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

---

Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chimeric receptors containing the entire or various cytoplasmic domains of either gp130 or leukemia inhibitory factor receptor alpha (LIFR) were used to identify signaling molecules and regions of these polypeptides required for the stimulation of mitogen-activated protein kinase (MAPK). Coexpression of dominant-negative Jak2 inhibited chimeric receptor-stimulated MAPK activity by approximately 70%, while expression of dominant-negative Ras completely blocked MAPK activation by either receptor polypeptide. Deletion analysis identified a 24-amino acid region of gp130 that was necessary for maximal stimulation of MAPK, and contained box 3 (positions 120-129) and a consensus tyrosine binding motif (Tyr-118) for the protein-tyrosine phosphatase, SHP2. Expression of receptors lacking this region or of chimeric gp130(Y118F) point mutants inhibited MAPK activity by approximately 55%, suggesting that Tyr-118, but not box 3, was required during activation of MAPK by gp130. Similarly, expression of chimeric LIFR constructs lacking box 3 maximally stimulated MAPK activity, while those lacking Tyr-115, a putative SHP2 binding site, inhibited stimulation of MAPK by this polypeptide. Our results demonstrate that gp130 and LIFR stimulate MAPK activity through box 3-independent mechanisms involving: (i) effects at Tyr-118 and Tyr-115, respectively, for maximal stimulation of MAPK activity and (ii) a Jak/Tyk-dependent pathway that, together with Tyr-118- or Tyr-115-generated signals, converges at the level of Ras during activation of MAPK by cytokine.
...
PMID:Box 3-independent signaling mechanisms are involved in leukemia inhibitory factor receptor alpha- and gp130-mediated stimulation of mitogen-activated protein kinase. Evidence for participation of multiple signaling pathways which converge at Ras. 919 77

Activation of early response genes by interferons (IFNs) and other cytokines requires tyrosine phosphorylation of a family of transcription factors termed signal transducers and activators of transcription (Stats). The Janus family of tyrosine kinases (Jak1, Jak2, Jak3, and Tyk2) is required for cytokine-induced tyrosine phosphorylation and dimerization of the Stat proteins. In order for IFNs to stimulate maximal expression of Stat1alpha-regulated genes, phosphorylation of a serine residue in the carboxy terminus by mitogen-activated protein kinase (MAPK) is also required. In HeLa cells, both IFN-beta and oncostatin M (OSM) stimulated MAPK and Raf-1 enzyme activity, in addition to Stat1 and Stat3 tyrosine phosphorylation. OSM stimulation of Raf-1 correlated with GTP loading of Ras, whereas IFN-beta activation of Raf-1 was Ras independent. IFN-beta- and OSM-induced Raf-1 activity could be coimmunoprecipitated with either Jak1 or Tyk2. Furthermore, HeLa cells lacking Jak1 displayed no activation of STAT1alpha, STAT3, and Raf-1 by IFN-beta or OSM and also demonstrated no increase in the relative level of GTP-bound p21ras in response to OSM. The requirement for Jak1 for IFN-beta- and OSM-induced activation of Raf-1 was also seen in Jak1-deficient U4A fibrosarcoma cells. Interestingly, basal MAPK, but not Raf-1, activity was constitutively enhanced in Jak1-deficient HeLa cells. Transient expression of Jak1 in both Jak-deficient HeLa cells and U4A cells reconstituted the ability of IFN-beta and OSM to activate Raf-1 and decreased the basal activity of MAPK, while expression of a kinase-inactive form of the protein showed no effect. Moreover, U4A cells selected for stable expression of Jak1, or COS cells transiently expressing Jak1 or Tyk2 but not Jak3, exhibited enhanced Raf-1 activity. Therefore, it appears that Jak1 is required for Raf-1 activation by both IFN-beta and OSM. These results provide evidence for a link between the Jaks and the Raf/MAPK signaling pathways.
...
PMID:Beta interferon and oncostatin M activate Raf-1 and mitogen-activated protein kinase through a JAK1-dependent pathway. 919 17

