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)

The transendothelial movement of solutes is a dynamic process controlled by a complex interaction between the cytoskeleton and adhesion proteins. The aim of this study was to examine whether protein tyrosine phosphorylation is involved in the regulation of endothelial barrier function. The apparent permeability coefficient of albumin (Pa) was measured in isolated and perfused coronary venules. Tyrosine phosphatase inhibitors, including phenylarsine oxide and sodium orthovanadate, dose and time dependently increased basal Pa. Western blot analysis of cultured coronary venular endothelial cells revealed that inhibition of tyrosine phosphatase induced an increase in phosphotyrosine content in a number of proteins, including bands at 65-70 and 120-130 kDa, which were identified as paxillin and focal adhesion kinase (pp125FAK), respectively. The time course and dose responsiveness of protein tyrosine phosphorylation were tightly correlated with those of increases in Pa. Furthermore, stimulation of endothelial cells with histamine or phorbol myristate acetate (PMA) enhanced tyrosine phosphorylation of paxillin and pp125FAK, which was blocked by the tyrosine kinase inhibitor damnacanthal. Correspondingly, the increases in venular permeability elicited by histamine and PMA were abolished in damnacanthal-treated venules. Taken together, the data suggest a possible involvement of protein tyrosine phosphorylation in the control of endothelial barrier function. Paxillin and its associated focal adhesion proteins may play a specific role in agonist-induced hyperpermeability responses in the endothelium of exchange vessels.
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PMID:Tyrosine phosphorylation of paxillin/pp125FAK and microvascular endothelial barrier function. 968 99

We examined potential mechanisms by which angiotensin subtype-2 (AT2) receptor stimulation induces net fluid absorption and serosal guanosine cyclic 3',5'-monophosphate (cGMP) formation in the rat jejunum. L-arginine (L-ARG) given intravenously or interstitially enhanced net fluid absorption and cGMP formation, which were completely blocked by the nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine methylester (L-NAME), but not by the specific AT2 receptor antagonist, PD-123319 (PD). Dietary sodium restriction also increased jejunal interstitial fluid cGMP and fluid absorption. Both could be blocked by PD or L-NAME, suggesting that the effects of sodium restriction occur via ANG II at the AT2 receptor. L-ARG-stimulated fluid absorption was blocked by the soluble guanylyl cyclase inhibitor 1-H-[1,2,4]oxadiazolo[4, 2-alpha]quinoxalin-1-one (ODQ). Cyclic GMP-specific phosphodiesterase in the interstitial space decreased extracellular cGMP content and prevented the absorptive effects of L-ARG. Angiotensin II (ANG II) caused an increase in net Na+ and Cl- ion absorption and 22Na+ unidirectional efflux (absorption) from the jejunal loop. In contrast, intraluminal heat-stable enterotoxin of Escherichia coli (STa) increased loop cGMP and fluid secretion that were not blocked by either L-NAME or ODQ. These findings suggest that ANG II acts at the serosal side via AT2 receptors to stimulate cGMP production via soluble guanylyl cyclase activation and absorption through the generation of NO, but that mucosal STa activation of particulate guanylyl cyclase causes secretion independently of NO, thus demonstrating the opposite effects of cGMP in the mucosal and serosal compartments of the jejunum.
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PMID:Compartmentalization of extracellular cGMP determines absorptive or secretory responses in the rat jejunum. 991 28

