Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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 dual signal hypothesis of apoptosis holds that a common signal can activate both apoptotic and proliferative pathways. The fate of a cell is dependent on which of these two pathways predominates. In the MAPK family of kinases, ERK and JNK have been proposed to mediate apoptosis whereas the PI3K-stimulated kinase, Akt/PKB, has been shown to inhibit apoptosis. The object of this study was to determine the role of these kinases in a glioma model of apoptosis. We have previously shown that K252a induces apoptosis and inhibits kinase activity. In this study we confirm these results and show that the protein tyrosine phosphatase inhibitor sodium vanadate activates ERK, JNK and Akt/PKB, but does not stimulate proliferation. Vanadate did protect T98G cells from K252a-induced apoptosis, an effect that was abolished by addition of the PI3K inhibitor wortmannin. This suggests that PI3K and Akt/PKB may be responsible for mediating vanadate's protective effect on glioma cells. We conclude that the intracellular balance between protein phosphorylation pathways is a critical determinant of both cell proliferation and cell death.
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PMID:Sodium vanadate inhibits apoptosis in malignant glioma cells: a role for Akt/PKB. 1034 70

The comparison of distinct cell-differentiation models can help to answer the question whether there are common signalling pathways activated in the cells during the differentiation process or not. The differentiation of PC12 pheochromocytoma cells in response to NGF, the differentiation of melanoma B16 cells triggered by alpha-MSH, the formation of myotubes by L6E9 skeletal muscle myoblasts deprived of FCS or differentiation of HL-60 cells in response to steroid hormone 1,25-dihydroxyvitamin D3 share some similarities in the activation of signal transduction pathways. Differentiation-inducing agents stimulate sustained activation and nuclear translocation of MAP kinases (ERK1 and ERK2). Some of differentiation-inducing agents activate PI3-kinase as well, and the inhibition of the PI3K/p70S6K pathway blocks the process of differentiation in the cells.
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PMID:[Does the universal "signal transduction pathway of differentiation" exist? Comparison of different cell differentiation experimental models with differentiation of HL-60 cells in response to 1,25-dihydroxyvitamin D3]. 1035 95

In this work, we analyzed the role of the PI3K-p70 S6 kinase (S6K) signaling cascade in the stimulation of endothelial cell proliferation. We found that inhibitors of the p42/p44 MAPK pathway (PD98059) and the PI3K-p70 S6K pathway (wortmannin, Ly294002, and rapamycin) all block thymidine incorporation stimulated by fetal calf serum in the resting mouse endothelial cell line 1G11. The action of rapamycin can be generalized, since it completely inhibits the mitogenic effect of fetal calf serum in primary endothelial cell cultures (human umbilical vein endothelial cells) and another established capillary endothelial cell line (LIBE cells). The inhibitory effect of rapamycin is only observed when the inhibitor is added at the early stages of G(0)-G(1) progression, suggesting an inhibitory action early in G(1). Rapamycin completely inhibits growth factor stimulation of protein synthesis, which perfectly correlates with the inhibition of cell proliferation. In accordance with its inhibitory action on protein synthesis, activation of cyclin D1 and p21 proteins by growth factors is also blocked by preincubation with rapamycin. Expression of a p70 S6K mutant partially resistant to rapamycin reverses the inhibitory effect of the drug on DNA synthesis, indicating that rapamycin action is via p70 S6K. Thus, in vascular endothelial cells, activation of protein synthesis via p70 S6K is an essential step for cell cycle progression in response to growth factors.
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PMID:p70 S6 kinase-mediated protein synthesis is a critical step for vascular endothelial cell proliferation. 1048 Aug 82

Extracellular signals often result in simultaneous activation of both the Raf-MEK-ERK and PI3K-Akt pathways (where ERK is extracellular-regulated kinase, MEK is mitogen-activated protein kinase or ERK kinase, and PI3K is phosphatidylinositol 3-kinase). However, these two signaling pathways were shown to exert opposing effects on muscle cell hypertrophy. Furthermore, the PI3K-Akt pathway was shown to inhibit the Raf-MEK-ERK pathway; this cross-regulation depended on the differentiation state of the cell: Akt activation inhibited the Raf-MEK-ERK pathway in differentiated myotubes, but not in their myoblast precursors. The stage-specific inhibitory action of Akt correlated with its stage-specific ability to form a complex with Raf, suggesting the existence of differentially expressed mediators of an inhibitory Akt-Raf complex.
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PMID:Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. 1057 41

