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)

Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X(L) and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.
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PMID:Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. 1528 11

We have previously identified C1 domain-containing phosphatase and TENsin homologue (C1-TEN) as being an intracellular binding partner for Axl receptor tyrosine kinase (RTK). C1-TEN is a tensin-related protein that houses an N-terminal region with predicted structural similarity to PTEN. Here, we report our observations on the effects of ectopic expression of C1-TEN in HEK293 cells, which resulted in profound molecular and phenotypic changes. Stable expression of C1-TEN altered cellular morphology, with less cell spreading and weaker filamentous actin staining. Cells overexpressing C1-TEN were inhibited greatly in their proliferation and migration rates as compared with mock-transfected cells. Furthermore, serum starvation-induced apoptosis caused a twofold increase in caspase 3 activity in C1-TEN-overexpressing cells vs. mock cells. In addition, C1-TEN-overexpressing cells showed a markedly reduced phosphorylation of Akt/PKB kinase and its substrate GSK3, as well as reduced Akt enzymatic activity. No such effects on JNK were observed. Also, serum-stimulated activation of Akt was delayed in C1-TEN-overexpressing cells, while no difference in profile of ERK activation was observed. Furthermore, cells expressing a C1-TEN mutant where the putative phosphatase active site cysteine at position 231 was substituted for a serine displayed full restoration of both cell proliferation and Akt activation. In conclusion, C1-TEN appears to be a novel intracellular phosphatase that negatively regulates the Akt/PKB signaling cascade, and is similar to its relative PTEN in this respect. However, the particular domain organization of C1-TEN may enable it to regulate RTK and other signaling complexes that are linked to Akt/PKB signaling in a unique manner.
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PMID:C1-TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration. 1581 39

Thyroid hormone is known to cause hypertrophy, tachycardia, vasorelaxation, and enhanced contractile function. The exact mechanisms responsible for these effects are unknown but classical regulation of gene expression through binding to nuclear receptors has been widely implicated. Data have also accumulated suggesting that TH can exert effects through non-classical mechanisms involving activation of signal transduction pathways. Whether thyroid hormone can activate signal transduction pathways in the heart is unknown. In this study, we treated neonatal rat cardiomyocytes with T3 and determined the expression and phosphorylation of signaling molecules. T3 caused specific activation of Akt/PKB signaling after 24 h of treatment. Since Akt is known to protect against cell death, cells were serum-starved in the presence or absence of T3 to determine whether T3 could protect against serum starvation-induced cell death. Indeed, myocytes treated with T3 displayed enhanced sarcomeric structure after 4 days of serum starvation. T3 increased cell viability as measured by MTT assays, prevented DNA laddering, and reduced TUNEL positive cells, which was associated with increased phosphorylated Akt and glycogen synthase kinase 3beta (GSK-3beta). The protective effect of T3 on cell viability, DNA laddering and TUNEL positive cells were blocked by LY294002, a phosphoinositide-3 kinase (PI3K) inhibitor that blocks Akt signaling. Overall these data suggest that T3 can activate Akt in cardiomyocytes which protects myocytes against cell death.
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PMID:Thyroid hormone activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiomyocytes. 1617 8

Autophagy is a major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles in eukaryotic cells. A large number of intracellular/extracellular stimuli, including amino acid starvation and invasion of microorganisms, are able to induce the autophagic response in cells. The discovery of the ATG genes in yeast has greatly advanced our understanding of the molecular mechanisms participating in autophagy and the genes involved in regulating the autophagic pathway. Many yeast genes have mammalian homologs, suggesting that the basic machinery for autophagy has been evolutionarily conserved along the eukaryotic phylum. The regulation of autophagy is a very complex process. Many signaling pathways, including target of rapamycin (TOR) or mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase-I (PI3K-I)/PKB, GTPases, calcium and protein synthesis all play important roles in regulating autophagy. The molecular mechanisms and regulation of autophagy are discussed in this review.
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PMID:Molecular mechanism and regulation of autophagy. 1629 39

