Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stromal cell-derived factor 1 (SDF-1/CXCL12) is believed to mediate migration of leukocytes. To explore potential mechanisms, we evaluated the signal transduction pathways activated by SDF-1 in the Jurkat T cell line. Src kinase was phosphorylated and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activated in a time-related fashion after SDF-1 stimulation. Chemotaxis of Jurkat cells was partially blocked by pretreatment with the src kinase inhibitor PP2 in a dose-dependent manner. Wiskott-Aldrich Syndrome Protein (WASP) regulates actin polymerization and cytoskeletal organization in T cells. We found WASP complexed to activated src after SDF-1 stimulation, suggesting a possible interacting role for src kinase and WASP in mediating SDF-1 action. J.CaM1.6 cells, which have lost expression of the src kinase p56(lck) (lck), responded to chemotaxis induced by SDF-1 as well as the parental Jurkat cells. Because J.CaM1.6 cells respond as well as the parental cells to SDF-1 in terms of ERK activation and tyrosine phosphorylation of WASP after SDF-1 stimulation, it appears that src kinase, but not the src kinase family member lck, mediates chemotaxis of Jurkat cells in response to SDF-1 induction and that src kinase may link with WASP in this effect.
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PMID:Src kinase, but not the src kinase family member p56lck, mediates stromal cell-derived factor 1alpha/CXCL12-induced chemotaxis of a T cell line. 1259 Jul 7

It is well known that GH-PRL secreting GH3 cells express constitutive neuronal nitric oxide synthase (nNOS) and produce nitric oxide (NO*). In addition, these cells possess plasma membrane prolactin (PRL) receptors which can be responsible for an autocrine 'short-loop' feedback. The aim of the present study was to investigate whether the activation of PRL receptors modulates the expression of the different spliced forms of nNOS gene, and the transductional mechanisms involved in this action. In GH3 cells, both exon 2-containing nNOSalpha and exon 2-lacking nNOSbeta were time-dependently expressed, whereas the other two isoforms eNOS and iNOS were not. The antibodies directed against the residues 53-68 of the external domain common to both the long and short form of rat PRL receptors, and the selective D2 agonist cabergoline (1 nm) reduced both basal and exogenous PRL-induced expressions of nNOSalpha and nNOSbeta, but to a greater extent for the beta splicing form. In line with these results, oPRL (1 and 10 microm) added to the incubation medium increased to a greater extent the expression of nNOSbeta form than of the nNOSalpha. The receptor and non-receptor protein tyrosine kinase (PTK) inhibitors, genistein (10 microm), the Src-specific tyrosine kinase inhibitor PP2 (100 microm), the MAPK inhibitor PD 098059 (50 nm) and the two PI3'-K inhibitors, wortmannin (300 nm) and LY-294002 (25 microm) prevented both basal and exogenous PRL-induced expression of nNOSalpha and nNOSbeta isoforms. In addition, exogenous PRL induced a phosphorylation of protein kinase B (PKB) (Akt) that was prevented both by the two MAPK inhibitors PD 098059 and U 0126, and by the PI3'-K inhibitors wortmannin and LY-294002. Up-regulation of the expression of the two splicing forms of nNOS elicited by PRL-receptor activation was mirrored by the increased synthesis of NO*. In conclusion, PRL receptor activation up-regulated the expression of both nNOSalpha and nNOSbeta proteins via a PTK, PI3'-K, MAPK and PKB signalling transduction components. This action may represent the molecular mechanism by which PRL exerts the 'short-loop' feedback on its own secretion.
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PMID:Involvement of PI3'-K, mitogen-activated protein kinase and protein kinase B in the up-regulation of the expression of nNOSalpha and nNOSbeta splicing variants induced by PRL-receptor activation in GH3 cells. 1261 37