The Gab1-docking protein has been shown to regulate phosphatidylinositol 3-kinase PI3K activity and potentiate nerve growth factor (NGF)-induced survival in PC12 cells. Here, we investigated the potential of Gab1 to induce neurite outgrowth and DNA synthesis, two other important aspects of NGF-induced neuronal differentiation of PC12 cells and NGF-independent survival. We generated a recombinant adenovirus encoding hemagglutinin (HA)-epitope-tagged Gab1 and expressed this protein in PC12 cells. HA-Gab1 was constitutively tyrosine-phosphorylated in PC12 cells and induced the phosphorylation of Akt/protein kinase B and p44/42 mitogen-activated protein kinase. HA-Gab1-stimulated a 10-fold increase in neurite outgrowth in the absence of NGF and a 5-fold increase in NGF-induced neurite outgrowth. HA-Gab1 also stimulated DNA synthesis and caused NGF-independent survival in PC12 cells. Finally, we found that HA-Gab1-induced neuritogenesis was completely suppressed by pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) activity and 50% suppressed by inhibition of PI3K activity. In contrast, HA-Gab1-stimulated cell survival was efficiently suppressed only by inhibition of both PI3K and MEK activities. These results indicate that Gab1 is capable of mediating differentiation, DNA synthesis, and cell survival and uses both PI3K and MEK signaling pathways to achieve its effects.
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PMID:Gab1 mediates neurite outgrowth, DNA synthesis, and survival in PC12 cells. 1060 Dec 97

Kit, a tyrosine kinase growth factor receptor, and its ligand, stem cell factor (SCF), are commonly coexpressed in breast cancer. We have previously shown that MCF7 cells (that naturally express SCF) transfected with a c-kit expression vector exhibit enhanced growth in serum-free medium supplemented with IGF-1. Consequently, we wished to examine the interaction of Kit/SCF with additional growth factors important in the biology of breast cancer. MCF7 transfectants expressing Kit, cultured in serum-free medium supplemented with EGF, displayed more than twice the growth of controls at identical EGF concentrations. Similar responses were seen in the presence of heregulin alpha. The specificity of the Kit-mediated response was illustrated by a reduction in heregulin-stimulated growth in the presence of a monoclonal antibody directed against the Kit receptor. In addition, EGF- and heregulin-stimulated growth of the ZR75-1 cell line that naturally coexpresses Kit and SCF was also inhibited by the Kit blocking antibody. Preliminary investigations into the signal transduction pathways activated by these growth factors revealed that SCF activated both the Ras-MAP kinase and phosphatidyl-inositol-3-kinase (PI3 kinase) pathway. Both EGF and heregulin activated MAPK but to a lesser degree than SCF, and combination of SCF with these growth factors resulted in enhanced MAPK activation. Assessment of PI3K pathway activation using antiphospho-Akt antibodies revealed that EGF was a poor activator of Akt; activation of this pathway was markedly enhanced by the addition of SCF. Heregulin activated Akt and addition of SCF provided no further activation. Taken together these results suggest that coexpression of SCF and Kit may enhance responsiveness to erbB ligands by enhancing activation of the MAPK and PI3K pathways.
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PMID:Coexpression of c-kit and stem cell factor in breast cancer results in enhanced sensitivity to members of the EGF family of growth factors. 1063 12

