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)

The phosphatidylinositol (PI)-3 kinase-Akt/PKB survival pathway protects neurons from apoptosis caused by diverse stress stimuli. However, its protective effect against neurotoxins that produce oxidative stress and neurodegeneration has not been investigated. We analyzed the effect of this pathway on the action of the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Overexpression of a membrane-targeted, N-myristylated fusion protein of enhanced green fluorescence protein (EGFP) and mouse Akt1 attenuated the apoptotic effect of the neurotoxin in PC12 cells. This effect was not due to protection of mitochondrial complex I activity or restoration of energy charge. Following MPP+-treatment, myr-EGFP-Akt1-transfected cells exhibited an unaltered mitochondrial membrane potential and lower ROS levels than control cells. These results provide a new site of action of Akt/PKB at the level of the oxidative detoxifying cell machinery and suggest that this effect may be responsible in part for the resistance of myr-EGFP-Akt1-expressing cells to oxidative stress and MPP+-induced apoptosis.
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PMID:Akt1/PKBalpha protects PC12 cells against the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium and reduces the levels of oxygen-free radicals. 1116 70

The parkinsonian neurotoxin methylpyridinium (MPP(+)) mimics the neuropathology of Parkinson's disease (PD) and likely kills neurons by inhibiting complex I of the electron transport chain and increasing oxidative stress. We examined the time course of activation/inactivation of multiple pro- and anti-apoptotic signaling pathways in MPP(+)-induced apoptotic death of SH-SY5Y neuroblastoma cells. We found an early increase and later decrease of transcriptional activity of the generally anti-apoptotic nuclear factor kappa-beta (NF-kappa B) and early increases in activating phosphorylation of the anti-apoptotic upstream kinase protein kinase B (PKB, also known as AKT). Sequestration-inducing phosphorylation of pro-apoptotic BAD protein increased early then declined. A small biphasic increase in the generally pro-apoptotic p38 kinase activity paralleled the biphasic rise in NF-kappa B-mediated transcription. Inhibition of p38 kinase with 5 micro M SB203540, inhibition of MEK-ERK with 50 micro M U0126, or inhibition of phosphatidylinositol-3-kinase (PI3K) with 10 micro M LY294002 reduced cell viability by 4, 18 or 37%, respectively, after 24 h. All three kinase inhibitors increased cell death in response to 24 h of MPP(+), with the greatest effect shown by LY294002. Nerve growth factor (NGF) caused an early increase in activating phosphorylation of PKB/AKT and MEK-ERK and increased cell survival during MPP(+) exposure. We found that acute MPP(+) exposure activates multiple interacting death- and survival-promoting pathways. Survival-promoting MEK-ERK and PI3K pathways contribute to viability during MPP(+) exposure, both are activated by NGF, and loss of PI3K-mediated signaling and NF-kappa B-mediated transcription may commit cells irreversibly to apoptosis in this model. It remains unknown to what extent these signaling pathways modulate dopamine neuronal death in PD.
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PMID:Methylpyridinium (MPP(+))- and nerve growth factor-induced changes in pro- and anti-apoptotic signaling pathways in SH-SY5Y neuroblastoma cells. 1236 9

BCR-ABL oncoprotein-expressing cells are associated with a relative increase of intracellular reactive oxygen species (ROS), which is thought to play a role in transformation. Elevated ROS levels in BCR-ABL-transformed cells were found to be blocked by the mitochondrial complex I inhibitor rotenone as well as the glucose transport inhibitor phloretin, suggesting that the source of increased ROS might be related to increased glucose metabolism. The glucose analog 2-deoxyglucose (2-DOG) reduced ROS to levels found in non-BCR-ABL-transformed cells and inhibited cell growth alone or in cooperation with imatinib mesylate (Gleevec). A mutant of BCR-ABL that is defective in transformation of myeloid cells, Tyr177Phe, was also found to be defective in raising intracellular ROS levels. Glucose metabolism in BCR-ABL-transformed cells is likely to be mediated by activation of the phosphatidylinositol-3'-kinase (PI3K) pathway, which is regulated through this site. Inhibition of PI3K or mTOR led to a significant decrease in ROS levels. Overall, our results suggest that elevated levels of ROS in BCR-ABL-transformed cells are secondary to a transformation-associated increase in glucose metabolism and an overactive mitochondrial electron transport chain and is specifically regulated by PI3K. Finally, these results hint at novel targets for drug development that may aid traditional therapy.
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PMID:Activation of the PI3K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species. 1548 67

