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)

Reovirus is a benign human virus that was recently found to have oncolytic properties and is currently in clinical trials as a potential cancer therapy. We have previously demonstrated that activation of Ras signaling, a common event in cancer, renders cells susceptible to reovirus oncolysis. In this study, we investigate which elements downstream of Ras are important in reovirus infection. By using a panel of NIH 3T3 cells transformed with activated Ras mutated in the effector-binding domain, we found that only the RasV12G37 mutant, which was unable to signal to Raf or phosphatidylinositol 3-kinase but retained signaling capability to guanine nucleotide-exchange factors (GEFs) for the small G protein, Ral (known as RalGEFs), was permissive to reovirus. Expression of the activated mutant of the RalGEF, Rlf, also allowed reovirus replication. Specific inhibition of the Ral pathway by using dominant-negative RalA rendered normally permissive H-Ras cells (cells expressing activated Ras) resistant to reovirus. To further identify elements downstream of RalGEF that promote reovirus infection, we used chemical inhibitors of the downstream signaling elements p38 and JNK. We found that reovirus infection was blocked in the presence of the p38 inhibitor but not the JNK inhibitor. Together, these results implicate a Ras/RalGEF/p38 pathway in the regulation of reovirus replication and oncolysis.
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PMID:Reovirus oncolysis: the Ras/RalGEF/p38 pathway dictates host cell permissiveness to reovirus infection. 1526 68

To analyze the roles of insulin receptor substrate (IRS) proteins in insulin-stimulated cell cycle progression, we examined the functions of rat IRS-1 and IRS-3 in Chinese hamster ovary cells overexpressing the human insulin receptor. In this type of cell overexpressing IRS-1 or IRS-3, we showed that: 1) overexpression of IRS-3, but not IRS-1, suppressed the G1/S transition induced by insulin; 2) IRS-3 was more preferentially localized to the nucleus than IRS-1; 3) phosphorylation of glycogen synthase kinase 3 and MAPK/ERK was unaffected by IRS-3 overexpression, whereas that of protein kinase B was enhanced by either IRS; 4) overexpressed IRS-3 suppressed cyclin D1 expression in response to insulin; 5) among the signaling molecules regulating cyclin D1 expression, activation of the small G protein Ral was unchanged, whereas insulin-induced gene expression of c-myc, a critical component for growth control and cell cycle progression, was suppressed by overexpressed IRS-3; and 6) insulin-induced expression of p21, a cyclin-dependent kinase inhibitor, was decreased by overexpressed IRS-3. These findings imply that: 1) IRS-3 may play a unique role in mitogenesis by inhibiting insulin-stimulated cell cycle progression via a decrease in cyclin D1 and p21 expressions as well as suppression of c-myc mRNA induction in a manner independent of the activation of MAPK, protein kinase B, glycogen synthase kinase 3 and Ral; and 2) the interaction of IRS-3 with nuclear proteins may be involved in this process.
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PMID:Insulin-induced cell cycle progression is impaired in chinese hamster ovary cells overexpressing insulin receptor substrate-3. 1533 70

L-ascorbic acid (LAA) shows cytotoxicity and induces apoptosis of malignant cells in vitro, but the mechanisms by which such effects occur have not been elucidated. In the present study, we provide evidence that the ERK MAP kinase pathway is activated in response to LAA (< 1 mM) in acute myeloid leukemia cell lines. LAA treatment of cells induces a dose-dependent phosphorylation of extracellular signal-regulated kinases (ERK) and results in activation of its catalytic domain. Our data also demonstrate that the small G protein Raf1 and MAPK-activated protein kinase 2 are activated by LAA as an upstream and a downstream regulator of ERK, respectively. Although the ERK pathway has been known to activate cell proliferation, pharmacologic inhibition of ERK reduces LAA-dependent apoptosis and growth inhibitory response of acute myeloid leukemia cell lines, suggesting that this signaling cascade positively regulates induction of apoptotic response by LAA.
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PMID:Activation of Raf1 and the ERK pathway in response to l-ascorbic acid in acute myeloid leukemia cells. 1545 Oct 31

Monocyte chemoattractant protein-1 (MCP-1) has been recognized as an angiogenic chemokine. In the present study, we investigated the detailed mechanism by which MCP-1 induces angiogenesis. We found that MCP-1 up-regulated hypoxia-inducible factor 1 alpha (HIF-1 alpha) gene expression in human aortic endothelial cells (HAECs), which induced vascular endothelial growth factor-A(165) (VEGF-A(165)) expression in the aortic wall and HAECs through activation of p42/44 mitogen-activated protein kinase (MAPK). In vivo angiogenesis assay using chick chorioallantoic membrane (CAM) showed that MCP-1-induced angiogenesis was as potent as that induced by VEGF-A(165) and completely inhibited by a VEGF inhibitor, Flt(2-11). The inhibition of RhoA small G protein did not affect MCP-1-induced VEGF-A(165) production and secretion but completely blocked both MCP-1- and VEGF-A-induced new vessel formation, as determined by CAM assay. These results suggest that MCP-1-induced angiogenesis is composed largely of 2 sequential steps: the induction of VEGF-A gene expression by MCP-1 and the subsequent VEGF-A-induced angiogenesis.
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PMID:Monocyte chemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth factor-A. 1549 48