Loss of functional hematopoietic cell phosphatase (HCP) underlies severe hematopoietic and immunologic abnormalities in mice homozygous for the motheaten and viable motheaten mutations. These mice die from pulmonary accumulation of macrophages that are regulated by macrophage colony-stimulating factor (M-CSF) and granulocyte (G)-M-CSF. We determined the growth response of motheaten macrophages to the two growth factors and looked for potential HCP substrates in these cells. Motheaten macrophages showed increased proliferative responses to GM-CSF but not to M-CSF, demonstrating that HCP plays a critical role in downregulating GM-CSF mitogenic signaling. Despite the heightened growth responses of the motheaten macrophages to GM-CSF, there were no marked differences between motheaten macrophages and normal controls in GM-CSF-induced phosphorylation of GM-CSFR beta, Jak2, STAT5 and MAPK, indicating that these molecules are not major HCP substrates in GM-CSF signaling. Interestingly, several markedly hyperphosphorylated proteins were detected in the motheaten macrophages, including a novel 126-kDa phosphotyrosine protein that associated with the phosphatase via its SH2 domains, suggesting that these proteins depend on HCP for dephosphorylation and may mediate the heightened growth responses to GM-CSF. Our data indicate that macrophage hypersensitivity to GM-CSF may be a major factor in motheaten pathogenesis and that HCP may dephosphorylate novel substrates critical in GM-CSF mitogenic signaling.
...
PMID:Macrophages from motheaten and viable motheaten mutant mice show increased proliferative responses to GM-CSF: detection of potential HCP substrates in GM-CSF signal transduction. 921 34

Interleukin-5 (IL-5) regulates the growth and function of eosinophils. It induces rapid tyrosine phosphorylation of Lyn and Jak2 tyrosine kinases. The role of tyrosine phosphatases in IL-5 signal transduction has not been investigated. In this study, we provide first evidence that SH2 protein tyrosine phosphatase 2 (SHPTP2) phosphotyrosine phosphatase plays a key role in prevention of eosinophil death by IL-5. We found that IL-5 produced a rapid activation and tyrosine phosphorylation of SHPTP2 within 1 min. The tyrosine phosphorylated SHPTP2 was complexed with the adapter protein Grb2 in IL-5-stimulated eosinophils. Furthermore, SHPTP2 appeared to physically associate with beta common (betac) chain of the IL-5 receptor (IL-5betacR). The association of SHPTP2 with IL-5betacR was reconstituted using a synthetic phosphotyrosine-containing peptide, betac 605-624, encompassing tyrosine (Y)612. The binding to the phosphotyrosine-containing peptide increased the phosphatase activity of SHPTP2, whereas the same peptide with the phosphorylated Y612--> F mutation did not activate SHPTP2. Only SHPTP2 antisense oligonucleotides, but not sense SHPTP2, could inhibit tyrosine phosphorylation of microtubule-associated protein kinase, and reverse the eosinophil survival advantage provided by IL-5. Therefore, we conclude that the physical association of SHPTP2 with the phosphorylated betac receptor and Grb2 and its early activation are required for the coupling of the receptor to the Ras signaling pathway and for prevention of eosinophil death by IL-5.
...
PMID:Src homology 2 protein tyrosine phosphatase (SHPTP2)/Src homology 2 phosphatase 2 (SHP2) tyrosine phosphatase is a positive regulator of the interleukin 5 receptor signal transduction pathways leading to the prolongation of eosinophil survival. 925 54

Gamma interferon (IFN-gamma) induces both tyrosine and serine phosphorylation of Stat1. Stat1 serine phosphorylation is required for maximal transcriptional activity of Stat1. In this report, we present evidence that Stat1 tyrosine phosphorylation is not a prerequisite for Stat1 serine phosphorylation, although an active Jak2 kinase is required for both phosphorylation events. Stat1 serine phosphorylation occurs with a more delayed time course than tyrosine phosphorylation. The occurrence of serine phosphorylation without tyrosine phosphorylation suggests that serine phosphorylation takes place in the cytoplasm. Experiments performed with cells expressing either dominant-negative or constitutively active Ras protein indicated that the Ras-mitogen-activated protein kinase pathway is probably not involved in IFN-gamma-induced Stat1 serine phosphorylation. Finally, a kinase capable of correct Stat1 serine phosphorylation was detected in partially purified cytoplasmic extracts from both IFN-gamma-treated and untreated cells.
...
PMID:Stat1 serine phosphorylation occurs independently of tyrosine phosphorylation and requires an activated Jak2 kinase. 934 25

