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)

Glial glutamate receptors are likely to play a role in plasticity, learning, and memory and in a number of neuropathologies. An enhanced glutamate-dependent tyrosine phosphorylation has been detected in such processes. Using primary cultures of chick Bergmann glia cells and chick cerebellar slices, we addressed whether glial glutamate receptors can activate the nonreceptor tyrosine kinase pp125 focal adhesion kinase (pp125(FAK)). A dose- and time-dependent tyrosine phosphorylation of pp125(FAK) was found in both preparations upon glutamate treatment. This effect was mediated through alpha-amino-3-hydroxy-5-methyl-4-isoaxazolepropionate (AMPA)/kainate (KA) receptors, as shown by its inhibition by the specific antagonists 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7- sulfonamide (NBQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX) and the lack of effect of metabotropic agonists. FAK tyrosine phosphorylation was dependent on phosphatidylinositol 3-kinase activity. As expected, an increase in pp125(FAK) catalytic activity was found upon glutamate treatment. Immunprecipitation experiments demonstrated that FAK associates with ionotropic glutamate receptors. Taken together, these results suggest a role for glial glutamate receptors in cytoskeletal rearrengments and focal adhesion contact formation and provide new insight into the signaling transactions elicited by this neurotransmitter in glial cells.
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PMID:Glutamate activates PP125(FAK) through AMPA/kainate receptors in Bergmann glia. 1174 93

Protein tyrosine phosphorylation is a dynamic reversible process in which the level of phosphorylation, at any time, is the result of phosphatase and/or kinase activity. This balance is critical for control of growth and differentiation. The role of tyrosine phosphatases during nephrogenesis and in kidney disease requires delineation. Appropriate regulation of focal adhesion proteins such as focal adhesion kinase (FAK) and paxillin are important in cell adhesion, migration, and differentiation. We have previously shown that B cell lymphoma/leukemia-2 (bcl-2) -/- mice develop cystic kidneys and exhibit sustained phosphorylation of FAK and paxillin. We have examined the expression and activity of focal adhesion tyrosine phosphatases [Src homology-2 domain phosphatase (SHP-2), protein tyrosine phosphatase (PTP 1B), and PTP-proline, glutamate, serine, and threonine sequences (PEST)] during normal nephrogenesis and in cystic kidneys from bcl-2 -/- mice. Cystic kidneys from postnatal day 20 bcl-2 -/- mice demonstrate a reduced expression, sixfold decrease in activity, and altered distribution of SHP-2 and PTP 1B. PTP-PEST expression and distribution were similar in both bcl-2 +/+ and bcl-2 -/- mice. The altered regulation of PTP 1B and SHP-2 in kidneys from bcl-2 -/- mice correlates with sustained phosphorylation of FAK and paxillin. Thus renal cyst formation in the bcl-2 -/- mice may be the result of an inability of complete differentiation due to continued activation of growth processes, including activation of FAK and paxillin.
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PMID:Altered regulation of SHP-2 and PTP 1B tyrosine phosphatases in cystic kidneys from bcl-2 -/- mice. 1183 24

Ca2+ influx through NMDA receptors can initiate molecular changes in neurones which may underlie synaptic plasticity, neuronal development, survival and excitotoxicity. Signalling through the MAP kinase (Erk1/2) cascade may be central to these processes. We previously demonstrated that Ca2+-permeable AMPA receptors activate Erkl/2 through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent mechanism. We now report that NMDA receptor activation of Erk1/2 was also blocked by inhibitors of PI 3-kinase (LY 294002, wortmannin). In addition, pre-treatment of neurones with pertussis toxin inhibited NMDA-induced Erk1/2 activation, indicating a role for heterotrimeric Gi/o proteins. PI 3-kinase directs activation of the serine-threonine kinase Akt (PKB). Treatment of striatal neurones with glutamate induced a rapid Ca2+-dependent and PI 3-kinase-dependent phosphorylation of Akt (Ser473), which was not blocked by the Mek inhibitors PD98059 or U0126. Targets for Erk1/2 and Akt pathways include transcription factors. Glutamate-induced phosphorylation of cAMP response element binding protein (CREB; Ser133) was partially blocked with either PD98059, U0126, LY294002 or wortmannin but was very strongly inhibited on co-application of LY294002 and PD98059. We propose that NMDA receptor stimulation can activate Erk1/2 and Akt signalling pathways in a PI 3-kinase dependent manner which may target CREB in the nucleus.
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PMID:Phosphatidylinositol 3-kinase is a central mediator of NMDA receptor signalling to MAP kinase (Erk1/2), Akt/PKB and CREB in striatal neurones. 1190 14