To investigate a possible new physiological role of carbon monoxide (CO), an endogenous gas involved in cell signaling and cytotoxicity, we tested the hypothesis that the mitochondrial generation of reactive oxygen species by CO activates mitochondrial biogenesis in the heart. In mice, transient elevations of cellular CO by five- to 20-fold increased the copy number of cardiac mitochondrial DNA, the content of respiratory complex I-V and interfibrillar mitochondrial density within 24 hours. Mitochondrial biogenesis is activated by gene and protein expression of the nuclear respiratory factor 1 (NRF1) and NRF2, of peroxisome proliferator-activated receptor gamma co-activator-1alpha, and of mitochondrial transcription factor A (TFAM), which augmented the copy number of mitochondrial DNA (mtDNA). This is independent of nitric oxide synthase (NOS), as demonstrated by the identical responses in wild-type and endothelial NOS (eNOS)-deficient mice, and by the inhibition of inducible NOS (iNOS). In the heart and in isolated cardiomyocytes, CO activation involved both guanylate cyclase and the pro-survival kinase Akt/PKB. Akt activation was facilitated by mitochondrial binding of CO and by production of hydrogen peroxide (H(2)O(2)). Interference with Akt activity by blocking PI 3-kinase and by mitochondrial targeting of catalase to scavenge H(2)O(2) prevented binding of NRF1 to the Tfam promoter, thereby connecting mitochondrial H(2)O(2) to the pathway leading to mtDNA replication. The findings disclose mitochondrial CO and H(2)O(2) as new activating factors in cardiac mitochondrial biogenesis.
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PMID:A new activating role for CO in cardiac mitochondrial biogenesis. 1717 7

We speculated that focal adhesion kinase (FAK) might play a critical role in the TNFalpha-induced cell death. In this study, we found that FAK-/- cells are more sensitive to TNFalpha-induced apoptosis in the presence of actinomycin D (Act D) compared to FAK+/- cells. Prosurvival pathways are activated by the rapid recruitment of complex I, comprising TNFR1, TRADD, RIP and TRAF2, which leads to the activation of the NF-kappaB pathway. On the other hand, proapoptotic pathways are activated by complex II, the death-inducing signaling complex (DISC), which contains TNFR1, TRADD, RIP, and FADD, and procaspase-8 proteins. As TNFR1, TRADD, and RIP are included in both Complex I and DISC, we speculated that RIP might be a key protein. Coimmunoprecipitation assays revealed that RIP is included in complex I in FAK+/- cells, and FAK was associated with RIP. On the other hand, RIP is included in DISC in FAK-/- cells. FAK might be a key protein in the formation of complex I and the activation of NF-kappaB. Furthermore, Akt was activated in FAK+/- cells, but not FAK-/- cells. In conclusion, we first demonstrated that FAK determines the pathway leading to death or survival in TNFalpha/ActD-stimulated fibroblasts.
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PMID:Focal adhesion kinase determines the fate of death or survival of cells in response to TNFalpha in the presence of actinomycin D. 1719 95

Reactive oxygen species (ROS) play a key role in regulation of activation-induced T-cell death (AICD) by induction of CD95L expression. However, the molecular source and the signaling steps necessary for ROS production are largely unknown. Here, we show that the proximal T-cell receptor-signaling machinery, including ZAP70 (zeta chain-associated protein kinase 70), LAT (linker of activated T cells), SLP76 (SH2 domain-containing leukocyte protein of 76 kDa), PLCgamma1 (phospholipase Cgamma1), and PKCtheta (protein kinase Ctheta), are crucial for ROS production. PKCtheta is translocated to the mitochondria. By using cells depleted of mitochondrial DNA, we identified the mitochondria as the source of activation-induced ROS. Inhibition of mitochondrial electron transport complex I assembly by small interfering RNA (siRNA)-mediated knockdown of the chaperone NDUFAF1 resulted in a block of ROS production. Complex I-derived ROS are converted into a hydrogen peroxide signal by the mitochondrial superoxide dismutase. This signal is essential for CD95L expression, as inhibition of complex I assembly by NDUFAF1-specific siRNA prevents AICD. Similar results were obtained when metformin, an antidiabetic drug and mild complex I inhibitor, was used. Thus, we demonstrate for the first time that PKCtheta-dependent ROS generation by mitochondrial complex I is essential for AICD.
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PMID:Novel role for mitochondria: protein kinase Ctheta-dependent oxidative signaling organelles in activation-induced T-cell death. 1733 28