Transforming growth factor (TGF) beta-like trophic factors have been shown to be protective in acute neuronal injury paradigms. In the current study, we analyzed and compared members of this growing family, including glial cell line-derived neurotrophic factor (GDNF), neurturin, nodal, persephin, and TGFbeta1, for protection against chronic glutamate toxicity. In parallel, we developed a organotypic spinal cord culture system to study the ability of these factors to promote motor axon outgrowth across white matter. Using these systems, we were able to differentiate the neuroprotective effect of the TGFbeta-like factors from their motor axon outgrowth-promoting activity. GDNF, neurturin, persephin, nodal, and TGFbeta1 all protected against excitotoxic motor neuron degeneration. Low amounts of GDNF (1 ng/ml) and high concentrations of neurturin induced vigorous motor axon outgrowth. In contrast, nodal, persephin, and TGFbeta1 did not induce motor axon outgrowth. Both GDNF and neurturin bind to Ret receptor complexes and were capable of activating the MAP kinase pathway. A specific inhibitor of MAP kinase kinase, PD98059, inhibited the motor axon outgrowth-promoting activity of the GDNF but not the neuroprotective activity. Similarly, the specific PI3K inhibitors, LY294002 and wortmannin, were able to inhibit the promotion of motor axon outgrowth by GDNF, but did not affect neuroprotective activity. Our results suggest that the neurite outgrowth-promoting effect of GDNF is mediated through the PI3K and MAP kinase pathways. The neuroprotective effect of GDNF appears to be through a separate pathway.
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PMID:TGFbeta trophic factors differentially modulate motor axon outgrowth and protection from excitotoxicity. 1068 85

Prolactin induces cell proliferation and cell differentiation through well-known MAPK Erk, and JAK2/STAT5 pathways depending on the cell line. The aim of the present study was to delineate the functional domains of the PRL receptor involved in PRL induced MAPK regulation. Using various PRL-R mutants of the cytoplasmic domain we found, that the membrane proximal domain is necessary for PRL induced MAPK activation and that the C-terminal part of the receptor exerts a negative regulatory role. A pharmacological approach, using different types of inhibitors, provided evidence that PRL induced MAPK activation requires both a MEK dependent pathway and a PI3K dependent pathway. The negative regulation induced by the carboxy-terminal part of the receptor involves a combination of tyrosine phosphatases and serine/threonine phosphatases as concluded from the actions of the phosphatase inhibitors: pervanadate, PAO and okadaic acid. The mechanism by which these phosphatases are recruited or are induced by the last 141 cytoplasmic residues of the receptor remains to be determined. Finally the negative regulatory role of the carboxy-terminal part of the receptor, first demonstrated in the present study, is discussed in terms of the regulation of different effects of PRL on growth and differentiation.
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PMID:Effect of PRL on MAPK activation: negative regulatory role of the C-terminal part of the PRL receptor. 1068 59

Engagement of the T cell receptor leads to activation of several tyrosine kinases and phosphorylation of many intracellular proteins. This is followed by Ca2+ mobilization and activation of multiple biochemical pathways, including the Ras/MAPK cascade, and several downstream serine/threonine kinases. Membrane-associated adaptor proteins play an important role in T cell activation by coupling TCR ligation at the membrane to distal signalling cascades. Several new membrane associated adaptors have been identified in recent years. LAT (linker for activation of T cells) is an adaptor molecule, which following its phosphorylation associates with Grb2, Gads, PLC-gamma 1, and other signalling molecules. The functional importance of this molecule has been demonstrated by the study of LAT-deficient cell lines and LAT-deficient mice. Two other recently identified adaptor proteins, TRIM (T cell receptor interacting molecule) and SIT (SHP2-interacting transmembrane adaptor protein), which constitutively associate with several surface molecules, bind to PI3K and SHP2, respectively, after T cell activation and might also function in the TCR signalling pathway.
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PMID:The role of membrane-associated adaptors in T cell receptor signalling. 1072 96

Motoneurons require neurotrophic factors for their survival and axonal projection during development, as well as nerve regeneration. By using the axotomy-induced neuronal death paradigm and adenovirus-mediated gene transfer, we attempted to gain insight into the functional significances of major growth factor receptor downstream cascades, Ras-extracellular signal-regulated kinase (Ras-ERK) pathway and phosphatidylinositol-3 kinase-Akt (PI3K-Akt) pathway. After neonatal hypoglossal nerve transection, the constitutively active Akt-overexpressing neurons could survive as well as those overexpressing Bcl-2, whereas the constitutively active ERK kinase (MEK)-overexpressing ones failed to survive. A dominant negative Akt experiment demonstrated that inhibition of Akt pathway hastened axotomy-induced neuronal death in the neonate. In addition, the dominant active Akt-overexpressing adult hypoglossal neurons showed accelerated axonal regeneration after axotomy. These results suggest that Akt plays dual roles in motoneuronal survival and nerve regeneration in vivo and that PI3K-Akt pathway is probably more vital in neuronal survival after injury than Ras-ERK pathway.
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PMID:Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration. 1075 40


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