Two subfamilies of UDP-GlcNAc C6 dehydratases were recently identified. FlaA1, a short soluble protein that exhibits a typical SYK catalytic triad, characterizes one of these subfamilies, and WbpM, a large membrane protein that harbors an altered SMK triad that was not predicted to sustain activity, represents the other subfamily. This study focuses on investigating the structure and function of these C6 dehydratases and the role of the altered triad as well as additional amino acid residues involved in catalysis. The significant activity retained by the FlaA1 Y141M triad mutant and the low activity of the WbpM M438Y mutant indicated that the methionine residue was involved in catalysis. A Glu(589) residue, which is conserved only within the large homologues, was shown to be essential for activity in WbpM. Introduction of this residue in FlaA1 enhanced the activity of the corresponding V266E mutant. Hence, this glutamate residue might be responsible for the retention of catalytic efficiency in the large homologues despite alteration of their catalytic triad. Mutations of residues specific for the short homologues (Asp(70), Asp(149)-Lys(150), Cys(103)) abolished the activity of FlaA1. Among them, C103M prevented dimerization but did not significantly affect the secondary structure. The fact that we could identify subfamily-specific residues that are essential for catalysis suggested an independent evolution for each subfamily of C6 dehydratases. Finally, the loss of activity of the FlaA1 G20A mutant provided evidence that a cofactor is involved in catalysis, and kinetic study of the FlaA1 H86A mutant revealed that this conserved histidine is involved in substrate binding. None of the mutations investigated altered the substrate, product, and function specificity of these enzymes.
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PMID:Structure-function studies of two novel UDP-GlcNAc C6 dehydratases/C4 reductases. Variation from the SYK dogma. 1200 63

We used cultured cerebellar granule cells to examine whether native group-III metabotropic glutamate (mGlu) receptors are coupled to the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI-3-K) pathways. Cultured granule cells responded to the group-III mGlu receptor agonist, L-2-amino-4-phosphonobutanoate (l-AP4), with an increased phosphorylation and activity of MAPKs (ERK-1 and -2) and an increased phosphorylation of the PI-3-K target, protein kinase B (PKB/AKT). These effects were attenuated by the group-III antagonists, alpha-methyl-serine-O -phosphate (MSOP) and (R,S )-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG), or by pretreatment of the cultures with pertussis toxin. l-AP4 also induced the nuclear translocation of beta-catenin, a downstream effector of the PI-3-K pathway. To assess the functional relevance of these mechanisms we examined the ability of l-AP4 to protect granule cells against apoptosis by trophic deprivation, induced by lowering extracellular K(+) from 25 to 10 mm. Neuroprotection by l-AP4 was attenuated by MSOP and abrogated by the compounds PD98059 and UO126, which inhibit the MAPK pathway, or by the compound LY294002, which inhibits the PI-3-K pathway. Taken together, these results show for the first time that native group-III mGlu receptors are coupled to MAPK and PI-3-K, and that activation of both pathways is necessary for neuroprotection mediated by this particular class of receptors.
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PMID:Native group-III metabotropic glutamate receptors are coupled to the mitogen-activated protein kinase/phosphatidylinositol-3-kinase pathways. 1212 22

