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)

We studied the ionic currents activated by basic fibroblast growth factor (bFGF) and insulin-like growth factor-I (IGF-I) in cultured bovine aortic endothelial cells (BAE-1) by using patch-clamp and single-cell fluorimetric calcium measurements. In whole-cell, voltage-clamp experiments at V(h) = -50 mV, the addition of either bFGF (20 ng/ml) or IGF-I (50 ng/ml) induced an inward current with similar amplitude, time course, and permeation properties. The response was dependent on receptor occupancy and showed a desensitisation in the continued presence of the factors. Ionic substitutions in whole-cell experiments indicated that the current barely discriminated among Na(+), Ca(+), and K(+) ions. Accordingly, stimulation with bFGF or IGF-I induced a dose-dependent [Ca(2+)](i) elevation completely due to entry from the extracellular medium, whereas no detectable release from internal stores was observed. Calcium influx was dependent on protein tyrosine kinase (PTK) activity; it was significantly inhibited by treatment with genistein or tyrphostin 47, two PTK inhibitors, and not affected by inactive analogues, daidzein, and tyrphostin 1. Moreover, addition of 200 microM Na(3)VO(4), an inhibitor of protein tyrosine phosphatase (PTP) activity, evoked the responses to the factors both in patch-clamp and in fluorimetric measurements. Cell-attached recordings using 100 mM CaCl(2) in the pipette showed that bFGF and IGF-I activate calcium-permeable channels with similar properties. These results provide evidence for a calcium influx induced by two factors that bind to tyrosine kinase receptors (RTK) in endothelial cells.
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PMID:Calcium influx induced by activation of tyrosine kinase receptors in cultured bovine aortic endothelial cells. 1105 17

The non-receptor protein tyrosine kinase Fyn, which is a member of the Src family of kinases, has been shown to be essential for normal myelination and has been suggested to play a role in oligodendrocyte development. However, oligodendrocyte development has not been studied directly in cells lacking Fyn. Additionally, because Fyn is expressed in neurons as well as oligodendrocytes, it is possible that normal myelination requires Fyn expression in neurons but not in oligodendrocytes. To address these issues, we analyzed the development of oligodendrocytes in neuron-free glial cell cultures from fyn(-/-) mice that express no Fyn protein. We observed that oligodendrocytes develop to the stage where they elaborate an extensive network of membranous processes and express the antigenic components of mature oligodendrocytes in the complete absence of Fyn. However, as compared with fyn(+/+) controls, fewer oligodendroglia developed in fyn(-/-) cell cultures, and a smaller proportion of them matured to the stage characterized by a high degree of morphological complexity. In addition, we found that insulin-like growth factor-I, a potent stimulator of oligodendrocyte development, failed to stimulate morphological maturation of fyn(-/-) oligodendroglia. The pyrazolopyrimidine PP2, believed to be a selective inhibitor of Fyn, did not prevent the development of morphologically complex oligodendrocytes. Unexpectedly, however, it was toxic to both fyn(+/+) and fyn(-/-) glial cells, indicating that this class of inhibitors can have significant effects that are independent of Fyn.
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PMID:Fyn tyrosine kinase regulates oligodendroglial cell development but is not required for morphological differentiation of oligodendrocytes. 1117 Jan 80

Various growth factor receptors contain intrinsic tyrosine kinase activity, indicating that protein tyrosine kinases (PTK) play an important role in signal transduction pathways for cell proliferation and differentiation. To identify oocyte-derived factors which control follicle cells as well as oocyte-controlling factors produced by follicle cells, we examined the expression of genes which contain the PTK domain in the porcine ovary, using a polymerase chain reaction-based amplification technique with degenerate oligonucleotide primers that are specific to the PTK domain. Clones for the porcine homologues of platelet-derived growth factor receptor alpha (PDGFRalpha) and of insulin-like growth factor-I receptor (IGF-IR) were found during follicle growth both in oocytes and follicle cells. Clones for the porcine homologues of focal adhesion kinase (FAK), of c-kit and of fms-like tyrosine kinase (FLT)-3 were found only in oocytes. Moreover, after 24 h of in-vitro maturation of the cumulus-oocyte complexes, clones for the porcine homologues of FLT-1, of FLT-4, of Tie2 and of RYK in oocytes were observed. Immunohistochemical studies revealed the existence of PDGFRalpha, platelet-derived growth factor A (PDGFA), FAK and FLT3 in oocytes at various stages of folliculogenesis. These results suggest that fluctuations in the expression of these PTK genes may be involved in follicle growth and maturation.
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PMID:Protein tyrosine kinase expression in the porcine ovary. 1147 Aug 59