Glycine-extended gastrin (G-Gly) is produced by colon cancers and has growth promoting and anti-apoptotic effects in the colonic epithelium. We have examined the anti-apoptotic effects of G-Gly and the signal transduction pathways involved. G-Gly stimulated HT-29 cell proliferation in a concentration dependent manner and inhibited serum-starvation and celecoxib-induced apoptosis. Inhibition of signalling via c-Jun NH2-terminal kinase (JNK) with SP600125 or PI3-kinase/Akt with LY294002 abolished the effects of G-Gly. G-Gly significantly increased phosphorylation of both JNK and Akt. The JAK2 inhibitor AG490 abolished the anti-apoptotic effect of G-Gly and inhibited phosphorylation of Akt but not of JNK. G-Gly stimulated tyrosine phosphorylation of JAK2. G-Gly-increased activation of AP-1 was JNK-dependant and activation of STAT3 was JAK2-dependant. We conclude that G-Gly promotes growth and inhibits apoptosis in colon cancer cells. These effects are mediated via the JAK2, PI3-kinase/Akt and JNK pathways. Activation of JAK2 is upstream of Akt but not of JNK.
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PMID:Glycine-extended gastrin inhibits apoptosis in colon cancer cells via separate activation of Akt and JNK pathways. 1644 4

The disruption of the gene encoding the Dictyostelium Ras subfamily protein, RasC, results in a strain that does not aggregate and has defects in both cAMP signal relay and cAMP chemotaxis. Disruption of a second gene in the rasC(-) strain by Restriction Enzyme Mediated Integration produced cells that were capable of forming multicellular structures in plaques on bacterial lawns. The disrupted gene (dmpA) encoded a novel membrane protein that was designated Dmp1. Although the rasC(-)/dmpA(-) cells progressed through early development, they did not form aggregation streams on a plastic surface under submerged starvation conditions. Phosphorylation of PKB in response to cAMP, which is significantly reduced in rasC(-) cells, remained low in the rasC(-)/dmpA(-) cells. However, in spite of this low PKB phosphorylation, the rasC(-)/dmpA(-) cells underwent efficient chemotaxis to cAMP in a spatial gradient. Cyclic AMP accumulation, which was greatly reduced in the rasC(-) cells, was restored in the rasC(-)/dmpA(-) strain, but cAMP relay in these cells was not apparent. These data indicate that although the rasC(-)/dmpA(-) cells were capable of associating to form multicellular structures, normal aggregative cell signaling was clearly not restored. Disruption of the dmpA gene in a wild-type background resulted in cells that exhibited a slight defect in aggregation and a more substantial defect in late development. These results indicate that, in addition to the role played by Dmp1 in aggregation, it is also involved in late development.
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PMID:A secondary disruption of the dmpA gene encoding a large membrane protein allows aggregation defective Dictyostelium rasC- cells to form multicellular structures. 1649 Jan 88

In Caenorhabditis elegans, several distinct apoptosis pathways have been characterized in the germline. The physiological pathway is though to eliminate excess germ cells during oogenesis to maintain gonad homeostasis and it is activated by unknown mechanisms. The DNA damage-induced germ cell apoptosis occurs in response to genotoxic agents and involves the proteins EGL-1 and CED-13, and the DNA damage response protein p53. Germ cell apoptosis can also be induced in response to pathogen infection through an EGL-1 dependent pathway. To gain insight into the mechanism and functions of germ cell apoptosis, we investigated whether and how other forms of stress induce this cell death. We found that oxidative, osmotic, heat shock and starvation stresses induce germ cell apoptosis through a p53 and EGL-1 independent pathway. We also learned that the MAPK kinases MEK-1 and SEK-1, and the p53 antagonist protein ABL-1, are essential for stress-induced germ cell apoptosis. We conclude that in C. elegans responses to various stresses that do not involve genotoxicity include an increase in germ cell apoptosis through the physiological pathway.
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PMID:Stress-induced germ cell apoptosis by a p53 independent pathway in Caenorhabditis elegans. 1672 24

