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

The signaling routes linking G-protein-coupled receptors to mitogen-activated protein kinase (MAPK) may involve tyrosine kinases, phosphoinositide 3-kinase gamma (PI3Kgamma), and protein kinase C (PKC). To characterize the mitogenic pathway of bradykinin (BK), COS-7 cells were transiently cotransfected with the human bradykinin B(2) receptor and hemagglutinin-tagged MAPK. We demonstrate that BK-induced activation of MAPK is mediated via the alpha subunits of a G(q/11) protein. Both activation of Raf-1 and activation of MAPK in response to BK were blocked by inhibitors of PKC as well as of the epidermal growth factor (EGF) receptor. Furthermore, in PKC-depleted COS-7 cells, the effect of BK on MAPK was clearly reduced. Inhibition of PI3-Kgamma or Src kinase failed to diminish MAPK activation by BK. BK-induced translocation and overexpression of PKC isoforms as well as coexpression of inactive or constitutively active mutants of different PKC isozymes provided evidence for a role of the diacylglycerol-sensitive PKCs alpha and epsilon in BK signaling toward MAPK. In addition to PKC activation, BK also induced tyrosine phosphorylation of EGF receptor (transactivation) in COS-7 cells. Inhibition of PKC did not alter BK-induced transactivation, and blockade of EGF receptor did not affect BK-stimulated phosphatidylinositol turnover or BK-induced PKC translocation, suggesting that PKC acts neither upstream nor downstream of the EGF receptor. Comparison of the kinetics of PKC activation and EGF receptor transactivation in response to BK also suggests simultaneous rather than consecutive signaling. We conclude that in COS-7 cells, BK activates MAPK via a permanent dual signaling pathway involving the independent activation of the PKC isoforms alpha and epsilon and transactivation of the EGF receptor. The two branches of this pathway may converge at the level of the Ras-Raf complex.
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PMID:Bradykinin B(2) receptor-mediated mitogen-activated protein kinase activation in COS-7 cells requires dual signaling via both protein kinase C pathway and epidermal growth factor receptor transactivation. 1040 20

To elucidate the role of endothelin in the regulation of vascular function, the cellular and subcellular mechanisms for the synthesis of endothelin and the function of endothelin-receptors have been studied extensively. In this article, recent results regarding these problems are reviewed. (1) Oxidatively modified low-density-lipoprotein (LDL) reduces nitric oxide (NO) release via inhibition of the high-affinity arginine transporter of endothelial cells. (2) Endothelin-1-induced vasoconstriction is mediated by Ca2+ influx through a non-selective cation channel sensitive to 1-[beta-[3-(4-methoxyphenyl) propoxyl]-4-methoxyphenethyl]-1H-imidazole HCl (SK & F96365). (3) A distinct domain of the endothelin-receptor is required for the coupling of different G(alpha)-proteins. (4) Endothelin ET(A) receptor-mediated mitogenic activity is mediated by two pathways, one classical protein kinase C(PKC)-dependent, and the other phosphoinositide 3-kinase dependent. Both stimulate mitogen-activated protein kinase (MAPK). Endothelin ET(B) receptor-mediated mitogenic activity is also mediated by the PKC-dependent pathway. In contrast, endothelin ET(B) receptor-mediates differentiation and apoptosis via G(alpha)i coupling.
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PMID:Subcellular mechanisms of endothelin action in vascular system. 1044 71

Eukaryotic initiation factor (eIF) 4E binds to the 5'-cap structure of eukaryotic mRNA and has a central role in the control of cell proliferation. We have shown previously that the stimulation of cultured Xenopus kidney cells with serum resulted in the activation of protein synthesis, enhanced phosphorylation of eIF4E and increased binding of the adapter protein, eIF4G, and poly(A)-binding protein (PABP) to eIF4E to form the functional initiation factor complex, eIF4F/PABP. We now show that cellular stresses such as arsenite, anisomycin and heat shock also result in increased phosphorylation of eIF4E, eIF4F complex formation and the association of PABP with eIF4G, in conditions under which the rate of protein synthesis is severely inhibited. In contrast with reported effects on mammalian cells, the stress-induced increase in eIF4F complex formation occurs in the absence of changes in the association of eIF4E with its binding proteins 4E-BP1 or 4E-BP2. The stress-induced changes in eIF4E phosphorylation were totally abrogated by the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580, and were partly inhibited by the phosphoinositide 3-kinase inhibitor LY294002 and the mammalian target of rapamycin (mTOR) inhibitor rapamycin. However, eIF4E phosphorylation was unaffected by extracellular signal-regulated protein kinase (MAP kinase) inhibitor PD98059. These results indicate that cellular stresses activate multiple signalling pathways that converge at the level of eIF4F complex formation to influence the interactions between eIF4E, eIF4G and PABP.
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PMID:Cellular stress in xenopus kidney cells enhances the phosphorylation of eukaryotic translation initiation factor (eIF)4E and the association of eIF4F with poly(A)-binding protein. 1047 62