Neuronal damage and death are consistent pathologic findings in the brains of patients with ADC, and multiple cell model systems have demonstrated neurotoxicity through the effects of HIV-1 infection in macrophages and microglia. Brain MRI studies (1H-MRS) indicate that reversible neuronal cell dysfunction occurs early during the course of HIV-1 infection, long before overt symptoms of ADC appear. Epidemiologic studies suggest that a high viral load in the CNS is a major risk factor for ADC and that HAART may significantly reduce, but not eliminate, the risk of developing ADC. Targeted adjunctive therapies administered early are likely necessary to maximize CNS protection against HIV, and rational approaches to such therapy are rapidly evolving through in vitro analysis of the mechanisms of HIV-associated neurotoxicity. Soluble factors released by infected cells may directly or indirectly damage neurons and induce apoptosis at the level of NMDA subtype of glutamate receptors, and NMDA receptor antagonists represent a major therapeutic option currently under intense clinical investigation. Likewise, drugs with antioxidant or free radical scavenging effects offer another rational approach to adjunctive therapy and are also under intense clinical scrutiny. Finally, agents that inhibit neuronal death-signaling pathways (e.g., p38 MAPK inhibitors) and that stimulate cell survival pathways (e.g., Akt/PKB) may represent the next investigational step in designing anti-ADC therapies.
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PMID:Neuropathogenesis of central nervous system HIV-1 infection. 1224 93

The chicken retina was exposed to 20% hyposmotic or ischaemia-like (54 mM KCl and 1 mM ouabain) conditions and changes in cell volume, amino acid release and activation of protein tyrosine kinases measured. To investigate possible connection between these cellular events, the effect of tyrosine kinase blockers on (3)H-taurine, (3)H-GABA and (3)H- D-aspartate (as a tracer for glutamate) efflux was examined. Both hyposmotic and ischaemic conditions increased phosphorylation of the tyrosine kinase p125 focal adhesion kinase (p125(FAK)) and the mitogen-activated protein kinase-p38 (MAPK-p38), but not of the extracellular-signal-related kinases-1/2 (ERK1/ERK2), and markedly activated the tyrosine kinase target enzyme phosphatidylinositide 3-kinase (PI3K). Hyposmolarity and ischaemia both led to rapid retinal swelling followed by active volume recovery of 84% (hyposmolarity) and 40% (ischaemia), together with rapid release of taurine, GABA and D-aspartate. Taurine and GABA efflux under both conditions was reduced markedly by tyrosine kinase and PI3K blockers (50 microM tyrphostin A23, 50 microM genistein, 100 nM wortmannin, 25 microM LY294002) and was decreased by 85% when ischaemia-induced swelling was prevented. About 65% of D-aspartate efflux occurred irrespective of swelling in ischaemia and was either less sensitive (hyposmotic) or largely resistant (ischaemia) to the blockers. These results suggest that in ischaemia, GABA and taurine react primarily to swelling with a typical osmolyte response, while glutamate differs in its release mechanisms under both hyposmotic and ischaemic conditions. These findings suggest new strategies for evaluating the contribution of swelling to excitotoxicity in ischaemia.
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PMID:Tyrosine kinases and amino acid efflux under hyposmotic and ischaemic conditions in the chicken retina. 1239 92

Glutamate receptor activation of mitogen-activated protein (MAP) kinase signalling cascades has been implicated in diverse neuronal functions such as synaptic plasticity, development and excitotoxicity. We have previously shown that Ca2+-influx through NMDA receptors in cultured striatal neurones mediates the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt/protein kinase B (PKB) through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. Exposing neurones to the Src family tyrosine kinase inhibitor PP2, but not the inactive analogue PP3, inhibited NMDA receptor-induced phosphorylation of ERK1/2 and Akt/PKB in a concentration-dependent manner, and reduced cAMP response element-binding protein (CREB) phosphorylation. To establish a link between Src family tyrosine kinase-mediated phosphorylation and PI 3-kinase signalling, affinity precipitation experiments were performed with the SH2 domains of the PI 3-kinase regulatory subunit p85. This revealed a Src-dependent phosphorylation of a focal adhesion kinase (FAK)-p85 complex on glutamate stimulation. Demonstrating that PI3-kinase is not ubiquitously involved in NMDA receptor signal transduction, the PI 3-kinase inhibitors wortmannin and LY294002 did not prevent NMDA receptor Ca2+-dependent phosphorylation of c-Jun N-terminal kinase 1/2 (JNK1/2). Further, inhibiting Src family kinases increased NMDA receptor-dependent JNK1/2 phosphorylation, suggesting that Src family kinase-dependent cascades may physiologically limit signalling to JNK. These results demonstrate that Src family tyrosine kinases and PI3-kinase are pivotal regulators of NMDA receptor signalling to ERK/Akt and JNK in striatal neurones.
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PMID:Inhibiting Src family tyrosine kinase activity blocks glutamate signalling to ERK1/2 and Akt/PKB but not JNK in cultured striatal neurones. 1500 68