The duration as well as the magnitude of mitogen-activated protein kinase activation has been proposed to regulate gene expression and other specific intracellular responses in individual cell types. Activation of ERK1/2 by the hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH) is relatively sustained in alpha T3-1 pituitary gonadotropes and HEK293 cells but is transient in immortalized GT1-7 neurons. Each of these cell types expresses the epidermal growth factor receptor (EGFR) and responds to EGF stimulation with significant but transient ERK1/2 phosphorylation. However, GnRH-induced ERK1/2 phosphorylation caused by EGFR transactivation was confined to GT1-7 cells and was attenuated by EGFR kinase inhibition. Neither EGF nor GnRH receptor activation caused translocation of phospho-ERK1/2 into the nucleus in GT1-7 cells. In contrast, agonist stimulation of GnRH receptors expressed in HEK293 cells caused sustained phosphorylation and nuclear translocation of ERK1/2 by a protein kinase C-dependent but EGFR-independent pathway. GnRH-induced activation of ERK1/2 was attenuated by the selective Src kinase inhibitor PP2 and the negative regulatory C-terminal Src kinase in GT1-7 cells but not in HEK293 cells. In GT1-7 cells, GnRH stimulated phosphorylation and nuclear translocation of the ERK1/2-dependent protein, p90RSK-1 (RSK-1). These results indicate that the duration of ERK1/2 activation depends on the signaling pathways utilized by GnRH in specific target cells. Whereas activation of the Gq/protein kinase C pathway in HEK293 cells causes sustained phosphorylation and translocation of ERK1/2 to the nucleus, transactivation of the EGFR by GnRH in GT1-7 cells elicits transient ERK1/2 signals without nuclear accumulation. These findings suggest that transactivation of the tightly regulated EGFR can account for the transient ERK1/2 responses that are elicited by stimulation of certain G protein-coupled receptors.
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PMID:Roles of Src and epidermal growth factor receptor transactivation in transient and sustained ERK1/2 responses to gonadotropin-releasing hormone receptor activation. 1264 80

Eph receptors and their cognate ligand ephrins play important roles in various biological processes such as cell migration, axon guidance, and synaptic plasticity. One characteristic feature of the Eph-ephrin signal transduction is that, upon interaction with the receptor, the transmembrane B-class ephrins become tyrosine-phosphorylated and transduce intracellular signals that lead to reorganization of the cytoskeleton. Although in vitro and genetic studies have demonstrated unequivocally the significance of this reverse signaling, the underlying mechanism remains unclear. We report here that transfection of ephrin-B1 into 293 cells resulted in robust increase in JNK activity, whereas expression of truncated ephrin-B1 lacking the cytoplasmic domain had a negligible effect, indicating that the induction of JNK activity was attributed mainly to the reverse signaling. The ephrin-B1-mediated JNK activation was reduced significantly by dominant-negative TAK1, MKK4, or MKK7. Ephrin-B1 over-expressing 293 cells became rounded in morphology. Surprisingly, ephrin-B1 that lacked all six intracellular tyrosine residues still triggered JNK activation and rounding morphology of the transfected cells. Consistent with these observations, activation of JNK and the resulting morphological changes mediated by ephrin-B1 could be abolished by the JNK inhibitor SP600125 but not the Src inhibitor PP2. Taken together, our findings have identified a novel reverse signaling pathway transduced by ephrin-B1, which is independent of tyrosine phosphorylation but involves the activation of JNK through TAK1 and MKK4/MKK7 and leads to changes in cell morphology.
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PMID:Ephrin-B1 reverse signaling activates JNK through a novel mechanism that is independent of tyrosine phosphorylation. 1270 32

Both integrin-based focal adhesion complexes and receptor tyrosine kinases have been proposed as scaffolds on which the G protein-coupled receptor (GPCR)-induced signaling complex might assemble. We have recently reported that Ca2+-sensitive tyrosine kinase, Pyk2, and epidermal growth factor receptor (EGFR) act as independently regulated scaffolds in cardiomyocytes. In this report, we investigated the activation and regulation of p130Cas, Crk, Pyk2, and c-Src by a well-known hypertrophic agonist, endothelin-1 (ET), and determined their contributions to the activation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in cardiomyocytes. Like Pyk2, ET-induced tyrosine phosphorylation of p130Cas was significantly inhibited by either chelating intracellular Ca2+ ([Ca2+]i) or a protein kinase C inhibitor, calphostin C. This activation of p130Cas was also abrogated by the tetrapeptide RGDS, which disrupts integrin heterodimerization; cytochalasin D, which depolymerizes the actin cytoskeleton; or a selective Src family kinase inhibitor, PP2, but not by an EGFR inhibitor, AG1478. We also observed ET-induced temporal associations of Pyk2 with active c-Src, followed by p130Cas with Pyk2, c-Src, and Crk. Overexpression of a dominant-negative mutant of p130Cas (CasDeltaSD), Crk (CrkSH2m), Pyk2 (PKM), or C-terminal Src kinase (Csk), but not of a deletion mutant of EGFR (533delEGFR), attenuated ET-induced JNK activation. Similarly, an ET-induced increase in c-jun promoter luciferase activity was inhibited by overexpression of CasDeltaSD, CrkSH2m, PKM, or Csk. In contrast, ET-induced ERK activation and c-fos gene expression were predominantly regulated by EGFR. Collectively, the focal adhesion-dependent p130Cas/Crk/Pyk2/c-Src-mediated pathway is selectively involved in ET-induced JNK activation in cardiomyocytes.
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PMID:Selective involvement of p130Cas/Crk/Pyk2/c-Src in endothelin-1-induced JNK activation. 1271 47