Fluoride is an acknowledged bone anabolic agent. Nevertheless, a narrow therapeutic window and the adverse effects at higher therapeutic doses prevent broad clinical application of fluoride for treatment of diseases of bone loss, such as osteoporosis. The cellular and molecular mechanisms of fluoride action are poorly understood. recent advances in the elucidation of signal transduction pathways induced by fluoride in osteoblastic cells are reviewed. Fluoride and traces of aluminum form a complex, fluoroaluminate, which stimulates cellular heterotrimeric G proteins. Such complex can form in food, drinking water and in the organism after administration of sodium fluoride. Fluoroaluminate crosses the cell membrane and directly binds to the membrane-associated inactive G alpha protein subunits. Within the G alpha subunit, fluoroaluminate occupies the position next to GDP. The resulting G alpha-GDP-AlF4- complex assumes an active state conformation, which resembles that of G alpha-GTP complex. Under physiological conditions, G alpha-GTP complex is formed upon activation of seven transmembrane receptors that couple to heterotrimeric G proteins. Both fluoroaluminate-activated and receptor-activated G alpha subunits are capable of transmitting intracellular signals that lead to cellular responses. In bone-forming cells osteoblasts, fluoroaluminate stimulates pertussis toxin-sensitive G alpha i proteins. G alpha i activation leads to the reduction in cAMP (cyclic adenosine monophosphate) levels and to the activation of mitogen activated protein kinases, Erks (extracellular signal-regulated kinases) and p70 S6 kinase. These kinases are involved in the regulation of gene transcription and protein syntheses. Fluoroaluminate also stimulates pertussis toxin-insensitive proteins. Pertussis toxin-insensitive G proteins, most likely from G alpha 12 class, cause the activation of several cytoplasmic protein tyrosine kinases [Src, Pyk2 (proline-rich tyrosine kinase 2), and Fak (focal adhesion kinase)]. Activation of Erks can lead to osteoblast proliferation and differentiation, while activation of Src, Pyk2 and Fak can modulate the adhesion properties of osteoblasts. Osteoblast adhesion may, in turn, influence differentiation, migration, and apoptosis of these cells. The susceptibility of osteoblasts to fluoroaluminate can be achieved by their specific cellular context and by the rigidity of the surrounding bone tissue. In particular, higher levels of G alpha i proteins and of certain focal adhesion proteins are expressed by osteoblastic rather than by fibroblastic cells. The rigidity of adhesion substratum of osteoblasts may signal on its own and potentiate the signaling by fluoroaluminate. The information on mechanisms of intracellular signaling by fluoroaluminate can be utilized to identify a fluoroaluminate mimic, a drug that exhibits anabolic action on bone with a broader therapeutic range and less adverse effects than fluoride.
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PMID:Heterotrimeric G proteins as fluoride targets in bone (review). 991 18

Cultured rat cerebellar granule cells depolarized by high KCl, display a large component of Ca2+ influx through L-type voltage-dependent Ca2+ channels as defined by a sensitivity to 1 microM nifedipine. This Ca2+ influx is not coupled to neurotransmitter exocytosis but has implications for neuronal development. KCl stimulation in the absence of external Ca2+ followed by the readdition of Ca2+ allows the coupling of a class of L-type Ca2+ channels to neurotransmitter exocytosis as assessed by loading of glutamatergic pools with [3H]-D-aspartate. KCl stimulation in the absence of external Ca2+ ('predepolarization') enhances tyrosine phosphorylation of several cellular proteins, and inhibitors of tyrosine kinases block both phosphorylation and the neurotransmitter release coupled to the L-type Ca2+ channel. More specifically, an inhibitor of src family tyrosine kinases, PP1, blocks the effects of predepolarization suggesting a role for a src family kinase in the process. Furthermore, L-type Ca2+ channel recruitment and modulation of release could be activated with the tyrosine phosphatase inhibitor sodium orthovanadate. The phosphoproteins enhanced by predepolarization, which include the cytoskeletal proteins focal adhesion kinase (FAK) and vinculin, are also highly phosphorylated early on in culture when neurite outgrowth occurs. As the neurons develop a network of neurites, both tyrosine phosphorylation and L-type Ca2+ channel activity decrease. These results show a novel mechanism for the recruitment of L-type Ca2+ channels and their coupling to neurotransmitter release which involves tyrosine phosphorylation. This phenomenon has a role in cerebellar granule cell development.
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PMID:Modulation of neurotransmitter release by dihydropyridine-sensitive calcium channels involves tyrosine phosphorylation. 998 31