Angiogenesis, a process of new blood vessel growth, contributes to various pathophysiologies such as cancer, diabetic retinopathy and atherosclerosis. Accumulating evidence suggests that cardiovascular diseases are associated with increased oxidative stress in blood vessels. Reactive oxygen species (ROS) such as superoxide and H2O2 cause blood vessels to thicken, produce inflammation in the vessel wall, and thus are regarded as "risk factors" for vascular disease, whereas ROS also act as signaling molecules in many aspects of growth factor-mediated physiological responses. Recent reports suggest that ROS play an important role in angiogenesis; however, its underlying molecular mechanisms remain unknown. Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating endothelial cell (EC) proliferation and migration primarily through the receptor tyrosine kinase VEGF receptor2 (Flk1/KDR). VEGF binding initiates tyrosine phosphorylation of KDR, which results in activation of downstream signaling enzymes including ERK1/2, Akt and eNOS, which contribute to angiogenic-related responses in EC. Importantly, the major source of ROS in EC is a NAD(P)H oxidase and EC express all the components of phagocytic NAD(P)H oxidase including gp91phox, p22phox, p47phox, p67phox and the small G protein Rac1. We have recently demonstrated that ROS derived from NAD(P)H oxidase are critically important for VEGF signaling in vitro and angiogenesis in vivo. Furthermore, a peptide hormone, angiotensin II, a major stimulus for vascular NAD(P)H oxidase, also plays an important role in angiogenesis. Because EC migration and proliferation are primary features of the process of myocardial angiogenesis, we would like to focus on the recent progress that has been made in the emerging area of NAD(P)H oxidase-derived ROS-dependent signaling in ECs, and discuss the possible roles in angiogenesis. Understanding these mechanisms may provide insight into the components of NAD(P)H oxidase as potential therapeutic targets for treatment of angiogenesis-dependent diseases such as cancer and atherosclerosis and for promoting myocardial angiogenesis in ischemic heart diseases.
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PMID:Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. 1554 38

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) ameliorate atherosclerotic diseases. Macrophages play an important role in the development and subsequent stability of atherosclerotic plaques. We reported previously that oxidized low density lipoprotein (Ox-LDL) induced macrophage proliferation through the secretion of granulocyte/macrophage colony-stimulating factor (GM-CSF) and the consequent activation of p38 MAPK. The present study was designed to elucidate the mechanism of the inhibitory effect of statins on macrophage proliferation. Mouse peritoneal macrophages were used in our study. Cerivastatin and simvastatin each inhibited Ox-LDL-induced [(3)H]thymidine incorporation into macrophages. Statins did not inhibit Ox-LDL-induced GM-CSF production, but inhibited GM-CSF-induced p38 MAPK activation. Farnesyl transferase inhibitor and geranylgeranyl transferase inhibitor inhibited GM-CSF-induced macrophage proliferation, and farnesyl pyrophosphate and geranylgeranyl pyrophosphate prevented the effect of statins. GM-CSF-induced p38 MAPK phosphorylation was also inhibited by farnesyl transferase inhibitor or geranylgeranyl transferase inhibitor, and farnesyl pyrophosphate and geranylgeranyl pyrophosphate prevented the suppression of GM-CSF-induced p38 MAPK phosphorylation by statins. Furthermore, we found that statin significantly inhibited the membrane translocation of the small G protein family members Ras and Rho. GM-CSF-induced p38 MAPK activation and macrophage proliferation was partially inhibited by overexpression of dominant negative Ras and completely by that of RhoA. In conclusion, statins inhibited GM-CSF-induced Ras- or RhoA-p38 MAPK signal cascades, thereby suppressing Ox-LDL-induced macrophage proliferation. The significant inhibition of macrophage proliferation by statins may also explain, at least in part, their anti-atherogenic action.
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PMID:Statins suppress oxidized low density lipoprotein-induced macrophage proliferation by inactivation of the small G protein-p38 MAPK pathway. 1561 Oct 87