Complement receptors (CRs), along with Fc receptors, play a primary role in the removal of bacterial pathogens in poultry. The binding of serum-opsonized bacteria to CR results in the secretion of both toxic oxygen metabolites and antibacterial granules. We have previously shown that the stimulation of chicken heterophils with serum-opsonized Salmonella enteritidis induced tyrosine kinase-dependent phosphorylation regulated degranulation. In the present studies, we used selective pharmacological inhibitors to investigate the roles of protein tyrosine kinases, phospholipases C and D (PLC and PLD), phosphatidylinositol 3'-kinase (PI3-K), and the super family of mitogen-activated protein kinases (MAPKs) on CR-mediated heterophil degranulation. Inhibitors of receptor-linked tyrosine kinases (the tryphostins AG1478 and AG1296) had no attenuating effects on CR-mediated degranulation. However, PP2, a selective inhibitor of the src family of protein tyrosine kinases, and piceatannol, an inhibitor of Syk tyrosine kinases, both significantly attenuated the CR-mediated degranulation. Additionally, the specific inhibitors of PLC, U73122, and PI3-K, LY294002, significantly decreased CR-mediated heterophil degranulation. Two inhibitors of PLD-mediated signaling, 2,3-diphosphoglycerate (2,3-DPG) and 1-butanol, hindered degranulation. Addition of purified PLD restored control levels of degranulation in heterophils in which PLD was inhibited. Lastly, SP600125, a selective inhibitor of c-Jun N-terminal kinase (JNK), inhibited degranulation; whereas neither PD98059, the inhibitor of p38 MAPK, nor SB203580, the inhibitor of extracellular signal-regulated kinase, had any effect on CR-mediated heterophil degranulation. These studies demonstrate that CRs on chicken heterophils lack intrinsic tyrosine kinase activity, but that binding of serum-opsonized bacteria activates both proximal tyrosine kinases (src and Syk kinases), but differentially activates downstream tyrosine kinases (JNK, but not p38 nor ERK). Activation of src and Syk kinases plays a significant role in signal transduction of heterophil degranulation probably by stimulating downstream phosphorylation of PLC, PLD, and PI3-K. PI3-K has also been recently shown to be an upstream mediator of JNK activation, suggesting that this enzyme can induce signaling as both a lipid kinase and protein kinase. Engaging CRs on chicken heterophils activates a proximal tyrosine kinase (src and Syk kinases)-->PLC (PLD)-->PI3-K-->JNK signal transduction pathway that induces degranulation.
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PMID:The use of selective pharmacological inhibitors to delineate signal transduction pathways activated during complement receptor-mediated degranulation in chicken heterophils. 1275 38

Emerging evidence indicates that intracellular signaling cascades mediate entry of pathogenic adenoviruses into target host cells as well as some of the undesirable inflammatory responses to adenoviral gene vectors. We found that Ad19 infection of cultured human corneal fibroblasts induced IL-8 gene transcription independently of IL-1beta, TNF-alpha, and viral gene expression, suggesting that intracellular signaling events might mediate early inflammatory events in adenovirus keratitis. Heat but not UV light inactivation of the virus abrogated the effect of infection on IL-8 mRNA and protein levels, consistent with a viral binding-mediated mechanism. The tyrosine kinase inhibitor herbimycin blocked Ad19-induced IL-8 expression. Western blot analysis revealed tyrosine phosphorylation of the functionally related kinases c-Src and extracellular signal-regulated kinase (ERK) 1/2 in corneal fibroblasts within 15 min after infection. Respective inhibitors of these kinases, PP2 and PD98059, also blocked Ad19-induced IL-8 mRNA and protein expression. Application of inhibitors to Src and ERK kinase assays suggested an upstream relationship of c-Src to ERK. Finally, DNA microarray studies performed 1 h after Ad19 or mock infection of corneal fibroblasts in the presence or absence of the Src-specific inhibitor PP2 confirmed a relationship between c-Src and IL-8 expression in Ad19-infected corneal cells. c-Src may act as a global regulator of early proinflammatory host responses to Ad19 infection of the human cornea.
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PMID:Corneal IL-8 expression following adenovirus infection is mediated by c-Src activation in human corneal fibroblasts. 1279 55