Insulin and insulin-like growth factors (IGFs) elicit distinct but overlapping biological effects in vivo. To investigate whether differences in intrinsic signaling capacity of receptors contribute to biological specificity, we constructed chimeric receptors containing the extracellular portion of the neurotrophin receptor TrkC fused to the intracellular portion of the insulin or IGF-I receptors. Chimeras were stably expressed in 3T3-L1 adipocytes at levels comparable to endogenous insulin receptors and were efficiently activated by neurotrophin-3. The wild-type insulin receptor chimera mediated approximately 2-fold greater phosphorylation of insulin receptor substrate 1 (IRS-1), association of IRS-1 with phosphoinositide 3-kinase, stimulation of glucose uptake, and GLUT4 translocation, compared with the IGF-I receptor chimera. In contrast, the IGF-I receptor chimera mediated more effective Shc phosphorylation, association of Shc with Grb2, and activation of mitogen-activated protein kinase compared with the insulin receptor chimera. The two receptors elicited similar activation of protein kinase B, p70S6 kinase, and glycogen synthesis. We conclude that the insulin receptor mediates some aspects of metabolic signaling in adipocytes more effectively than the IGF-I receptor, as a consequence of more efficient phosphorylation of IRS-1 and greater recruitment/activation of phosphoinositide 3-kinase.
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PMID:Differences in signaling properties of the cytoplasmic domains of the insulin receptor and insulin-like growth factor receptor in 3T3-L1 adipocytes. 1052 79

The p21-activated protein kinase gamma-PAK is activated 2-5-fold in response to ionizing radiation (IR) in 3T3-L1 fibroblasts and U937 leukemia cells. gamma-PAK is activated in a dose- and time-dependent manner. Doses from 1 to 100 Gy result in significant stimulation of activity at 30 min, whereas maximal stimulation is observed at 120 min after irradiation. UV (80 J/m(2)) and the DNA-damaging drugs cytosine beta-D-arabinofuranoside (AraC) and cis-platinum(II)diammine dichloride (cisplatin) also induce gamma-PAK activation. The activation of gamma-PAK in response to IR or AraC is dependent on tyrosine kinase and phosphoinositide 3-kinase activity, as demonstrated by use of the inhibitors genistein and wortmannin; in contrast activation of gamma-PAK by cisplatin and UV is not affected significantly by these inhibitors, suggesting that gamma-PAK can be activated by more than one pathway in response to different types of DNA damage. In contrast to gamma-PAK, alpha-PAK and JNK are activated only by cisplatin and UV in 3T3-L1 cells, suggesting differential regulation of the protein kinases. This is the first time that members of the Ste20/PAK family of protein kinases have been shown to be involved in the cellular response to IR and other DNA-damaging agents.
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PMID:p21-activated protein kinase gamma-PAK is activated by ionizing radiation and other DNA-damaging agents. Similarities and differences to alpha-PAK. 1053 Dec 98

Activation of p70 S6 kinase (p70(S6K)) by growth factors requires multiple signal inputs involving phosphoinositide 3-kinase (PI3K), its effector Akt, and an unidentified kinase that phosphorylates Ser/Thr residues (Ser(411), Ser(418), Ser(424), and Thr(421)) clustered at its autoinhibitory domain. However, the mechanism by which G protein-coupled receptors activate p70(S6K) remains largely uncertain. By using vascular smooth muscle cells in which we have demonstrated Ras/extracellular signal-regulated kinase (ERK) activation through Ca(2+)-dependent, epidermal growth factor (EGF) receptor transactivation by G(q)-coupled angiotensin II (Ang II) receptor, we present a unique cross-talk required for Ser(411) phosphorylation of p70(S6K) by Ang II. Both p70(S6K) Ser(411) and Akt Ser(473) phosphorylation by Ang II appear to involve EGF receptor transactivation and were inhibited by dominant-negative Ras, whereas the phosphorylation of p70(S6K) and ERK but not Akt was sensitive to the MEK inhibitor. By contrast, the phosphorylation of p70(S6K) and Akt but not ERK was sensitive to PI3K inhibitors. Similar inhibitory pattern on these phosphorylation sites by EGF but not insulin was observed. Taken together with the inhibition of Ang II-induced p70(S6K) activation by dominant-negative Ras and the MEK inhibitor, we conclude that Ang II-initiated activation of p70(S6K) requires both ERK cascade and PI3K/Akt cascade that bifurcate at the point of EGF receptor-dependent Ras activation.
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PMID:Intracellular signaling of angiotensin II-induced p70 S6 kinase phosphorylation at Ser(411) in vascular smooth muscle cells. Possible requirement of epidermal growth factor receptor, Ras, extracellular signal-regulated kinase, and Akt. 1060 Dec 35