Tissue factor (TF) is a transmembrane glycoprotein that initiates blood coagulation when complexed with factor VIIa (FVIIa). TF is constitutively expressed in a variety of tumor cells and has been shown to play a role in cellular signaling and tumor progression. In this study, we investigated the effect of TF-FVIIa mediated signaling on apoptosis in human breast cancer cells. Apoptosis was induced by prolonged serum starvation and studied using the Adr-MCF-7 cell line, which has high endogenous TF expression. Treatment of the cells with the combination of FVIIa (10 nM) and FX (150 nM), reduced apoptosis by nearly 50% compared with untreated, control cells using an ELISA that detects histone-DNA fragments. In contrast, FVIIa (10 nM) alone did not significantly prevent apoptosis. Pretreatment of the Adr-MCF-7 cells with hirudin, a specific thrombin inhibitor, did not inhibit the anti-apoptotic effect of the combination of FVIIa and FX, whereas this effect could be abrogated by inhibition of phosphorylation of either p44/42 mitogen-activated protein kinase (MAPK) or protein kinase B (PKB/Akt). In addition, treatment of the Adr-MCF-7 cells with the combination of FVIIa and FX led to a 30-50% increase in the level of the anti-apoptotic protein, survivin, compared with untreated cells using Western blot analysis. These results indicate that formation of TF-FVIIa-FXa complex prevents apoptosis in breast cancer cells by a thrombin-independent pathway. Moreover, the anti-apoptotic effect of this signaling pathway involves phosphorylation of both p44/42 MAPK and PKB/Akt and might be mediated in part by an increase in cell survivin levels.
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PMID:Formation of tissue factor-factor VIIa-factor Xa complex prevents apoptosis in human breast cancer cells. 1689 64

The insulin-like signaling pathway is known to regulate fat metabolism, dauer formation, and longevity in Caenorhabditis elegans. Here, we report that this pathway is also involved in salt chemotaxis learning, in which animals previously exposed to a chemoattractive salt under starvation conditions start to show salt avoidance behavior. Mutants of ins-1, daf-2, age-1, pdk-1, and akt-1, which encode the homologs of insulin, insulin/IGF-I receptor, PI 3-kinase, phosphoinositide-dependent kinase, and Akt/PKB, respectively, show severe defects in salt chemotaxis learning. daf-2 and age-1 act in the ASER salt-sensing neuron, and the activity level of the DAF-2/AGE-1 pathway in this neuron determines the extent and orientation of salt chemotaxis. On the other hand, ins-1 acts in AIA interneurons, which receive direct synaptic inputs from sensory neurons and also send synaptic outputs to ASER. These results suggest that INS-1 secreted from AIA interneurons provides feedback to ASER to generate plasticity of chemotaxis.
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PMID:The insulin/PI 3-kinase pathway regulates salt chemotaxis learning in Caenorhabditis elegans. 1695 Jan 59

C/EBP homologous protein (CHOP) is a transcriptional factor and is induced under conditions such as the unfolded protein response or amino acid starvation. A previous study showed that the transcriptional level of CHOP was highly increased in rat liver in which hepatocellular apoptosis was induced by cycloheximide (CHX) treatment. Here, we investigated the relationship between hepatocellular apoptosis and CHOP-mediated apoptotic pathway, and studied the mechanisms of induction of CHOP gene in the liver of rats treated with CHX. Male F344 rats were treated intravenously with 6mg/kg CHX, and sacrificed at 1, 2 and 6h after the treatment. In the gene expression assay using quantitative RT-PCR, the genes related to CHOP-mediated apoptosis such as the C/EBPbeta, ATF3 and ATF4 genes were significantly increased corresponding to the induction of hepatocellular apoptosis in rats treated with CHX. However the GRP78/Bip gene, which serves as a representative marker for the unfolded protein response, did not change after the treatment. Toxicoproteomics using two-dimensional difference gel electrophoresis and mass spectrometry indicated that GRP78/Bip was inactivated by the CHX treatment. Furthermore, the CHX-treated animals exhibited a significant decrease of phosphorylated Akt/PKB (protein kinase B). These results indicate that the protein synthesis inhibition by CHX induces the CHOP gene through a pathway similar to that of amino acid starvation, and that Akt/PKB inactivation enhances the CHOP-mediated hepatocellular apoptosis.
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PMID:Toxicoproteomic investigation of the molecular mechanisms of cycloheximide-induced hepatocellular apoptosis in rat liver. 1706 31


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