Upon the addition of different growth factors and cytokines, the Gab1 docking protein is tyrosine phosphorylated and in turn activates different signaling pathways. On the basis of the large body of evidence concerning cross talk between the signaling pathways activated by growth factors and oxidative stress, we decided to investigate the role of Gab1 in oxidative injury. We stimulated wild-type mouse embryo fibroblasts (MEF) or MEF with a homozygous deletion of the Gab1 gene (-/- MEF) with H(2)O(2). Our results show that Gab1 is phosphorylated in a dose- and time-dependent manner after H(2)O(2) triggering. Gab1 then recruits molecules such as SHP2, phosphatidylinositol 3-kinase (PI3K), and Shc. Gab1 phosphorylation is sensitive to the Src family kinase inhibitor PP2. Furthermore, we demonstrate that Gab1 is required for H(2)O(2)-induced c-Jun N-terminal kinase (JNK) activation but not for ERK2 or p38 activation. Reconstitution of Gab1 in -/- MEF rescues JNK activation, and we find that this is dependent on the SHP2 binding site in Gab1. Cell viability assays reveal that Gab1 has a dual role in cell survival: a positive one through its interaction with PI3K and a negative one through its interaction with SHP2. This is the first report identifying Gab1 as a component in oxidative stress signaling and one that is required for JNK activation.
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PMID:Gab1 is an integrator of cell death versus cell survival signals in oxidative stress. 1280 90

Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase critical for both cardiomyocyte survival and sarcomeric assembly during endothelin (ET)-induced cardiomyocyte hypertrophy. ET-induced FAK activation requires upstream activation of one or more isoenzymes of protein kinase C (PKC). Therefore, with the use of replication-defective adenoviruses (Adv) to overexpress constitutively active (ca) and dominant negative (dn) mutants of PKCs, we examined which PKC isoenzymes are necessary for FAK activation and which downstream signaling components are involved. FAK activation was assessed by Western blot analysis with an antibody specific for FAK autophosphorylated at Y397 (Y397pFAK). ET (10 nmol/l; 2-30 min) resulted in the time-dependent activation of FAK which was inhibited by chelerythrine (5 micromol/l; 1 h pretreatment). Adv-caPKC epsilon, but not Adv-caPKC delta, activated FAK compared with a control Adv encoding beta-galactosidase. Conversely, Adv-dnPKC epsilon inhibited ET-induced FAK activation. Y-27632 (10 micromol/l; 1 h pretreatment), an inhibitor of Rho-associated coiled-coil-containing protein kinases (ROCK), prevented ET- and caPKC epsilon-induced FAK activation as well as cofilin phosphorylation. Pretreatment with cytochalasin D (1 micromol/l, 1 h pretreatment) also inhibited ET-induced Y397pFAK and cofilin phosphorylation and caPKC epsilon-induced Y397pFAK. Neither inhibitor, however, interfered with ET-induced ERK1/2 activation. Finally, PP2 (50 micromol/l; 1 h pretreatment), a highly selective Src inhibitor, did not alter basal or ET-induced Y397pFAK. PP2 did, however, reduce basal and ET-induced phosphorylation of other sites on FAK, namely, Y576, Y577, Y861, and Y925. We conclude that the ET-induced signal transduction pathway resulting in downstream Y397pFAK is partially dependent on PKC epsilon, ROCK, cofilin, and assembled actin filaments, but not ERK1/2 or Src.
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PMID:Activation of focal adhesion kinase by protein kinase C epsilon in neonatal rat ventricular myocytes. 1282 27

The role of human leukocyte antigen (HLA) class II molecules on non-antigen presenting cells has been a matter of controversy. We recently reported that ligation of HLA-DR molecule with anti-HLA-DR antibodies (L243) and/or antigenic peptide/T cell receptor complex resulted in a secretion of several chemokines such as RANTES. In the present study, we aimed to detect putative signal transduction pathway leading to RANTES production from fibroblasts when the DR molecules were ligated with L243. Protein tyrosine kinase inhibitor (GF109203X) suppressed RANTES expression in a dose dependent manner for up to 50% from gingival fibroblasts (GF), while protein kinase C inhibitor (genistein) had no inhibitory effect. Ligation of DR molecules with L243 resulted in tyrosine phosphorylation of 54 kDa cellular protein. Thus, we suspected that either Jun N-terminal kinase-2 (JNK-2) or Src family proteins were involved in HLA-DR-mediated signaling. JNK inhibitor (SP600125), but not Src inhibitor (PP2), suppressed both L243 stimulated RANTES mRNA expression and protein secretion. The maximum inhibition for RANTES production by SP600125 was more than 80%. Additionally, JNK inhibitor nearly completely blocked tumor necrosis factor-alpha (TNF-alpha)-induced RANTES production in GF. Furthermore, ligation of GF HLA-DR with L243 induced selective phosphorylation of JNK-2. We concluded that JNK-2 was one of the HLA-DR-mediated signal transduction pathways.
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PMID:Ligation of IFN-gamma-induced HLA-DR molecules on fibroblasts induces RANTES expression via c-Jun N-terminal kinase (JNK) pathway. 1284 58


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