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)

Eukaryotic cells use the extracellular signal regulated kinase (ERK) cascade to connect cell-surface receptors to intracellular targets. Although various signals are routed through the ERK pathway, cells respond accordingly to a given stimulus. To regulate proper signal transduction, scaffolds and adaptors are employed to organize specific signaling units. The scaffold protein MP1 (MEK1 partner) assembles a scaffold complex in the ERK cascade. We show that p14 functions as an adaptor protein, which is required and sufficient to localize MP1 to endosomes. Reduction of MP1 or p14 protein levels by siRNAi results in defective signal transduction. Therefore, our results suggest that the endosomal localization of the p14/MP1-MAPK scaffold complex is crucial for signal transduction.
 ...
PMID:Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction. 1247 6

Following observations that curcumin inhibited proliferation (IC(50)=1-5 microM), invasiveness and progression through S/G2/M phases of the cell cycle in the non-tumourigenic HBL100 and tumourigenic MDA-MB-468 human breast cell lines, it was noted that apoptosis was much more pronounced in the tumour line. Therefore, the ability of curcumin to modulate signalling pathways which might contribute to cell survival was investigated. After pre-treatment of cells for 20 min, curcumin (40 microM) inhibited EGF-stimulated phosphorylation of the EGFR in MDA-MB-468 cells and phosphorylation of extracellular signal regulated kinases (ERKs) 1 and 2, as well as ERK activity and levels of nuclear c-fos in both cell lines. At a lower dose (10 microM), it also inhibited the ability of anisomycin to activate JNK, resulting in decreased c-jun phosphorylation, although it did not inhibit JNK activity directly. In contrast, the activation of p38 mitogen activated protein kinase (MAPK) by anisomycin was not inhibited. Curcumin inhibited basal phosphorylation of Akt/protein kinase B (PKB) in both cell lines, but more consistently and to a greater extent in the MDA-MB-468 cells. The MAPK kinase (MKK) inhibitor U0126 (10 microM), while preventing ERK phosphorylation in MDA-MB-468 cells, did not induce apoptosis. The PI3K inhibitor LY294002 (50 microM) inhibited PKB phosphorylation in both cells lines, but only induced apoptosis in the MDA-MB-468 line. These results suggest that while curcumin has several different molecular targets within the MAPK and PI3K/PKB signalling pathways that could contribute to inhibition of proliferation and induction of apoptosis, inhibition of basal activity of Akt/PKB, but not ERK, may facilitate apoptosis in the tumour cell line.
 ...
PMID:Relevance of mitogen activated protein kinase (MAPK) and phosphotidylinositol-3-kinase/protein kinase B (PI3K/PKB) pathways to induction of apoptosis by curcumin in breast cells. 1252 29

Experience-dependent remodeling of the postsynaptic density (PSD) is critical for synapse formation and plasticity in the mammalian brain. Here, in cultured rat hippocampal neurons, I found long-lasting, global changes in the molecular composition of the PSD dictated by synaptic activity. These changes were bidirectional, reversible, modular, and involved multiple classes of PSD proteins. Moreover, activity-dependent remodeling was accompanied by altered protein turnover, occurred with corresponding increases or decreases in ubiquitin conjugation of synaptic proteins and required proteasome-mediated degradation. These modifications, in turn, reciprocally altered synaptic signaling to the downstream effectors CREB (cyclic AMP response element binding protein) and ERK-MAPK (extracellular signal regulated kinase-MAP kinase). These results indicate that activity regulates postsynaptic composition and signaling through the ubiquitin-proteasome system, providing a mechanistic link between synaptic activity, protein turnover and the functional reorganization of synapses.
 ...
PMID:Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. 3025 Feb 64

Disruption of actin filaments affects multiple cell functions including motility, signal transduction and cell division, ultimately culminating in cell death. Although this is the usual sequence of events, we have made the interesting observation that disruption of actin filaments by the potent toxin cytochalasin D (Cyto D) causes one cell type, mouse mesangial cells (MMC), to undergo apoptosis, while in another cell type (NIH 3T3), it has the opposite effect, resulting in production of survival signals. The purpose of this study was to investigate the molecular basis for these observed differences. In the present communication, we demonstrate that exposure to Cyto D induces the pro-apoptotic pathways, p38 and stress-activated protein kinase (SAPK)/jun amino-terminal kinase (JNK), in both cell types. However, in 3T3, but not MMC, the extracellular signal regulated kinase (ERK) 1/2 pathway is protected from inhibition following treatment with Cyto D-leading to phosphorylation of Bclxi/Bcl 2-associated death promoter (BAD). Inhibition of Cyto D-induced secretion and activation of gelatinase A in 3T3 cells reverses the production of survival signals by Cyto-D. To investigate this effect further we employed CS-1 cells, a well-characterized melanoma cell line that lacks integrin beta3, and also does not secrete gelatinase A. Co-transfection of CS-1 cells with integrin beta3 and a gelatinase A transgene, which enables the cells to secrete constituitively active gelatinase A, enhances CS-1 cell survival signals. Together, our findings suggest that extracellularly activated gelatinase A, through interaction with integrin alphaVbeta3, elicits survival signals mediated through ERK 1/2 that override activation of p38 and SAPK/JNK stress pathways.
 ...
PMID:Cytochalasin D disruption of actin filaments in 3T3 cells produces an anti-apoptotic response by activating gelatinase A extracellularly and initiating intracellular survival signals. 1258 69

