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)

Plasma membrane Ca(2+) -ATPase isoform 4b (PMCA4b) is phosphorylated on a tyrosine residue during platelet activation resulting in inhibition of its ATPase activity. We now report that tyrosine 1176 (Y(1176)) in the carboxyl (C-) terminal domain of PMCA4b is the phosphorylated residue. Two tyrosine residues located in the C-terminus of PMCA4b, Y(1122) and Y(1176) can be removed by calpain-dependent cleavage. This truncation removes all of the tyrosine phosphates added to PMCA during platelet activation. Sequence analysis indicates that Y(1176) is a likely substrate for focal adhesion kinase (FAK), while Y(1122) is not located in a tyrosine phosphorylation motif. This is the same residue we reported earlier to be phosphorylated by Src kinase in vitro. Thus we conclude that Y(1176) is the only tyrosine phosphorylated during platelet activation. Results of co-immunoprecipitation, treatment with tyrosine kinase inhibitors and integrin inhibition experiments suggest that FAK is responsible for PMCA4b tyrosine phosphorylation during platelet activation.
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PMID:Plasma membrane Ca2+-ATPase isoform 4b is phosphorylated on tyrosine 1176 in activated human platelets. 1254 Sep 62

Ca2+ sensitivity of smooth muscle and nonmuscle myosin II reflects the ratio of activities of myosin light-chain kinase (MLCK) to myosin light-chain phosphatase (MLCP) and is a major, regulated determinant of numerous cellular processes. We conclude that the majority of phenotypes attributed to the monomeric G protein RhoA and mediated by its effector, Rho-kinase (ROK), reflect Ca2+ sensitization: inhibition of myosin II dephosphorylation in the presence of basal (Ca2+ dependent or independent) or increased MLCK activity. We outline the pathway from receptors through trimeric G proteins (Galphaq, Galpha12, Galpha13) to activation, by guanine nucleotide exchange factors (GEFs), from GDP. RhoA. GDI to GTP. RhoA and hence to ROK through a mechanism involving association of GEF, RhoA, and ROK in multimolecular complexes at the lipid cell membrane. Specific domains of GEFs interact with trimeric G proteins, and some GEFs are activated by Tyr kinases whose inhibition can inhibit Rho signaling. Inhibition of MLCP, directly by ROK or by phosphorylation of the phosphatase inhibitor CPI-17, increases phosphorylation of the myosin II regulatory light chain and thus the activity of smooth muscle and nonmuscle actomyosin ATPase and motility. We summarize relevant effects of p21-activated kinase, LIM-kinase, and focal adhesion kinase. Mechanisms of Ca2+ desensitization are outlined with emphasis on the antagonism between cGMP-activated kinase and the RhoA/ROK pathway. We suggest that the RhoA/ROK pathway is constitutively active in a number of organs under physiological conditions; its aberrations play major roles in several disease states, particularly impacting on Ca2+ sensitization of smooth muscle in hypertension and possibly asthma and on cancer neoangiogenesis and cancer progression. It is a potentially important therapeutic target and a subject for translational research.
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PMID:Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. 1450 7

ACK2 (activated Cdc42-associated tyrosine kinase 2) is a specific downstream effector for Cdc42, a member of the Rho family of small G-proteins. ACK2 interacts with clathrin, an endocytic vesicle coating protein, and SH3PX1, a sorting nexin, and is involved in clathrin-mediated endocytosis. While searching for proteins that interact with ACK2, we found that HSP90 (heat-shock protein 90) binds to ACK2. Analysis of a series of truncation mutants of ACK2 has defined the regions within the kinase domain of ACK2 that are required for binding to HSP90. The binding of HSP90 to ACK2 is blocked upon treatment with geldanamycin, an HSP90-specific ATPase inhibitor, and is required for the in vivo kinase activity of ACK2 and its association with Cdc42. Overall, our data suggest a novel mechanism of regulation in which HSP90 serves as a regulatory component in an ACK2 functional complex and plays a role in sustaining its kinase activity.
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PMID:Interaction of activated Cdc42-associated tyrosine kinase ACK2 with HSP90. 1514 35