Cyclic AMP inhibited both ERK and Akt activities in rat C6 glioma cells. A constitutively active form of phosphatidylinositol 3-kinase (PI3K) prevented cAMP from inhibiting Akt, suggesting that the inactivation of Akt by cAMP is a consequence of PI3K inhibition. Neither protein kinase A nor Epac (Exchange protein directly activated by cAMP), two known direct effectors of cAMP, mediated the cAMP-induced inhibition of ERK and Akt phosphorylation. Cyclic AMP inhibited Rap1 activation in C6 cells. Moreover, inhibition of Rap1 by a Rap1 GTPase-activating protein-1 also resulted in a decrease in ERK and Akt phosphorylation, which was not further decreased by cAMP, suggesting that cAMP inhibits ERK and Akt by inhibiting Rap1. The role of Rap1 in ERK and Akt activity was further demonstrated by our observation that an active form of Epac, which activated Rap1 in the absence of cAMP, increased ERK and Akt phosphorylation. Inhibition of ERK and/or PI3K pathways mediated the inhibitory effects of cAMP on insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 gene expression. Moreover, cAMP, as well as ERK and PI3K inhibitors produced equivalent stimulation and inhibition, respectively, of p27(Kip1) and cyclin D2 protein levels, potentially explaining the observation that cAMP prevented C6 cells from entering S phase.
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PMID:Cyclic AMP inhibits extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/Akt pathways by inhibiting Rap1. 1147 6

It has been proposed that binding of ligand to the estrogen receptor (ER) releases its association with transcriptional corepressors, allowing the ER to recruit coactivators, which possess histone acetylase activity, and induce transcription of gene promoters containing estrogen response elements. It has also been proposed that the antiestrogen tamoxifen recruits transcriptional corepressors to the AF-2 region of the hormone-binding domain of the ER, thus blocking ER-mediated transcription. The ER cross-talks with a number of mitogenic signaling pathways and second messengers, like the epidermal growth factor receptor, the insulin-like growth factor-I receptor, mitogen-activated protein (MAP) kinase, phosphatidylinositol-3 kinase/Akt, dopamine, and cyclic AMP. Some of these molecules may: (a) support ligand-independent ER transcription; (b) increase the association of ER with coactivators of transcription; and/or (c) reduce the antiestrogen-induced association of ER with corepressors. These events either alone or in combination may result in hormone independence and/or antiestrogen resistance. We have examined whether signaling by HER2/neu (erbB-2) receptor tyrosine kinase, which can induce antiestrogen resistance, can also disrupt the tamoxifen-induced interaction of ER with transcriptional corepressors. Notably, tamoxifen-induced association of ER with the transcriptional corepressors N-CoR or SMRT was reduced in HER2-overexpressing breast tumor cells but not in cells with low HER2 levels. Small molecule inhibitors of the HER2 kinase or MAP extracellular signal-regulated kinase 1/2 or dominant-negative MAP extracellular signal-regulated kinase 1/2 constructs restored the inhibitory effect of tamoxifen on both ER-mediated transcription and tumor cell proliferation. Treatment with both tamoxifen and the small molecule HER1/2 kinase inhibitor AG1478 reduced mitogen-activated protein kinase activity and markedly reduced growth of established MCF-7/HER2 xenografts in athymic nude mice. Similar results have been obtained with ZD1839 ("Iressa"), an epidermal growth factor receptor (HER1) tyrosine kinase inhibitor. Taken together, these data suggest that exogenous inhibitors of the HER-signaling network and other mitogenic pathways can abrogate or delay the emergence of antiestrogen resistance, thus providing an evaluable therapeutic strategy in human breast carcinoma.
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PMID:Inhibition of erbB receptor (HER) tyrosine kinases as a strategy to abrogate antiestrogen resistance in human breast cancer. 1191 37