Mitochondria, besides playing a central role in energy metabolism within the cell, are involved in a cohort of other processes like cellular differentiation and apoptosis. Investigations during recent few years have shown that protein kinases, including PKA, PKB/Akt, PKC, Raf-1, p38 MAPK, JNK, ERK1/2, Src, Fyn and Csk, may directly interact with mitochondrial proteins. Their role mainly concentrates at phosphorylation of pro- and anti-apoptotic proteins (Bad, Bax, Bcl-2, Bcl-xL), phosphorylation/modification of electron transport chain proteins (complex I, COIV), MPTP forming proteins VDAC and ANT, proteins of mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) and phospholipid scramblase 3 (PLSCR3). Many experimental data showed the presence of protein kinases in the outer and inner mitochondrial membranes as well as in the mitochondrial matrix during in vitro cell stimulations, in neurodegenerative diseases and in in vivo ischaemia heart preconditioning. These data show that translocation of protein kinases to mitochondria plays an important role especially during ischaemia/reperfusion in brain and heart.
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PMID:[Protein kinases in mitochondria]. 1880 32

Parkinson's disease (PD) is the most common neurodegenerative disease after Alzheimer's disease. Although the pathogenetic mechanisms underlying PD is largely unknowm, it is widely believed that multiple genetic as well as environmental factors play critical roles in the development of PD. Alpha synuclein (a-SYN) and the disturbance of a-SYN metabolism seems to play the most important role in PD pathogenesis. a-SYN, the gene causative in PARK1, is the major component of Lewy bodies. Gene duplication or triplication of a-SYN leads to autosomal dominant form of familial PD, suggesting that disturbance of a-SYN may represent the etiology of sporadic PD. GBA and LRRK, the genes responsible for Gaucher disease and PARK8, respetively, are also likely to affect the development of PD. Studies of PD brains suggest that mitochondrial impairment and oxidative stress may contribute to the pathogenesis of sporadic PD. Mitochondrial complex I inhibitors, such as MPTP and rotenone, induce selective dopaminergic neuronal death, suggesting that chemicals may constitute risk factors of sporadic PD. Not only continuous infusion, but oral intake of rotenone is effective to establish animal models of PD. Further studies will reveal genetic or environmental risk factors, that are the good targets for prevention and therapy of PD.
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PMID:[Pathogenesis of sporadic Parkinson's disease: contribution of genetic and environmental risk factors]. 2003 Feb 38

Acrolein (ACR) exposure leads to the formation of protein-ACR adducts. Protein modification by ACR has been associated with various chronic diseases including cardiovascular and neurodegenerative diseases. Here, we report an analytical strategy that enables the quantification of Michael-type protein adducts of ACR in mitochondrial proteome samples using liquid chromatography in combination with tandem mass spectrometry and selected ion monitoring (LC-MS/MS SRM) analysis. Our approach combines site-specific identification and relative quantification at the peptide level of protein-ACR adducts in relation to the unmodified protein thiol pool. Treatment of 3-month-old rats with CCl(4) , an established in vivo model of acute oxidative stress, resulted in significant increases in the ratios of distinct ACR-adducted peptides to the corresponding unmodified thiol-peptides obtained from proteins that were isolated from cardiac mitochondria. The mitochondrial proteins that were found adducted by ACR were malate dehydrogenase, NADH dehydrogenase [ubiquinone] flavoprotein 1, cytochrome c oxidase subunit VIb isoform 1, ATP synthase d chain, and ADP/ATP translocase 1. The findings indicate that protein modification by ACR has potential value as an index of mitochondrial oxidative stress.
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PMID:Mass spectrometry-based quantification of myocardial protein adducts with acrolein in an in vivo model of oxidative stress. 2180 40

The present study was aimed to investigate the behavioral and molecular effects of lamotrigine. To this aim, Wistar rats were treated with lamotrigine (10 and 20 mg/kg) or imipramine (30 mg/kg) acutely and chronically. The behavior was assessed using forced swimming test. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), Proteina Kinase B (PKB, AKT), glycogen synthase kinase 3 (GSK-3) and B-cell lymphoma 2 (Bcl-2) levels, citrate synthase, creatine kinase and mitochondrial chain (I, II, II-III and IV) activities were assessed in the brain. The results showed that both treatments reduced the immobility time. The BDNF were increased in the prefrontal after acute treatment with lamotrigine (20 mg/kg), and the BDNF and NGF were increased in the prefrontal after chronic treatment with lamotrigine in all doses. The AKT increased and Bcl-2 and GSK-3 decreased after both treatments in all brain areas. The citrate synthase and creatine kinase increased in the amygdala after acute treatment with imipramine. Chronic treatment with imipramine and lamotrigine (10 mg/kg) increased the creatine kinase in the hippocampus. The complex I was reduced and the complex II, II-III and IV were increased, but related with treatment and brain area. In conclusion, lamotrigine exerted antidepressant-like, which can be attributed to its effects on pathways related to depression, such as neurotrophins, metabolism energy and signaling cascade.
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PMID:Effects of acute and chronic treatment elicited by lamotrigine on behavior, energy metabolism, neurotrophins and signaling cascades in rats. 2204 72


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