Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed an image-based technique for signal pathway analysis, target validation, and compound screening related to mammary epithelial cell differentiation. This technique used the advantages of optical imaging and the HC11-Lux model system. The HC11-Lux cell line is a subclone of HC11 mammary epithelial cells transfected stably with a luciferase construct of the beta-casein gene promoter (p-344/-1betac-Lux). The promoter activity was imaged optically in real time following lactogenic induction. The imaging signal intensity was closely correlated with that measured using a luminometer following protein extraction (R=0.99, P<0.0001) and consistent with the messenger RNA (mRNA) level of the endogenous beta -casein gene. Using this technique, we examined the roles of JAK2/Stat5A, Raf-1/MEK/MAKP, and PI3K/Akt signal pathways with respect to differentiation. The imaging studies showed that treatment of the cells with epidermal growth factor (EGF), AG490 (JAK2-specific inhibitor), and LY294002 (PI3K-specific inhibitor) blocked lactogenic differentiation in a dose-dependent manner. PD98059 (MEK-specific inhibitor) could reverse EGF-mediated differentiation arrest. These results indicate that these pathways are essential in cell differentiation. This simple, sensitive, and reproducible technique permits visualization and real-time evaluation of the molecular events related to milk protein production. It can be adopted for high-throughput screening of small molecules for their effects on mammary epithelial cell growth, differentiation, and carcinogenesis.
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PMID:Image-based evaluation of the molecular events underlying HC11 mammary epithelial cell differentiation. 1872 92

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

Although Ras is a potent oncogene, its tumorigenicity depends on cellular context and cooperative events. Tumor suppressor PTEN is the most important negative regulator of the cell-survival signaling pathway initiated by phosphoinositide 3-OH kinase. Previously, we established various NIH/3T3 cells expressing H-Ras mutant proteins. This report shows that expression of PTEN is suppressed by the oncogenic H-Ras at its protein and transcript levels as well as by oncogenic K- and N-Ras. This activity of oncogenic Ras is mediated by Raf-1/Erk/MEK signaling pathway. In our previous reports, FAK Y(861) phosphorylation is higher in H-Ras transformed NIH/3T3 cells. In this report, level of FAK pY(861) was examined in Ras mutant cell lines. By generating wild-type PTEN, lipid phosphatase-deficient PTEN and activity-inert PTEN-inducible cell lines in the background of oncogenic H-Ras stable expression in NIH/3T3 cells, we show level of FAK pY(861) is decreased by protein phosphatase activity of PTEN.
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PMID:A cross-talk between oncogenic Ras and tumor suppressor PTEN through FAK Tyr861 phosphorylation in NIH/3T3 mouse embryonic fibroblasts. 1900 Jun 54

By interfering with signal transduction events that control cell proliferation and fate, kinase inhibitors (KIs) hold promise as anticancer agents. Nevertheless, the functional role of a kinase depends on the cellular context and hence kinase inhibition in off-target cells could lead to side effects. For instance, this context dependence renders many KIs potentially cardiotoxic since inhibition of primary cancer targets such as ABL, RAF1 or AMPK recruits pro-apoptotic pathways in cardiomyocytes. Motivated by these observations, we propose a mode of 'therapeutic editing' where one drug (the editor) suppresses the side effect promoted by the primary drug as it impacts off-target cells. Editor and primary drug have overlapping therapeutic impact, and the editor suppresses the downstream propagation of toxicity-related signaling.
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PMID:Selective antagonism of anticancer drugs for side-effect removal. 1959 65