SARCOPENIA: Aging is accompanied by the progressive reduction in cardio-pulmonary capacity and muscular strength. These two phenomena are partly related to the decrease in muscle mass, or sarcopenia. CARDIO-PULMONARY CAPACITY: Measured by maximum oxygen consumption (VO2max), it demonstrates the individual's capacity for movement. It is also the principle marker of mortality due to cardiovascular events. VO2max decreases by around 0.8% each year, in close correlation with the evolution in muscle mass. These phenomena are partly related to reduced physical activity and, particularly, intense activity greater than 6 MET. Regular practice of moderately intense physical activity can maintain VO2max at a level 20 to 35% superior to that of the mean level in the same age range, and is associated with increased autonomic nervous system activity. DECREASED MUSCULAR STRENGTH: Sarcopenia and the proportional decrease in fast-twitch muscle fibers are related to a reduction in physical activity. The decrease in muscular strength is a handicapping factor and increases the risk of falls. Two sessions of training per week can increase by more than 30% the strength of the muscles concerned, by increasing the muscle volume and the maximum frequency of emission of motoneuron influx. The production of somatotropin, insulin-like growth factor-I and testosterone can also be increased. High-resistance exercises are themselves sufficient to increase bone density. In the light of these advantages, the practice of workouts in endurance and strength should be encouraged.
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PMID:[Physical activity to delay the effects of aging on mobility]. 1219 31

Insulin-like growth factor-I (IGF-I) and its cognate receptor, the type 1 IGF receptor (IGF1R), as well as high-affinity IGF binding proteins (IGFBP) that modulate IGF-I actions, are expressed throughout the course of brain development. These observations, taken together with studies in cultured neural cells demonstrating a variety of IGF-I growth-promoting activities, provide a strong argument for IGF-I having a central role in the growth and development of the CNS. This report reviews studies of brain development in mutant mice with alterations of IGF-I expression or action. Transgenic (Tg) mice overexpressing IGF-I postnatally exhibit brain overgrowth characterized by increased neuron and oligodendrocyte number, as well as marked increases in myelination. Mutant mice with ablated IGF-I and IGF1R expression, as well as those with overexpression of IGFBPs capable of inhibiting IGF actions, exhibit brain growth retardation with a variety of growth deficits. These studies confirm a role for IGF-I in neural development, and indicate that IGF-I stimulates neurogenesis and synaptogenesis, facilitates oligodendrocyte development, promotes neuron and oligodendrocyte survival, and stimulates myelination. Evidence from experiments in these mouse models also indicates that IGF-I has a role in recovery from neural injury.
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PMID:Mutant mouse models of insulin-like growth factor actions in the central nervous system. 1235 11