The phosphorylation of an "activation loop" within protein kinases is commonly associated with establishing catalytic competence, and phosphorylation of the Tyr(1007) residue in the activation loop of Janus kinase 2 (JAK2) has been shown to be essential for intracellular propagation of cytokine-initiated signaling. We provide evidence for the presence of a basal activity state of JAK2, which was observed in the absence of activation loop phosphorylation. Phosphorylation of the JAK2 activation loop was essential for conversion to the high-activity state, characterized by high-efficiency ATP utilization during autophosphorylation. Mutagenesis of activation loop tyrosine residues Tyr(1007/1008) to phenylalanine residues impaired, but did not abolish, the enzyme's ability to autophosphorylate. The activation loop mutant JAK2 could also transphosphorylate an inactive JAK2 fragment coexpressed in Sf21 cells, providing evidence of exogenous substrate phosphorylation. The mutant enzyme remained in a basal activity state characterized by low-efficiency ATP utilization during autophosphorylation. Mutagenesis of a critical Lys(882) residue to a glutamate residue abolished all evidence of kinase activity, confirming that the observed activity of Tyr-to-Phe mutants was not due to another kinase. Our data are consistent with the proposal that JAK2 is an inefficient but active enzyme in the absence of activation loop phosphorylation and is capable of conversion to a high-activity state by autophosphorylation under physiological ATP concentrations. This theoretically precludes the need for an upstream activating kinase. The activation process of JAK2 may be envisioned as a multistate process involving at least two kinetically distinct states of activity.
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PMID:Tyrosine phosphorylation of the Janus kinase 2 activation loop is essential for a high-activity catalytic state but dispensable for a basal catalytic state. 1506 71

Nitric oxide (NO) donors such as glyceryl trinitrate cause headache, which suggests involvement of NO in trigeminovascular sensory processing. Sensory transmission at first-order synapses is believed to involve glutamate and the question arises as to whether it is also involved in trigeminovascular sensation and whether it might interact with nitrergic mechanisms. We investigated these questions at the first central synapse in the trigeminovascular sensory system of the cat. Neuronal action potentials in the trigeminal nucleus were recorded while the superior sagittal sinus (SSS) or facial receptive field (RF) were stimulated electrically. Drugs, including the neuronal excitant glutamate, were applied to neurons via microiontophoresis. Results were obtained from 152 neurons activated with A-delta latencies by SSS stimulation and by glutamate. The NO donor S-nitrosoglutathione (SNOG, 50 nA) was applied iontophoretically to 41 neurons during SSS stimulation and 13 neurons during pulsatile glutamate ejection. Responses to both modes of stimulation were enhanced by SNOG; the proportion of neurons enhanced was 56% to SSS stimulation and 59% to glutamate. The inhibitor of nitric oxide synthase (NOS), N(omega)-propyl-L-arginine (p-ARG, 50 nA) was applied iontophoretically to 17 neurons during stimulation of SSS and to 10 neurons during pulsatile glutamate ejection. Responses to both stimuli were suppressed by p-ARG: The proportion of neurons suppressed were: to SSS stimulation 59% and to glutamate 80%. Microiontophoretic ejection of eletriptan (50 nA) reversibly suppressed responses of neurons to SSS stimulation, to RF electrical stimulation and to pulsatile iontophoretic application of glutamate. This suppression of responses was antagonised by the concurrent local iontophoretic application of the 5-HT1B/1D receptor antagonist GR127935 or by concurrent iontophoretic application of the selective 5-HT1D receptor antagonist BRL155732. These results suggest that glutamatergic mechanisms are important in sensory transmission in the trigeminovascular system and that they can be modulated by nitrergic and serotonergic mechanisms.
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PMID:Nitrergic and glutamatergic neuronal mechanisms at the trigeminovascular first-order synapse. 1516 37


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