Niacin content must be included on food labels of infant formula products and bakery products containing enriched flour. Liquid chromatographic (LC) determination of niacin in complex food matrixes is complicated by the presence of endogenous compounds that absorb at the commonly used wave-length of 260 nm. Also, the presence of particulate matter in the standard sulfuric acid extraction procedure results in reduced life of LC columns and precolumns. A simple, rapid, solid-phase extraction (SPE) procedure for separation and cleanup of niacin from a complex food matrix digest has been developed. By using a vacuum manifold with the SPE column system, multiple samples can be processed quickly and efficiently for LC analysis, compared with gravimetric column cleanup. Sulfuric acid sample digest is passed over an aromatic sulfonic acid cation-exchange (ArSCX-SPE) or a sulfonated Florisil SPE column. Niacin is eluted with 0.25M sodium acetate-acetic acid, pH 5.6 buffer in vacuo. LC chromatograms of the resulting eluate are free of interference from other components absorbing at 260 nm at the retention time of niacin. Validation of the method was obtained from agreement of analytical results on available reference materials. For both SPE methods, values for niacin in SRM 1846 Infant Formula (milk-based powder) were within uncertainty ranges of the certified value. Use of several calibration procedures (the LC computer program, a peak area response graphic standard curve, or the method of standard additions) with both SPE procedures resulted in niacin values for 3 RM-Wheat Flours (not certified for niacin) in agreement (90-105%) with their respective values reported in the literature. Several commercial wheat flours showed a broad 260 nm interference, resulting in high niacin values. Niacin recoveries from spiked soy-based liquid infant formulas ranged from 95-107% with the ArSCX-SPE column. Calibration curves of niacin were linear up to 400 micrograms/mL, with a detection limit of 0.2 microgram/mL.
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PMID:Determination of niacin in infant formula and wheat flour by anion-exchange liquid chromatography with solid-phase extraction cleanup. 1002 81

The Antarctic psychrotrophic bacterium Pseudomonas syringae contains a 66-kDa cytoplasmic protein which was found to by phosphorylated on a tyrosine residue [Ray, M.K. et al. (1994) FEMS Microbiol. Lett. 122, pp. 49-54]. To investigate the nature of the cytoplasmic protein tyrosine kinase and its role in the bacterial physiology, we carried out some biochemical studies of the enzyme in vitro in the presence of exogenous peptide substrates and expression studies in vivo at low and high temperature during various phases of growth. The results suggest that the protein tyrosine kinase associated with the cytoplasmic fraction of the bacterium has certain similarities and dissimilarities with the known eukaryotic tyrosine kinases. The protein tyrosine kinase could phosphorylate exogenous substrate corresponding to the N-terminal peptide of p34cdc2 kinase but could not do so on poly(Glu:Tyr). The enzyme could not be inhibited by genistein, staurosporine and dimethyl aminopurine, but could be inhibited by piceatannol which is a known competitive inhibitor of the peptide binding site of mammalian protein tyrosine kinases. The enzyme activity in the cytoplasm is uniquely inhibited by sodium orthovanadate (IC50 = 20 microM) which is a known protein tyrosine phosphatase inhibitor. The expression studies show that the enzyme is produced more at a higher temperature (22 degrees C) of growth than at lower temperature (4 degrees C) and during the stationary phase of growth of P. syringae.
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PMID:Studies on the cytoplasmic protein tyrosine kinase activity of the Antarctic psychrotrophic bacterium Pseudomonas syringae. 1022 68

Intense flashes of light were observed in sodium bicarbonate and hydrogen peroxide solutions when they were exposed to pulsed microwave radiation, and the response was greatly enhanced by a microwave-absorbing, biosynthesized polymer, diazoluminomelanin. A FPS-7B radar transmitter, operating at 1.25 GHz provided pulses of 5.73 +/- 0.09 micros in duration at 10.00 +/- 0.03 pulses/s with 2.07 +/- 0.08 MW forward power (mean +/- standard deviation), induced the effect but only when the appropriate chemical interaction was present. This phenomenon involves acoustic wave generation, bubble formation, pulsed luminescence, ionized gas ejection, and electrical discharge. The use of pulsed microwave radiation to generate highly focused energy deposition opens up the possibility of a variety of biomedical applications, including targeting killing of microbes or eukaryotic cells. The full range of microwave intensities and frequencies that induce these effects has yet to be explored and, therefore, the health and safety implications of generating the phenomena in living tissues remain an open question.
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PMID:Pulsed microwave induced light, sound, and electrical discharge enhanced by a biopolymer. 1023 Sep 35