A putative Akt kinase phosphorylation site ((64)ydRIRplSYp(73)) was found in Rac1/CDC42 and Rho family proteins (RhoA, RhoB, RhoC, and RhoG). Phosphorylation of Rac1 by Akt kinase was assayed with recombinant Rac1 protein and the fluorescein-labeled Rac1 peptide. It was shown that the Rac1 peptide and the recombinant protein were phosphorylated by the activated recombinant Akt kinase and the lysate of SK-MEL28 cells, a human melanoma cell line. The phosphorylation of Rac1 inhibited its GTP-binding activity without any significant change in GTPase activity. Both the GTP-binding and GTPase activities of Rac1 S71A protein (with the serine residue to be phosphorylated replaced with alanine) were abolished regardless of the treatment of Akt kinase. Akt kinase activity and Rac1 peptide phosphorylation were down-regulated by the treatment of SK-MEL28 cells with wortmannin or LY294002 (a phosphoinositide 3-kinase inhibitor), but JNK/SAPK kinase activity was up-regulated. Thus, the results suggest that Akt kinase of the phosphoinositide 3-kinase signal transduction pathway phosphorylates serine 71 of Rac1 as one of its authentic substrates and modulates the Rac1 signal transduction pathway through phosphorylation.
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PMID:Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1. 1061 34

Cell adhesion mediated by beta1 integrin receptors leads to the initiation of intracellular signals that affect cell differentiation and survival. Here we have analysed the mechanism by which the alpha4beta1 integrin activates the mitogen-activated protein kinase pathway in HL60 cells, a myelomonocytic cell line that lacks the expression of focal adhesion kinase. A role for phosphoinositide 3-kinase (PI-3K) in alpha4 integrin-mediated activation of extracellular signal-regulated protein kinase 2 (ERK2) is suggested by the ability of PI-3K inhibitors and a dominant-negative form of the p85 subunit of PI-3K to block the activation of ERK2 by integrin. Stimulation of alpha4beta1 integrins on HL60 cells also leads to increased tyrosine phosphorylation of the 120 kDa adaptor protein Cbl. PI-3K activity associated with Cbl also increases on the stimulation of alpha4beta1 integrins, although immunodepletion experiments suggest that Cbl-associated PI-3K does not account for all of the PI-3K activity induced on the stimulation of integrins in these cells. The expression of wild-type Cbl or the 70Z/3 Cbl mutant enhances basal ERK2 activity in transfectants with a minimal effect on alpha4 integrin-mediated ERK2 activity. In contrast, overexpression of the Hut Cbl truncation mutant, which does not associate with p85, has no effect on the ERK2 pathway. These results suggest that PI-3K has a major role in coupling alpha4beta1 integrins to ERK2 activation in myeloid cells and that the Cbl adaptor protein has a role in basal, but not alpha4beta1 integrin-mediated, activation of ERK2.
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PMID:Role of phosphoinositide 3-kinase and the Cbl adaptor protein in coupling the alpha4beta1 integrin to mitogen-activated protein kinase signalling. 1062 May 16

Two p53-null T lymphoma cell lines proved to be highly sensitive to inhibition of gene expression. With either actinomycin D or cycloheximide, apoptosis commenced within 2 h, as indicated by loss of membrane integrity, degradation of certain proteins (including the phosphatase calcineurin) and DNA fragmentation. These effects were ablated by co-expression of Bcl-2 or co-incubation with the caspase inhibitor Z-VAD-fmk. These results suggest that the apoptotic machinery is in place in these cells but held in check by an unknown labile protein, which probably acts upstream of Bcl-2. Although cycloheximide can activate the JNK or p38 MAP kinases in some cells, neither was implicated here. However, disruption of phosphoinositide 3-kinase signaling may be involved, because the cells were also sensitive to wortmannin. The high sensitivity of the p53-null lymphoma cells to inhibitors of gene expression suggests that such inhibitors might prove useful in the cytotoxic therapy of certain tumors.
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PMID:Interference with gene expression induces rapid apoptosis in p53-null T lymphoma cells. 1063 38

Fibroblast growth factor-mediated signalling was studied in porcine aortic endothelial cells expressing either wild-type fibroblast growth factor receptor-1 or a mutant receptor (Y766F) unable to bind phospholipase C-(&ggr;). Stimulation of cells expressing the wild-type receptor resulted in activation of phospholipases C, D and A(2) and increased phosphoinositide 3-kinase activity. Stimulation of the wild-type receptor also resulted in stress fibre formation and a cellular shape change. Cells expressing the Y766F mutant receptor failed to stimulate phospholipase C, D and A(2) as well as phosphoinositide 3-kinase. Furthermore, no stress fibre formation or shape change was observed. Both the wild-type and Y766F receptor mutant activated MAP kinase and elicited proliferative responses in the porcine aortic endothelial cells. Thus, fibroblast growth factor receptor-1 mediated activation of phospholipases C, D and A(2) and phosphoinositide 3-kinase was dependent on tyrosine 766. Furthermore, whilst tyrosine 766 was not required for a proliferative response, it was required for fibroblast growth factor receptor-1 mediated cytoskeletal reorganisation.
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PMID:Tyrosine 766 in the fibroblast growth factor receptor-1 is required for FGF-stimulation of phospholipase C, phospholipase D, phospholipase A(2), phosphoinositide 3-kinase and cytoskeletal reorganisation in porcine aortic endothelial cells. 1065 57


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