Shc is a prototype adapter protein that is expressed from the earliest stages of T-cell development. Shc becomes rapidly tyrosine phosphorylated after T-cell receptor (TCR) engagement. Expression of dominant negative forms of Shc in T-cell lines had also suggested a role for this adapter downstream of the TCR. However, until recently, the relative significance of Shc compared to several other adapters in T cells was unclear. Mice lacking Shc expression specifically in the T-cell lineage together with inducible expression of dominant negative Shc in transgenic mice have revealed an essential and nonredundant role for Shc in thymic T-cell development. Functional defects in a Jurkat T-cell line lacking Shc expression also suggest a role for Shc in mature T-cell functions. While the requirement of Shc in T-cell signaling is now established, precisely what signaling pathways downstream of Shc make this adapter unique are less clear. Although the Shc-mediated activation of the extracellular signal regulated kinase (Erk)/mitogen-activated protein kinase (MAPK) pathway could be one component, Shc likely signals to other pathways in T cells that are not yet discovered. A better molecular understanding of Shc function in the future could provide insights into how multiple adapters coordinate the various outcomes downstream of the TCR.
 ...
PMID:Role of Shc in T-cell development and function. 1261 60

We investigated the activation of mitogen-activated protein kinases (MAPKs) pathways by purinergic stimulation in cardiac myocytes from adult rat hearts. ATPgammaS increased the phosphorylation (activation) of the extracellular signal regulated kinase 1 and 2 (ERK1/2) and p38 MAPK. ERK1/2 and p38 MAPK activation was differential, ERK1/2 being rapid and transient while that of p38 MAPK slow and sustained. Using selective inhibitors, activation of ERK1/2 was shown to involve protein kinase C and MEK1/2 while that of p38 MAPK was regulated by both protein kinase C and protein kinase A. Furthermore, we show that purinergic stimulation induces the phosphorylation of the MAPK downstream target, mitogen- and stress-activated protein kinase 1 (MSK1), in cardiac myocytes. The time course of MSK1 phosphorylation closely follows that of ERK activation. Inhibitors of the ERK and p38 MAPK pathways were tested on the phosphorylation of MSK1 at two different time points. The results suggest that ERKs initiate the response but both ERKs and p38 MAPK are required for the maintenance of the complete phosphorylation of MSK1. The temporal relationship of MSK1 phosphorylation and cPLA2 translocation induced by purinergic stimulation, taken together with previous findings, is an indication that cPLA2 may be a downstream target of MSK1.
 ...
PMID:Regulation of MAPK pathways in response to purinergic stimulation of adult rat cardiac myocytes. 1261 79

The MAP Kinase pathway is a key signalling mechanism that regulates many cellular functions such as cell growth, transformation and apoptosis. One of the essential components of this pathway is the serine/threonine kinase, Raf. Raf (MAPKK kinase, MAPKKK) relays the extracellular signal from the receptor/Ras complex to a cascade of cytosolic kinases by phosphorylating and activating MAPK/ERK kinase (MEK; MAPK kinase, MAPKK) that phosphorylates and activates extracellular signal regulated kinase (ERK; mitogen-activated protein kinase, MAPK), which phosphorylates various cytoplasmic and nuclear proteins. Regulation of both Ras and Raf is crucial in the proper maintenance of cell growth as oncogenic mutations in these genes lead to high transforming activity. Ras is mutated in 30% of all human cancers and B-Raf is mutated in 60% of malignant melanomas. The mechanisms that regulate the small GTPase Ras as well as the downstream kinases MEK and extracellular signal regulated kinase (ERK) are well understood. However, the regulation of Raf is complex and involves the integration of other signalling pathways as well as intramolecular interactions, phosphorylation, dephosphorylation and protein-protein interactions. From studies using mammalian isoforms of Raf, as well as C. elegans lin45-Raf, common patterns and unique differences of regulation have emerged. This review will summarize recent findings on the regulation of Raf kinase.
 ...
PMID:Mechanisms of regulating the Raf kinase family. 1263 9