To help preserve in-theater strength within deployed military units, commercially available, rapid, user-friendly ABO-Rh blood typing kits were evaluated to determine their stability in storage conditions commonly encountered by the warfighter. Methods for environmental exposure testing were based on MIL-STD-810F. When Eldon Home Kits 2511 were exposed to various temperature/relative humidity conditions, the results were comparable to those obtained with the control group and those obtained with industry-standard methods. For the ABO-Rh Combination Blood Typing Experiment Kits, 2 of the exposure treatments rendered them unusable. In addition, a third set of exposure treatments adversely affected the kits, resulting in approximately 30% blood type misclassifications. Collectively, this evaluation of commercial blood typing kits revealed that diagnostic performance can vary between products, lots, and environmental storage conditions.
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PMID:Stability of user-friendly blood typing kits stored under typical military field conditions. 1989 Dec 20

In normal epithelial cells hemidesmosomes mediate stable adhesion to the underlying basement membrane. In carcinoma cells a functional and spatial dissociation of the hemidesmosomal complex is observed stimulating the hypothesis that the beta4 integrin may trigger essential signalling cascades determining cell fate. In the present study we dissected the signalling pathways giving rise to PKB/Akt and ERK1/2 activation in response to beta4 ligation by 3E1. It was found that the activation of PKB/Akt is sensitive towards alterations of the keratin filament as demonstrated by using KEB-7 cells that carry a keratin mutation typical for epidermolysis bullosa simplex. Similar results were achieved by chemically induced keratin aggregations. Of note, the signalling to ERK1/2 was not affected. ERK1/2 activation utilizes an EGF-R transactivation mechanism as shown by dominant-negative expression experiments and also by treatment with a specific inhibitor (AG1478). Downstream from the EGF-R the activation of ERK1/2 takes the prototypical signalling cascade via Shc, Ras and Raf-1 as demonstrated by dominant-negative expression experiments. Taken together our data define a new model of beta4-dependent PKB/Akt and ERK1/2 activation demonstrating the keratin filament as a structure necessary in signal transmission.
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PMID:Ligation of beta4 integrins activates PKB/Akt and ERK1/2 by distinct pathways-relevance of the keratin filament. 2030 89

We have recently reported that activation of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2)/ERK1/2 signaling cascade in gastrointestinal carcinoid cell line (BON) alters cellular morphology and neuroendocrine phenotype. The mechanisms by which Raf-1 mediates these changes in carcinoid cells are unclear. Here, we report that activation of the Raf-1 signaling cascade in BON cells induced the expression of focal adhesion kinase (FAK) protein, suppressed the production of neuroendocrine markers, and resulted in significant decreases in cellular adhesion and migration. Importantly, inactivation of MEK1/2 by 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene or abolition of FAK induction in Raf-1-activated BON cells by targeted siRNA led to reversal of the Raf-1-mediated reduction in neuroendocrine markers and cellular adhesion and migration. Phosphorylation site-specific antibodies detected the phosphorylated FAK(Tyr407), but not FAK(Tyr397), in these Raf-1-activated cells, indicating that FAK(Tyr407) may be associated with changes in the neuroendocrine phenotype. Overexpression of constitutively active FAK plasmids (wild-type FAK or FAK(Tyr397) mutant) into BON cells reduced neuroendocrine markers, whereas the FAK(Tyr407) mutant plasmid did not show any decrease in the levels of neuroendocrine markers, indicating that phosphorylation of FAK at the Tyr(407) residue may be important for these effects. Our results showed for the first time that FAK is an essential downstream effector of the Raf-1/MEK1/2/ERK1/2 signaling cascade and negatively regulated the neuroendocrine and metastatic phenotype in BON cells.
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PMID:Focal adhesion kinase, a downstream mediator of Raf-1 signaling, suppresses cellular adhesion, migration, and neuroendocrine markers in BON carcinoid cells. 2040 18