This study investigated the ovarian function, metabolic profiles and fertility in first lactation Holstein-Friesian dairy cows (mean 305 day milk yield: 7417+/-191kg, n=37). Reproductive profiles obtained from milk progesterone analysis were categorized into normal (n=17) and four abnormal profiles (delayed ovulation, DOV1, n=9; DOV2, n=2; persistent corpus luteum, PCL1, n=6; PCL2, n=4; 1: immediately post-calving, 2: subsequent cycles). Fifty-five percent of cows had abnormal profiles with half of these being categorized as DOV1. Fertility of DOV1 and DOV2 cows was reduced whereas PCL1 and PCL2 cows had similar reproductive competence to normal profile cows. DOV1 animals had higher milk energy values, lower energy balances, lower dry matter intakes (DMI) and greater body weight and body condition score (BCS) losses post-calving than normal profile animals. DOV1 animals also had lower insulin-like growth factor-I (IGF-I) and higher betahydroxybutyrate (BHB) concentrations and tended to have the lower insulin and glucose concentrations in the pre-service period than normal profile cows. All PCL animals had vulval discharges postpartum. Despite this, the DMI, body weight and BCS changes, IGF-I concentrations and fertility of PCL1 animals was similar to normal profile cows. In conclusion, the high prevalence of delayed ovulation post-calving (DOV1) in primiparous high yielding cows lasted long enough (71+/-8.3 days) to have a detrimental impact on fertility and was associated with significant physiological changes. This study did not establish any detrimental effects of PCL profiles on fertility or production parameters.
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PMID:Metabolic profiles and progesterone cycles in first lactation dairy cows. 1255 70

Articular chondrocytes respond to mechanical forces by alterations in gene expression, proliferative status, and metabolic functions. Little is known concerning the cell signaling systems that receive, transduce, and convey mechanical information to the chondrocyte interior. Here, we show that ex vivo cartilage compression stimulates the phosphorylation of ERK1/2, p38 MAPK, and SAPK/ERK kinase-1 (SEK1) of the JNK pathway. Mechanical compression induced a phased phosphorylation of ERK consisting of a rapid induction of ERK1/2 phosphorylation at 10 min, a rapid decay, and a sustained level of ERK2 phosphorylation that persisted for at least 24 h. Mechanical compression also induced the phosphorylation of p38 MAPK in strictly a transient fashion, with maximal phosphorylation occurring at 10 min. Mechanical compression stimulated SEK1 phosphorylation, with a maximum at the relatively delayed time point of 1 h and with a higher amplitude than ERK1/2 and p38 MAPK phosphorylation. These data demonstrate that mechanical compression alone activates MAPK signaling in intact cartilage. In addition, these data demonstrate distinct temporal patterns of MAPK signaling in response to mechanical loading and to the anabolic insulin-like growth factor-I. Finally, the data indicate that compression coactivates distinct signaling pathways that may help define the nature of mechanotransduction in cartilage.
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PMID:Mechanical regulation of mitogen-activated protein kinase signaling in articular cartilage. 1295 76

Insulin-like growth factor-I (IGF-I) has been shown to stimulate a hypertrophy response in skeletal muscles in vivo. In vitro studies have delineated two primary intracellular pathways that appear to mediate the effects of IGF-I in skeletal muscle: the Ras-ERK pathway and the phosphoinositide-3 kinase pathway. In vitro, the Ras pathway appears to regulate the mitogenic effects of IGF-I signaling, whereas the phosphoinositide-3 kinase pathway is associated with cellular differentiation. On the basis of the results from in vitro studies, we hypothesized that the coinfusion of both IGF-I and an inhibitor of the Ras pathway would result in some increase in muscle protein but an inhibition of cell proliferation. Our results show that 14 days of coinfusion of MAPK/ERK kinase inhibitor PD-098059 (PD) limited the phosphorylation of ERK and prevented IGF-I induced increases in protein (18%, P < 0.05 vs. 7%, not significant) or myofibrillar protein (23%, P < 0.01 vs. 5%, not significant). However, there were similar increases in indicators of cell proliferation (e.g., total DNA, 50 and 52%, P < 0.001) in both the IGF- and IGF+PD-infused muscles. The most notable impact on IGF-I signaling was a significant blunting of IGF-I induced increase in S6K1 phosphorylation by PD-98059 coinfusion ( approximately 5-fold, P < 0.001 vs. 3-fold, P < 0.01). These results suggest that there are interactions between the various pathways down stream of the IGF-I receptor that may behave differently in vivo than in myogenic cell lines in vitro.
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PMID:Inhibition of MAP/ERK kinase prevents IGF-I-induced hypertrophy in rat muscles. 1295 52


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