Secretin evokes catecholamine secretion from PC12 pheochromocytoma cells. We tested whether secretin activates transcription of the major vesicular core protein chromogranin A (CgA). Secretin stimulated both endogenous CgA gene transcription (approximately 4-6-fold) as well as transfected CgA promoter activity (approximately 8-10-fold; EC50, approximately 7 nm) in PC12 cells. Studies on CgA promoter 5'-deletion mutant/luciferase reporter constructs, point mutations of the CgA cAMP response element (CRE), and their transfer to a heterologous promoter implicated CRE in cis as both necessary and sufficient for secretin-stimulated CgA gene transcription. Secretin-induced CgA gene transcription was inhibited/abolished by cytosolic Ca2+ chelation, chemical blockade of phospholipase C, protein kinase A (PKA), or mitogen-activated protein (MAP) kinase extracellular signal regulated kinase (ERK) 1/2 and the expression of dominant negative mutants of ERK1/2, CRE binding protein (CREB) kinase RSK2, or CREB. Secretin also augmented (approximately 4-fold) phosphorylation of ERK1/2. Trans-activation (approximately 21-fold) of GAL4-CREB fusion protein by secretin indicates involvement of CREB in secretin signaling to gene transcription. Electrophoretic mobility shift assays also identified CREB as the mediator of secretin-induced CgA gene transcription, and pCREB supershifts indicated Ser-133 as the active CREB moiety in vitro. This conclusion was reinforced in vivo by results of chromatin pCREB immunoprecipitation assays. We conclude that secretin signals to CgA gene transcription through the CRE domain in cis and through cAMP, Ca2+, PKA, MAP kinase, and the transcription factor CREB in trans. Thus, multiple signal transduction pathways seem to subserve the function of stimulus-transcription coupling after this peptidergic stimulus to chromaffin cells.
 ...
PMID:Secretin activation of chromogranin A gene transcription. Identification of the signaling pathways in cis and in trans. 1264 81

Mixed lineage kinases (MLKs) belong to the family of mitogen activated protein kinase kinase kinase (MAPKKK) and cause neuronal cell death mediated through c-Jun, N-terminal kinase (JNK) pathway. Recently, genetic studies in Drosophila revealed the presence of an MLK termed slipper (slpr). However, its biochemical features like physiological substrate, role in different MAPK pathways and developmental and tissue-specific expression pattern were not reported. Here, we report cDNA cloning, expression analysis and biochemical characterization of a Drosophila mixed lineage kinase (dMLK) that is also known as slipper. The protein structure analysis of dMLK/slipper revealed, in addition to the conserved domains, a stretch of glutamine in the amino terminus and an asparagine-threonine stretch at the carboxy-terminus. In situ hybridization and reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that dMLK is expressed in early embryonic stages, adult brain and thorax. Ectopic expression of dMLK either in Drosophila S2 or in mammalian HEK293 cells leads to activation of JNK, p38 and extracellular signal regulated kinase (ERK) pathways. Further, dMLK directly phosphorylates Hep, dMKK4 and also their mammalian counterparts, MKK7 and SEK1, in an in vitro kinase assay. Taken together, our results provide for the first time a comprehensive expression profile and new biochemical insight of dMLK/slipper.
 ...
PMID:Drosophila mixed lineage kinase/slipper, a missing biochemical link in Drosophila JNK signaling. 1267 57

Multidrug resistant (MDR) cancer cells overexpressing P-glycoprotein (P-gp) display variations in invasive and metastatic behavior. We previously reported that these properties of MDR cancer cell lines overexpressing P-gp could be altered by chemotherapeutic drugs or MDR modulators (R. S. Kerbel et al., Cancer Surv., 7: 597-629, 1988). To attempt to clarify the mechanism(s) underlying these observations, we studied the expression of extracellular matrix metalloproteinase inducer (EMMPRIN), a glycoprotein enriched on the surface of tumor cells that can stimulate the production of matrix metalloproteinases (MMPs), in sensitive and MDR cancer cells. Using immunofluorescence staining and fluorescence-activated cell sorting analysis, we found that EMMPRIN expression was increased in MDR carcinoma cell lines, MCF-7/AdrR, KBV-1, and A2780Dx5, as compared to their parental counterparts. The MDR cell lines produced more matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9), as determined by zymography, Western blot, and reverse transcription-PCR. Treatment of MDR cells with an anti-EMMPRIN antibody inhibited the activity of MMP-1, MMP-2, and MMP-9. In MDR cell line MCF-7/AdrR, an increased in vitro invasive ability was observed as compared with the sensitive line MCF-7, and EMMPRIN antibody could inhibit the in vitro invasion in drug-resistant cells. In addition, the expression and activity of MMP-1, MMP-2, and MMP-9 in MDR cells were decreased by treatment with U-0126, an inhibitor of mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/Erk). Our results suggest that during the development of MDR, the expression of EMMPRIN is responsible for the increased activity of MMP in MDR cell lines.
 ...
PMID:Overexpression of extracellular matrix metalloproteinase inducer in multidrug resistant cancer cells. 1269 61


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