In Drosophila embryos, the Torso receptor tyrosine kinase (RTK) activates the small G protein Ras (D-Ras1) and the protein kinase Raf (D-Raf) to activate ERK to direct differentiation of terminal structures . However, genetic studies have demonstrated that Torso, and by extension other RTKs, can activate Raf and ERK independently of Ras . In mammalian cells, the small G protein Rap1 has been proposed to couple RTKs to ERKs. However, the ability of Rap1 to activate ERKs remains controversial, in part because direct genetic evidence supporting this hypothesis is lacking. Here, we present biochemical and genetic evidence that D-Rap1, the Drosophila homolog of Rap1, can activate D-Raf and ERK. We show that D-Rap1 binds D-Raf and activates ERKs in a GTP- and D-Raf-dependent manner. Targeted disruption of D-Rap1 expression decreased both Torso-dependent ERK activation and the ERK-dependent expression of the zygotic genes tailless and huckebein to levels similar to those achieved in D-Ras1 null embryos. Furthermore, combined deficiencies of D-Ras1 and D-Rap1 completely abolished expression of these genes, mimicking the phenotype observed in embryos lacking D-Raf. These studies provide the first direct genetic evidence of Rap1-mediated activation of the MAP kinase cascade in eukaryotic organisms.
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PMID:Ras-independent activation of ERK signaling via the torso receptor tyrosine kinase is mediated by Rap1. 1572 99

The mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) is activated following engagement of the T-cell receptor and is required for interleukin 2 (IL-2) production and T-cell proliferation. This activation is enhanced by stimulation of the coreceptor CD28 and inhibited by the coreceptor CTLA-4. We show that the small G protein Rap1 is regulated in the opposite manner; it is inhibited by CD28 and activated by CTLA-4. Together, CD3 and CTLA-4 activate Rap1 in a sustained manner. To delineate T-cell function in the absence of Rap1 activity, we generated transgenic mice expressing Rap1GAP1, a Rap1-specific GTPase-activating protein. Transgenic mice showed lymphadenopathy, and transgenic T cells displayed increased ERK activation, proliferation, and IL-2 production. More significantly, the inhibitory effect of CTLA-4 on T-cell function in Rap1GAP1-transgenic T cells was reduced. We demonstrate that CTLA-4 activates Rap1, and we propose that intracellular signals from CTLA-4 antagonize CD28, at least in part, at the level of Rap1.
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PMID:Regulation of the small GTPase Rap1 and extracellular signal-regulated kinases by the costimulatory molecule CTLA-4. 1587 Feb 82

Small G proteins serve as critical control points in signal transduction, integrating a wide range of stimuli to dictate discrete cellular outcomes. The outcomes of small G-protein signaling can both potentiate and antagonize one another. Studies in hematopoietic cells have uncovered multiple functions for the small G protein, Rap1 (Ras-proximate-1). Because Rap1 can regulate cell proliferation, differentiation, and adhesion through distinct mechanisms, it serves as a paradigm for the need for tight cellular control of small G-protein function. Rap1 has received recent attention for its role in enhancing integrin-dependent signals. This action of Rap1 augments a variety of processes that characterize hematopoietic-cell function, including aggregation, migration, extravasation, and homing to target tissues. Rap1 may also regulate cellular differentiation and proliferation via pathways that are distinct from those mediating adhesion, and involve regulation of the mitogen-activated protein (MAP) kinase or ERK (extracellular signal-regulated kinase) cascade. These actions of Rap1 occur in selected cell types to enhance or diminish ERK signaling, depending on the expression pattern of the MAP kinase kinase kinases of the Raf family: Raf-1 and B-Raf. This review will examine the functions of Rap1 in hematopoietic cells, and focus on 3 cellular scenarios where the multiple actions of Rap1 function have been proposed. Recent studies implicating Rap1 in the maturation of megakaryocytes, the pathogenesis of chronic myelogenous leukemia (CML), and activation of peripheral T cells will receive particular attention.
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PMID:Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions. 1607 73

Protein kinase C, a highly conserved signaling molecule among eukaryotes, has been implicated in the regulation of cellular processes such as cell proliferation and polarized growth. In Saccharomyces cerevisiae, the unique protein kinase C Pkc1p is thought to have multiple functions, including the activation of the Mpk1p (Slt2p) MAP kinase pathway, which is essential for cell wall construction and bud emergence. However, little is known about the other functions of Pkc1p. In the course of screening for the mutants that suppress the Ca2+-sensitivity phenotype of the Ca2+-sensitive strain zdsDelta, we isolated a novel mutant allele (scz6/pkc1-834) of PKC1. Unlike the previously characterized PKC1 allele stt1-1, heat-shock-induced Mpk1p activation and cell-wall integrity were not impaired in the pkc1-834 mutant. By contrast, the mutant was defective in the maintenance of Ca2+-induced F-actin polarization in a manner independent of Mpk1p activation. This phenotype was caused by a decreased expression level of the G1 cyclin Cln2p. The Rho1 small G protein molecular switch was suggested to be involved in the novel Pkc1p function. The Pkc1p novel function was required for posttranscriptional upregulation of Cln2p and appeared to be important for the coordinated regulation of polar bud growth and the cell cycle.
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PMID:Implication of Pkc1p protein kinase C in sustaining Cln2p level and polarized bud growth in response to calcium signaling in Saccharomyces cerevisiae. 1614 Dec 37


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