We previously reported that thyroid hormone, 3,3',5-triiodo-l-thyronine (T3), increased Na,K-ATPase activity of adult rat alveolar epithelial cells in a transcription-independent manner via increased cell surface expression of the alpha(1) and beta(1) subunits of Na,K-ATPase. Now we sought to identify signaling molecules necessary for T3 stimulation of Na,K-ATPase activity in alveolar epithelial cells. Whereas protein kinase A inhibitor H-8 and protein kinase C inhibitor bisindolymaleimide did not block the T3-induced increase in Na,K-ATPase activity, two inhibitors of phosphoinositide 3-kinase (PI3K), wortmannin and Ly294002, and two Src kinase inhibitors, PP1 and PP2, blocked the T3-induced Na,K-ATPase activity. T3 stimulated the activity of PI3K as measured by phosphatidylinositol 3-phosphate. T3 also stimulated the serine 473 phosphorylation of the PI3K downstream molecule PKB/Akt in a dose-dependent manner. Transient expression of a constitutively active mutant of the PI3K catalytic subunit p110 augmented Na,K-ATPase activity and increased the amount of cell surface Na,K-ATPase alpha(1) subunit protein. T3 also stimulated Src family kinase activity. Transient expression of a constitutively active Src kinase increased Na,K-ATPase activity, PI3K activity, and phosphorylation of PKB/Akt at serine 473. PP1 or PP2 blocked T3-stimulated PKB/Akt phosphorylation at serine 473 and PI3K activity that was activated by an active mutant of Src; however, wortmannin did not inhibit the T3-stimulated Src kinase activity. Although PP1 and wortmannin abolished the increase in Na,K-ATPase activity induced by the active mutant of Src, PP1 did not inhibit the active mutant of PI3K-up-regulated Na,K-ATPase activity. In summary, T3 stimulates the PI3K/PKB pathway via the Src family of tyrosine kinases, and activation of both the Src family kinases and PI3K is required for the T3-induced stimulation of Na,K-ATPase activity and its cell surface expression in adult rat alveolar epithelial cells.
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PMID:3,3',5-Triiodo-L-thyronine up-regulation of Na,K-ATPase activity and cell surface expression in alveolar epithelial cells is Src kinase- and phosphoinositide 3-kinase-dependent. 1534 23

The serine-threonine kinase Akt/PKB mediates stimuli from different classes of cardiomyocyte receptors, including the growth hormone/insulin like growth factor and the beta-adrenergic receptors. Whereas the growth-promoting and antiapoptotic properties of Akt activation are well established, little is known about the effects of Akt on myocardial contractility, intracellular calcium (Ca(2+)) handling, oxygen consumption, and beta-adrenergic pathway. To this aim, Sprague-Dawley rats were subjected to a wild-type Akt in vivo adenoviral gene transfer using a catheter-based technique combined with aortopulmonary crossclamping. Left ventricular (LV) contractility and intracellular Ca(2+) handling were evaluated in an isolated isovolumic buffer-perfused, aequorin-loaded whole heart preparations 10 days after the surgery. The Ca(2+)-force relationship was obtained under steady-state conditions in tetanized muscles. No significant hypertrophy was detected in adenovirus with wild-type Akt (Ad.Akt) versus controls rats (LV-to-body weight ratio 2.6+/-0.2 versus 2.7+/-0.1 mg/g, controls versus Ad.Akt, P, NS). LV contractility, measured as developed pressure, increased by 41% in Ad.Akt. This was accounted for by both more systolic Ca(2+) available to the contractile machinery (+19% versus controls) and by enhanced myofilament Ca(2+) responsiveness, documented by an increased maximal Ca(2+)-activated pressure (+19% versus controls) and a shift to the left of the Ca(2+)-force relationship. Such increased contractility was paralleled by a slight increase of myocardial oxygen consumption (14%), while titrated dose of dobutamine providing similar inotropic effect augmented oxygen consumption by 39% (P<0.01). Phospholamban, calsequestrin, and ryanodine receptor LV mRNA and protein content were not different among the study groups, while sarcoplasmic reticulum Ca(2+) ATPase protein levels were significantly increased in Ad.Akt rats. beta-Adrenergic receptor density, affinity, kinase-1 levels, and adenylyl cyclase activity were similar in the three animal groups. In conclusion, our results support an important role for Akt/PKB in the regulation of myocardial contractility and mechanoenergetics.
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PMID:Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling. 1609 11