The dual signal hypothesis of apoptosis holds that a common signal can activate both apoptotic and proliferative pathways. The fate of a cell is dependent on which of these two pathways predominates. In the MAPK family of kinases, ERK and JNK have been proposed to mediate apoptosis whereas the PI3K-stimulated kinase, Akt/PKB, has been shown to inhibit apoptosis. The object of this study was to determine the role of these kinases in a glioma model of apoptosis. We have previously shown that K252a induces apoptosis and inhibits kinase activity. In this study we confirm these results and show that the protein tyrosine phosphatase inhibitor sodium vanadate activates ERK, JNK and Akt/PKB, but does not stimulate proliferation. Vanadate did protect T98G cells from K252a-induced apoptosis, an effect that was abolished by addition of the PI3K inhibitor wortmannin. This suggests that PI3K and Akt/PKB may be responsible for mediating vanadate's protective effect on glioma cells. We conclude that the intracellular balance between protein phosphorylation pathways is a critical determinant of both cell proliferation and cell death.
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PMID:Sodium vanadate inhibits apoptosis in malignant glioma cells: a role for Akt/PKB. 1034 70

This study was designed to determine whether mechanical stretch activates the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and, if so, by what mechanism. Neonatal rat/murine cardiomyocytes were cultured on malleable silicone dishes and were stretched by 20%. Mechanical stretch induced rapid phosphorylation of JAK1, JAK2, Tyk2, STAT1, STAT3, and glycoprotein 130 as early as 2 minutes and peaked at 5 to 15 minutes. It also caused gel mobility shift of sis-inducing element, which was supershifted by preincubation with anti-STAT3 antibody. Preincubation with CV11974 (AT1 blocker) partially inhibited the phosphorylation of STAT1, but not that of STAT3. Preincubation with TAK044 (endothelin-1-type A/B-receptor blocker) did not attenuate this pathway. RX435 (anti-glycoprotein 130 blocking antibody) inhibited the phosphorylation of STAT3 and partially inhibited that of STAT1. Phosphorylation of STAT1 and STAT3 was strongly inhibited by HOE642 (Na+/H+ exchanger inhibitor) and BAPTA-AM (intracellular calcium chelator), but not by gadolinium (stretch-activated ion channel inhibitor), EGTA (extracellular Ca2+ chelator), or KN62 (Ca2+/calmodulin kinase II inhibitor). Chelerythrine (protein kinase C inhibitor) partially inhibited the phosphorylation of STAT1 and STAT3. Mechanical stretch also augmented the mRNA expression of cardiotrophin-1, interleukin-6, and leukemia inhibitory factor at 60 to 120 minutes. These results indicated that the JAK/STAT pathway was activated by mechanical stretch, and that this activation was partially dependent on autocrine/paracrine-secreted angiotensin II and was mainly dependent on the interleukin-6 family of cytokines but was independent of endothelin-1. Moreover, certain levels of intracellular Ca2+ were necessary for stretch-induced activation of this pathway, and protein kinase C was also partially involved in this activation.
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PMID:Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. 1034 87

The increased phosphorylation and activity of protein kinase B (PKB/Akt) was found early upon butyrate treatment of HT-29 cells with a potent differentiating agent, sodium butyrate. It was accompanied by the increased phosphorylation of glycogen synthase kinase-3 (GSK-3) and the inhibition of the activity of GSK-3beta to catalyze phosphorylation of its substrate, translation initiation factor eIF2B. Phosphorylation of PKB and GSK-3 in HT-29 cells was reduced by wortmannin, the inhibitor of phosphatidylinositol-3' kinase (PI3'-kinase), which is upstream activator of PKB and GSK-3 in the intracellular signalling. Modulation of the activity and phosphorylation of these protein kinases during transient in vitro differentiation of HT-29 cells indicates that control of the PI3'-kinase/PKB-dependent signalling pathway may be implicated very early in the changes of malignant phenotype of HT-29 cells.
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PMID:Activity of glycogen synthase kinase-3beta is down-regulated during transient differentiation of human colon cancer HT-29 cells. 1037 64


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