesenchymal progenitors for skeletal biomedical devices. 1657 7

The liver is a major metabolic and endocrine organ in growing neonates, but the extent to which its hormone receptor (R) sensitivity is potentially determined by maternal parity and the mother's nutritional environment is unknown. This was therefore investigated by sampling livers from postnatal sheep born to nulliparous or multiparous mothers. Offspring were sampled 1 or 30 days after birth from mothers consuming either 100 or 50% [i.e., nutrient-restricted (NR) group] of total metabolizable energy requirements from 110 days gestation to term ( approximately 147 days). Regardless of maternal diet, offspring of nulliparous mothers were lighter at birth and had smaller livers. By 1 mo of age, they exhibited catch-up growth, an adaptation not seen when mothers were NR, but they retained their lighter livers. At both sampling ages, livers from offspring born to nulliparous mothers exhibited increased mRNA abundance for growth hormone (GH) receptor, IGF-IR, plus hepatocyte growth factor (HGF); and at day 1 only IGF-I, but not IGF-IIR mRNA was decreased. In addition, mRNA for IGF-II, the HGFR, c-Met, and Bax were persistently reduced in these offspring. Effects of parity were largely unaffected by maternal nutrient restriction. Maternal parity therefore has a substantial effect on liver size during postnatal development and its receptor population that is not dependent on maternal diet. First-born offspring appear to exhibit a resetting of the endocrine control of hepatic growth within the HGF and GH-IGF axis, which could have later consequences after their growth has caught up.
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PMID:Effects of maternal parity and late gestational nutrition on mRNA abundance for growth factors in the liver of postnatal sheep. 1720 89

An important function of growth hormone (GH) is to promote cell and tissue growth, and a key component of these effects is the stimulation of protein synthesis. In this study, we demonstrate that, in H4IIE hepatoma cells, GH acutely activated protein synthesis through signaling via the mammalian target of rapamycin (mTOR) and specifically through the rapamycin-sensitive mTOR complex 1 (mTORC1). GH treatment enhanced the phosphorylation of two targets of mTOR signaling, 4E-BP1 and ribosomal protein S6. Phosphorylation of S6 and 4E-BP1 was maximal at 30-45 min and 10-20 min after GH stimulation, respectively. Both proteins modulate components of the translational machinery. The GH-induced phosphorylation of 4E-BP1 led to its dissociation from eIF4E and increased binding of eIF4E to eIF4G to form (active) eIF4F complexes. The ability of GH to stimulate the phosphorylation of S6 and 4E-BP1 was blocked by rapamycin. GH also led to the dephosphorylation of a third translational component linked to mTORC1, the elongation factor eEF2. Its regulation followed complex biphasic kinetics, both phases of which required mTOR signaling. GH rapidly activated both the MAP kinase (ERK) and PI 3-kinase pathways. Signaling through PI 3-kinase alone was, however, sufficient to activate the downstream mTORC1 pathway. Consistent with this, GH increased the phosphorylation of TSC2, an upstream regulator of mTORC1, at sites that are targets for Akt/PKB. Finally, the activation of overall protein synthesis by GH in H4IIE cells was essentially completely inhibited by wortmannin or rapamycin. These results demonstrate for the first time that mTORC1 plays a major role in the rapid activation of protein synthesis by GH.
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PMID:The rapid activation of protein synthesis by growth hormone requires signaling through mTOR. 1728 72

An association between physical activity and premenopausal breast cancer risk may be due, in part, to relationships with sex hormones or growth factors. Therefore, we assessed whether MET-h/week of total physical activity (moderate-to-vigorous intensity), walking, or vigorous physical activity, and h/week of standing or sitting were associated with plasma concentrations of several hormones. We examined levels of estrogens, androgens, progesterone, prolactin, sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), IGF binding protein-3, and growth hormone (GH) in 565 premenopausal women, ages 33-52 years, from the Nurses' Health Study II (NHSII). About 87% of women had both timed follicular and luteal samples; other women had one untimed sample. In general we observed few associations between sex hormone or IGF levels and measures of physical activity or inactivity. However, free testosterone was modestly inversely associated with total physical activity (p-trend = 0.02). Luteal estradiol, free estradiol, and estrone also were inversely associated with total physical activity (p-trend = 0.10, 0.04, 0.01, respectively); however, the trend was substantially attenuated when excluding women with anovulatory cycles or irregular cycles. These cross-sectional results suggest that physical activity and inactivity have limited associations with premenopausal sex hormone and growth factor levels, except possibly luteal estrogens.
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PMID:Physical activity and inactivity in relation to sex hormone, prolactin, and insulin-like growth factor concentrations in premenopausal women - exercise and premenopausal hormones. 1754 94

Longitudinal growth of bone depends on the proliferation and differentiation of chondrocytes located in growth plate. Recent advances in understanding the process of chondrocyte proliferation and differentiation reveal the local and systemic factors responsible for the process. SOX9, Ihh and FGFR3 are the former, growth hormone and thyroid hormone the latter. Achondroplasia, a representative entity of skeletal dysplasia is caused by the abnormality of FGFR3 and exhibits short stature. Hypofunction of growth hormone and thyroid hormone are associated with short stature as well.
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PMID:[Mechanism of bone and cartilage growth during childhood and growth disorders]. 1844 90

The growth and metabolic actions of growth hormone (GH) are believed to be mediated through the GH receptor (GHR) by JAK2 activation. The GHR exists as a constitutive homodimer, with signal transduction by ligand-induced realignment of receptor subunits. Based on the crystal structures, we identify a conformational change in the F'G' loop of the lower cytokine module, which results from binding of hGH but not G120R hGH antagonist. Mutations disabling this conformational change cause impairment of ERK but not JAK2 and STAT5 activation by the GHR in FDC-P1 cells. This results from the use of two associated tyrosine kinases by the GHR, with JAK2 activating STAT5, and Lyn activating ERK1/2. We provide evidence that Lyn signals through phospholipase C gamma, leading to activation of Ras. Accordingly, mice with mutations in the JAK2 association motif respond to GH with activation of hepatic Src and ERK1/2, but not JAK2/STAT5. We suggest that F'G' loop movement alters the signalling choice between JAK2 and a Src family kinase by regulating TMD realignment. Our findings could explain debilitated ERK but not STAT5 signalling in some GH-resistant dwarfs and suggest pathway-specific cytokine agonists.
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PMID:An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway. 1848 18

The growth hormone-insulin-like growth factor-I (GH-IGF-I) axis plays a key role in intra-uterine growth and development. This review will describe the consequences of genetic defects in various components of the GH-IGF-I axis on intra-uterine growth and development. Animal knockout experiments have provided evidence for the GH-independent secretion of IGF-I and its effect in utero. Reports of patients with a deletion or mutation of the IGF-I and IGF1R genes have provided insight into the role of intra-uterine IGF-I in the human. Homozygous defects of the IGF-I gene have dramatic effects on intra-uterine growth and development, whereas heterozygous defects of the IGF1R gene have a more variable clinical presentation. The phenotype in relation to the genotype of the different disorders will be reviewed in this chapter.
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PMID:Single gene mutations causing SGA. 1853 84


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