Expression of Na+,K(+)-ATPase alfal-subunit and of oubain-sensitive rubidium influxes has been investigated in human peripheral blood lymphocytes. Isolated lymphocytes were stimulated by phytogemagglutinin (PHA) or interleukin-2 (IL-2). It has been shown that during the early stage of the PHA-activation the alfal-subunit abundance in the membrane fractions of the human blood lymphocytes does not change, whereas at the late stages of Go-->G1-->S transition (16-48 h) the alfa1 protein content increases. A translation inhibitor cycloheximide was found to prevent the late increase in alfa1-subunit expression. An immunosuppressant cyclosporin A decreases both IL-2-dependent T-lymphocyte progression and alfa1-subunit abundance by 48 h of PHA-induced lymphocyte activation. In the lymphocytes pretreated by PHA in submitogenic concentration (0.8-1.0 microg/ml) exogenous IL-2 (100 U/ml) induces a proliferative response as well as alfal-protein accumulation. A decrease in alfa1-protein accumulation in the presence of specific inhibitors of separate signal transduction pathways enables us to conclude that protein kinases ERK1/2 (MAPK pathway) and JAK3 (JAK-STAT pathway) mediate the IL-2-dependent regulation of Na+,K(+)-ATPase expression during lymphocyte transition from resting stage to proliferation. A correlation between changes in ouabain-sensitive rubidium influxes and the alfal-subunit amount has been demonstrated. It is concluded that IL-2-dependent-progression of normal human lymphocytes from quiescence to proliferation is accompanied by the increase in Na+,K(+)-ATPase alfa1-subunits expression, and the enhanced transport activity of a sodium pump during the prereplicative stage is provided by the increased number of functional pump units in plasma membrane.
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PMID:[Il-2-regulated expression of Na+,K(+)-ATPase in activated human lymphocytes]. 1660 40

We investigated the signal mediators and the cellular events involved in the nitric oxide (NO)-induced hepatocyte resistance to oxygen deprivation in isolated hepatocytes treated with the NO donor (Z)-1-(N-methyl-N-[6-(N-methylammoniohexyl)amino])diazen-1-ium-1,2-diolate (NOC-9). NOC-9 greatly induced PI3K activation, as tested by phosphorylation of PKB/Akt. This effect was prevented by either 1H-(1,2,4)-oxadiazolo-(4,3)-quinoxalin-1-one, an inhibitor of the soluble guanylate cyclase (sGC), or KT5823, an inhibitor of cGMP-dependent kinase (cGK), as well as by farnesyl protein transferase inhibitor, which blocks the function of Ras GTPase. Bafilomycin A, an inhibitor of the lysosome-type vacuolar H+-ATPase, cytochalasin D, which disrupts the cytoskeleton-dependent organelle traffic, and wortmannin, which inhibits the PI3K-dependent traffic of lysosomes, all abolished the NOC-9-induced hepatocyte protection. The treatment with NOC-9 was associated with the PI3K-dependent peripheral translocation and fusion with the plasma membrane of lysosomes and the appearance at the cell surface of the vacuolar H+-ATPase. Inhibition of sGC, cGK, and Ras, as well as the inhibition of PI3K by wortmannin, prevented the exocytosis of lysosomes and concomitantly abolished the protective effect of NOC-9 on hypoxia-induced pHi and [Na+]i alterations and cell death. These data indicate that NO increases hepatocyte resistance to hypoxic injury by activating a pathway involving Ras, sGC, and cGK that determines PI3K-dependent exocytosis of lysosomes.
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PMID:PI3K-dependent lysosome exocytosis in nitric oxide-preconditioned hepatocytes. 1667 13