When growth hormone binds to its receptor, which belongs to the cytokine receptor superfamily, it activates the Janus kinase Jak2 which has tyrosine-kinase activity and initiates an activation of several key intracellular proteins (for example, mitogen-activated protein (MAP) kinases) that eventually execute the biological actions induced by growth hormone, including the expression of particular genes. In contrast to receptors that themselves have tyrosine kinase activity, the signalling pathways leading to MAP kinase activation that are triggered by growth hormone are poorly understood, but appear to be mediated by the proteins Grb2 and Shc. We now show that growth hormone stimulates tyrosine phosphorylation of the receptor for epidermal growth factor (EGFR) and its association with Grb2 and at the same time stimulates MAP kinase activity in liver, an important target tissue of growth hormone. Expression of EGFR and its mutants revealed that growth-hormone-induced activation of MAP kinase and expression of the transcription factor c-fos requires phosphorylation of tyrosines on EGFR, but not its own intrinsic tyrosine-kinase activity. Moreover, tyrosine at residue 1,068 of the EGFR is proposed to be one of the principal phosphorylation sites and Grb2-binding sites stimulated by growth hormone via Jak2. Our results indicate that the role of EGFR in signalling by growth hormone is to be phosphorylated by Jak2, thereby providing docking sites for Grb2 and activating MAP kinases and gene expression, independently of the intrinsic tyrosine kinase activity of EGFR. This may represent a novel cross-talk pathway between the cytokine receptor superfamily and growth factor receptor.
...
PMID:Tyrosine phosphorylation of the EGF receptor by the kinase Jak2 is induced by growth hormone. 936 97

Biological effects of many hormones and cytokines are mediated through receptor-associated Jak tyrosine kinases and cytoplasmic Stat transcription factors, including critical physiological processes such as immunity, reproduction, and cell growth and differentiation. Pharmaceuticals that control Jak-Stat pathways are therefore of considerable interest. Here we demonstrate that a single Jak-Stat pathway can be activated by aurintricarboxylic acid (ATA), a negatively charged triphenylmethane derivative (475 Da) with anti-apoptotic properties. In prolactin (PRL)-dependent Nb2 lymphocytes, ATA sustained cell growth in the absence of hormone and mimicked rapid PRL-induced tyrosine phosphorylation of Jak2 and activation of Stat5a and Stat5b with tyrosine phosphorylation, heterodimerization, DNA binding, and induction of the Stat5-regulated pim-1 protooncogene. ATA also mimicked PRL activation of serine kinases ERK1 and ERK2. However, unlike PRL, ATA did not regulate Stat1 or Stat3. ATA also did not affect Jak3, which is activated in these cells by interleukin-2 family cytokines. Although the mechanism and specificity by which ATA activates Jak2, Stat5, and ERKs in Nb2 cells are still unclear, the present study demonstrates that certain hormone or cytokine effects on Jak-Stat pathways can be discretely imitated by a low molecular weight, non-peptide pharmaceutical. The results are also consistent with Stat5 involvement in lymphocyte growth and survival.
...
PMID:Activation of the Jak2-Stat5 signaling pathway in Nb2 lymphoma cells by an anti-apoptotic agent, aurintricarboxylic acid. 941 42

Mitogen-activated protein (MAP) kinases are activated by the sequential activation of Ras, Raf, and MEK (MAP kinase kinase) and regulate a wide variety of cell functions. To determine the kinase cascade for granulocyte-macrophage colony-stimulating factor (GM-CSF)- and IL-5-induced MAP kinase activation in eosinophils, we studied the effect of inhibitors of Jak2 kinase, tyrosine kinases, phosphatidylinositol 3-kinase, and protein kinase C on GM-CSF- and IL-5-induced MAP kinase activation in human eosinophils. GM-CSF and IL-5 activated 40, 42, and 44 kilodalton MAP kinase isoforms in eosinophils. This was indicated by the electrophoretic mobility shift of the three isoforms of MAP kinase in immunoblotting with anti-MAP kinase antibody and also by in-gel MAP kinase assay. MAP kinase activation was time- and dose-dependent, becoming maximal 3 to 15 minutes after stimulation. A Jak2 kinase inhibitor AG-490, a tyrosine kinase inhibitor genistein, and a phosphatidylinositol 3-kinase inhibitor wortmannin inhibited GM-CSF- and IL-5-induced MAP kinase activation in eosinophils, whereas a protein kinase C inhibitor staurosporine had a weak inhibitory effect. Furthermore, AG-490 and genistein prevented GM-CSF-induced tyrosine phosphorylation of Jak2 kinase in eosinophils. Taken together, these results indicate that GM-CSF and IL-5 activate MAP kinases through the signaling pathway of Jak2 kinase-tyrosine phosphorylated beta chain-phosphatidylinositol 3-kinase-Ras in eosinophils.
...
PMID:Granulocyte-macrophage colony-stimulating factor and IL-5 activate mitogen-activated protein kinase through Jak2 kinase and phosphatidylinositol 3-kinase in human eosinophils. 944 May 44