The central purpose of this study is to further evaluate the quality of the performance of a new algorithm. The study provides additional evidence on this algorithm that was designed to increase the overall efficiency of the original k-means clustering technique-the Fast, Efficient, and Scalable k-means algorithm (FES-k-means). The FES-k-means algorithm uses a hybrid approach that comprises the k-d tree data structure that enhances the nearest neighbor query, the original k-means algorithm, and an adaptation rate proposed by Mashor. This algorithm was tested using two real datasets and one synthetic dataset. It was employed twice on all three datasets: once on data trained by the innovative MIL-SOM method and then on the actual untrained data in order to evaluate its competence. This two-step approach of data training prior to clustering provides a solid foundation for knowledge discovery and data mining, otherwise unclaimed by clustering methods alone. The benefits of this method are that it produces clusters similar to the original k-means method at a much faster rate as shown by runtime comparison data; and it provides efficient analysis of large geospatial data with implications for disease mechanism discovery. From a disease mechanism discovery perspective, it is hypothesized that the linear-like pattern of elevated blood lead levels discovered in the city of Chicago may be spatially linked to the city's water service lines.
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PMID:A New-Fangled FES-k-Means Clustering Algorithm for Disease Discovery and Visual Analytics. 2068 10

Damage-risk criteria (DRC) for noise exposures are designed to protect 95% of the exposed populations from hearing injuries caused by those noise exposures. The current DRC used by the US military follows OSHA guidelines for continuous noise. The current military DRC for impulse exposures follows the recommendations from the National Academy of Sciences--National Research Council Committee on Hearing, Bioacoustics, and Biomechanics (CHABA) and are contained in the current military standard, MIL-STD-1474D "Noise Limits." Suggesting that the MIL-STD for impulse exposure is too stringent, various individuals have proposed that the DRC for exposure to high-level impulses be relaxed. The purpose of this study is to evaluate the current hearing status of US Army Soldiers, some of whom can be, by their military occupational specialties (MOS), reasonably expected to be routinely exposed to high-level impulses from weapon systems. The Defense Occupational and Environmental Health Readiness System--Hearing Conservation (DOEHRS-HC) was queried for the hearing status of enlisted Soldiers of 32 different MOSs. The results indicated that less than 95% of the Soldiers in the DOEHRS-HC database were classified as having normal hearing. In other words, the goal of the DRC used for limiting noise injuries (from continuous and impulse exposures) was not stringent enough to prevent hearing injuries in all but the most susceptible Soldiers. These results suggest that the current military noise DRC should not be relaxed.
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PMID:Analysis of army-wide hearing conservation database for hearing profiles related to crew-served and individual weapon systems. 2117 91

The main aim of the present work was to test the effects of glucose and fructose on the phosphorylation levels of proteins linked to the control of overall sperm function in two species with very different metabolic characteristics, dog and boar. Incubation of dog spermatozoa with 10mM glucose increased serine phosphorylation of proteins related to cell cycle and signal transduction including cyclins B and E, Cdk2, Cdk6, Cdc6, PYK2, c-kit, Raf-1, TRK and several protein phosphatases. Incubation of dog spermatozoa with 10mM fructose decreased serine phosphorylation levels of cyclins B and D3, Cdk1/Cdc2, Cdk2, Cdk6, Akt, PI3 kinase, ERK-1 and protein kinase C. Incubation of boar spermatozoa with glucose or fructose did not modify any of the phosphorylation patterns studied. Given that one important difference between dog and boar spermatozoa is the presence of glucokinase (GK) in dog but not in boar, GK-transfected COS7 cells were incubated with either 10mM glucose or 10mM fructose. Incubation of GK-transfected cells with fructose decreased serine phosphorylation of cyclin A, ERK-2 and Hsp-70. In contrast, incubation of control COS7 cells with fructose increased serine phosphorylation of Cdk6, Cdk1/Cdc2, protein kinase C and Hsp-70. Incubation with glucose did not induce any significant effect. Our results indicate that monosaccharides act as signalling compounds in dog spermatozoa after ejaculation through changes in the phosphorylation levels of specific proteins. One of the factors that may be related to the action of sugars is the equilibrium of the total sperm hexokinase activity, in which the presence or absence of GK appears to be relevant.
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PMID:Glucose and fructose as functional modulators of overall dog, but not boar sperm function. 2142 64


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