We have shown that the Na/K-ATPase and Src form a signaling receptor complex. Here we determined how alterations in the amount and properties of the Na/K-ATPase affect basal Src activity and ouabain-induced signal transduction. Several alpha1 subunit knockdown cell lines were generated by transfecting LLC-PK1 cells with a vector expressing alpha1-specific small interference RNA. Although the alpha1 knockdown resulted in significant decreases in Na/K-ATPase activity, it increased the basal Src activity and tyrosine phosphorylation of focal adhesion kinase, a Src effector. Concomitantly it also abolished ouabain-induced activation of Src and ERK1/2. When the knockdown cells were rescued by a rat alpha1, both Na/K-ATPase activity and the basal Src activity were restored. In addition, ouabain was able to stimulate Src and ERK1/2 in the rescued cells at a much higher concentration, consistent with the established differences in ouabain sensitivity between pig and rat alpha1. Finally both fluorescence resonance energy transfer analysis and co-immunoprecipitation assay indicated that the pumping-null rat alpha1 (D371E) mutant could also bind Src. Expression of this mutant restored the basal Src activity and focal adhesion kinase tyrosine phosphorylation. Taken together, the new findings suggest that LLC-PK1 cells contain a pool of Src-interacting Na/K-ATPase that not only regulates Src activity but also serves as a receptor for ouabain to activate protein kinases.
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PMID:Functional characterization of Src-interacting Na/K-ATPase using RNA interference assay. 1669 1

The cardiac steroid ouabain, a known inhibitor of the sodium pump (Na+, K+ -ATPase), has been shown to release endothelin from endothelial cells when used at concentrations below those that inhibit the pump. The present study addresses the question of which signaling pathways are activated by ouabain in endothelial cells. Our findings indicate that ouabain, applied at low concentrations to human umbilical cord endothelial cells (HUAECs), induces a reaction cascade that leads to translocation of endothelial nitric oxide synthase (eNOS) and to activation of phosphatidylinositol 3-kinase (PI3K). These events are followed by phosphorylation of Akt (also known as protein kinase B, or PKB) and activation of eNOS by phosphorylation. This signaling pathway, which results in increased nitric oxide (NO) production in HUAECs, is inhibited by the PI3K-specific inhibitor LY294002. Activation of the reaction cascade is not due to endothelin-1 (ET-1) binding to the ET-1 receptor B (ETB), since application of the ETB-specific antagonist BQ-788 did not have any effect on Akt or eNOS phosphorylation. The results shown here indicate that ouabain binding to the sodium pump results in the activation of the proliferation and survival pathways involving PI3K, Akt activation, stimulation of eNOS, and production of NO in HUAECs. Together with results from previous publications, the current investigation implies that the sodium pump is involved in vascular tone regulation.
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PMID:Signaling pathways involving the sodium pump stimulate NO production in endothelial cells. 1705

In previous works, it has been shown, by using ethylene inhibitors and precursors, that ethylene could participate in the regulation of the enhanced ferric reductase activity of Fe-deficient Strategy I plants. However, it was not known whether ethylene regulates the ferric reductase gene expression or other aspects related to this activity. This paper is a study of the effects of ethylene inhibitors and precursors on the expression of the genes encoding the ferric reductases and iron transporters of Arabidopsis thaliana (FRO2 and IRT1) and Lycopersicon esculentum (=Solanum lycopersicum) (FRO1 and IRT1) plants. The effects of ethylene inhibitors and precursors on the activity of the iron reductase and the iron transporter have been examined in parallel. Also studied were the effects of ethylene inhibitors and precursors on the expression of the H(+)-ATPase genes of cucumber (CsHA1 and CsHA2) and the transcription factor genes of tomato (LeFER) and Arabidopsis (AtFRU or AtFIT1, an LeFER homologue) that regulate ferric reductase, iron transporter, and H(+)-ATPse activity. The results obtained suggest that ethylene participates in the regulation of ferric reductase, the iron transporter, and H(+)-ATPase gene expression by affecting the FER (or FER-like) levels.
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PMID:Ethylene could influence ferric reductase, iron transporter, and H+-ATPase gene expression by affecting FER (or FER-like) gene activity. 1708 55


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