Cytokine-mediated inhibition of eosinophil apoptosis is a mechanism causing tissue eosinophilia. Previously published work suggested that activation of the Lyn-Ras-Raf-1-MAP kinase pathway is obligatory for prevention of eosinophil apoptosis by eosinophil hematopoietins. We demonstrate herein that activation of freshly isolated human blood eosinophils by granulocyte-macrophage colony-stimulating factor (GM-CSF) is associated with increased tyrosine phosphorylation of Jak2. The tyrosine kinase blocker, tyrphostin B42, prevented activation of Jak2 but not Lyn, suggesting that Jak2 is the specific target for tyrphostin B42 in eosinophils. In addition, since Lyn remained unaffected by tyrphostin B42, it is unlikely that Jak2 is required for Lyn activation in this model. To test whether tyrosine phosphorylation of Jak2 is linked to GM-CSF-mediated prolonged eosinophil survival, we determined the effect of tyrphostin B42 on eosinophil viability and apoptosis. Prevention of Jak2 activation by tyrphostin B42 was associated with the inability of GM-CSF to prevent eosinophil apoptosis. These data suggest that disruption of not only the Lyn-Ras-Raf-1-MAP kinase but also the Jak-STAT pathway blocks the ability of eosinophil survival factors to prevent apoptosis in eosinophils.
...
PMID:Anti-apoptotic signals of granulocyte-macrophage colony-stimulating factor are transduced via Jak2 tyrosine kinase in eosinophils. 946 45

Gene activation and cellular differentiation induced by interleukin-6 (IL-6) and transcription factor Stat3 are suppressed by several factors, including ionomycin, granulocyte/macrophage-colony-stimulating factor, and phorbol 12-myristate 13-acetate (PMA), that block IL-6-induced Stat3 activation. These inhibitory agents activate mitogen activated protein kinases (MAPKs), and thus the role of MAPKs in the mechanism of inhibition of Stat3 activation was investigated. Inhibition of IL-6-induced Stat3 activation by PMA and ionomycin was rapid (within 5 min) and did not require new RNA or protein synthesis. Inhibition of Stat3 DNA-binding activity and tyrosine phosphorylation by PMA, ionomycin, and granulocyte/macrophage-colony-stimulating factor was reversed when activation of the extracellular signal-regulated kinase (ERK) group of MAPKs was blocked by using specific kinase inhibitors. Expression of constitutively active MEK1, the kinase that activates ERKs, or overexpression of ERK2, but not JNK1, inhibited Stat3 activation. Inhibition of Stat3 correlated with suppression of IL-6-induction of a signal transducer and activator of transcription (STAT)-dependent reporter gene. In contrast to IL-6, activation of Stat3 by interferon-alpha was not inhibited. MEKs and ERKs inhibited IL-6 activation of Stat3 harboring a mutation at serine-727, the major site for serine phosphorylation, similar to inhibition of wild-type Stat3, and inhibited Janus kinases Jak1 and Jak2 upstream of Stat3 in the Jak-STAT-signaling pathway. These results demonstrate an ERK-mediated mechanism for inhibiting IL-6-induced Jak-STAT signaling that is rapid and inducible, and thus differs from previously described mechanisms for downmodulation of the Jak-STAT pathway. This inhibitory pathway provides a molecular mechanism for the antagonism of Stat3-mediated IL-6 activity by factors that activate ERKs.
...
PMID:Rapid inhibition of interleukin-6 signaling and Stat3 activation mediated by mitogen-activated protein kinases. 973 97


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---