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)

Using primary cultures of neonatal rat ventricular myocytes and isolated adult rat hearts as models, we have characterized extensively the regulation of MAPKs in the heart. The ERKs are activated primarily by GPCR agonists acting through PKC. These agonists can also activate the JNKs although the mechanism is unclear. Cellular stresses stimulate strong activation of the JNKs, but also cause some stimulation of ERKs. Activation of p38-MAPK has so far only been demonstrated in intact adult hearts subjected to stresses and probably leads to activation of MAPKAPK2. Both cellular stresses and GPCR agonists induce phosphorylation of c-Jun, but only the latter causes upregulation of c-Jun protein.
 ...
PMID:Regulation of mitogen-activated protein kinase cascades in the heart. 976 48

The last few years have seen a marked expansion in appreciation of the diversity of roles played by the betaArrestins in regulating GPCR functions. Originally discovered as molecules that desensitize such receptors, the roles of betaArrestins have expanded to include acting as signalling adapters or intermediates that recruit other key molecules to the GPCRs in an agonist-regulated fashion. For example, interactions with components of the endocytic machinery, such as clathrin, the adapter protein AP-2 and the N-ethylmaleimide sensitive fusion protein (NSF), demonstrate the ability of betaArrestins to act as adapters to facilitate the clathrin-mediated endocytosis of certain members of the GPCR family. BetaArrestins have also been shown to serve as signalling molecules. The Ras-dependent activation of ERK1/2 may involve the betaArrestin-dependent recruitment of c-Src to the beta2-adrenergic receptor (beta2-AR). More recently, betaArrestins have been shown to act as molecular scaffolds that coordinate the assembly of certain MAP kinase complexes that lead to the stimulation of either ERK1/2 or JNK3. Finally, long-term accumulation of arrestin-rhodopsin complexes, in photoreceptor cells has been shown to trigger apoptosis.
 ...
PMID:Beta-Arrestins: new roles in regulating heptahelical receptors' functions. 1160 78

Sphingosine-1-phosphate (SPP), formed by sphingosine kinase, is the ligand for EDG-1, a GPCR important for cell migration and vascular maturation. Here we show that cytoskeletal rearrangements, lamellipodia extensions, and cell motility induced by platelet-derived growth factor (PDGF) are abrogated in EDG-1 null fibroblasts. However, EDG-1 appears to be dispensable for mitogenicity and survival effects, even those induced by its ligand SPP and by PDGF. Furthermore, PDGF induced focal adhesion formation and activation of FAK, Src, and stress-activated protein kinase 2, p38, were dysregulated in the absence of EDG-1. In contrast, tyrosine phosphorylation of the PDGFR and activation of extracellular signal regulated kinase (ERK1/2), important for growth and survival, were unaltered. Our results suggest that EDG-1 functions as an integrator linking the PDGFR to lamellipodia extension and cell migration. PDGF, which stimulates sphingosine kinase, leading to increased SPP levels in many cell types, also induces translocation of sphingosine kinase to membrane ruffles. Hence, recruitment of sphingosine kinase to the cell's leading edge and localized formation of SPP may spatially and temporally stimulate EDG-1, resulting in activation and integration of downstream signals important for directional movement toward chemoattractants, such as PDGF. These results may also shed light on the vital role of EDG-1 in vascular maturation.
 ...
PMID:EDG-1 links the PDGF receptor to Src and focal adhesion kinase activation leading to lamellipodia formation and cell migration. 1172 41

Kaposi's sarcoma-associated herpes virus (KSHV) infects B cells and microvascular endothelium,and is linked to both lymphoid and endothelial neoplasms. KSHV encodes a G protein-coupled receptor (v-GPCR) that can bind several CC and CXC chemokines but is able to signal in the absence of known ligands. This signaling can transform cultured fibroblasts, promote angiogenesis in vitro and in vivo, and activate the mitogen-activated protein kinase, c-Jun-NH(2)-terminal kinase, and p38 pathways. To assess the potential impact of v-GPCR signaling on host cell biology we have examined cellular gene expression in v-GPCR-transfected cells using DNA microarrays. v-GPCR expression up-regulated numerous cellular transcripts in both BJAB B cells and SLK endothelial cells, but with a remarkable degree of cell-type specificity. Among the most highly regulated genes in endothelial cells were the cytokines interleukin 6 and GRO alpha; several genes affecting endothelial/vascular growth and remodeling were also induced, including plasminogen, thrombomodulin, the urokinase-type plasminogen activator receptor, and to a modest extent vascular endothelial growth factor C. By contrast, the most highly regulated genes in B cells were the CC chemokines macrophage inflammatory protein 1 alpha and macrophage inflammatory protein 1 beta. No genes other than members of the dual-specificity phosphatase family were induced in both cell lines. The results indicate that the effects of KSHV GPCR expression in these two target cell types differ considerably and suggest that signaling by this molecule may make different contributions to the pathogenesis of KSHV-related endothelial and lymphoproliferative lesions.
 ...
PMID:Modulation of host gene expression by the constitutively active G protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus. 1215 65

The small GTPases Ras or Rap1 were suggested to mediate the stimulatory effect of some G protein-coupled receptors on ERK activity in neuronal cells. Accordingly, we reported here that pituitary adenylate cyclase-activating polypeptide (PACAP), whose G protein-coupled receptor triggers neuronal differentiation of the PC12 cell line via ERK1/2 activation, transiently activated Ras and induced the sustained GTP loading of Rap1. Ras mediated peak stimulation of ERK by PACAP, whereas Rap1 was necessary for the sustained activation phase. However, PACAP-induced GTP-loading of Rap1 was not sufficient to account for ERK activation by PACAP because 1) PACAP-elicited Rap1 GTP-loading depended only on phospholipase C, whereas maximal stimulation of ERK by PACAP also required the activity of protein kinase A (PKA), protein kinase C (PKC), and calcium-dependent signaling; and 2) constitutively active mutants of Rap1, Rap1A-V12, and Rap1B-V12 only minimally stimulated the ERK pathway compared with Ras-V12. The effect of Rap1A-V12 was dramatically potentiated by the concurrent activation of PKC, the cAMP pathway, and Ras, and this potentiation was blocked by dominant-negative mutants of Ras and Raf. Thus, this set of data indicated that GPCR-elicited GTP loading of Rap1 was not sufficient to stimulate efficiently ERK in PC12 cells and required the permissive co-stimulation of PKA, PKC, or Ras.
 ...
PMID:Stimulation of the ERK pathway by GTP-loaded Rap1 requires the concomitant activation of Ras, protein kinase C, and protein kinase A in neuronal cells. 1247 65

Signal transduction research investigating mechanisms of androgen-independent prostate cancer cell proliferation has historically focused on the role of androgen and peptide growth factor receptors. More recent work has raised the idea that intracellular signaling mechanisms triggered by extracellular hormonal factors acting through heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) can also mediate and sustain this pathologic process. Prostate cancer patients with advanced disease express elevated levels of GPCRs and GPCR ligands, suggesting that the GPCR system is activated in the cancerous gland and may contribute to tumor growth. Importantly, inhibition of G protein signaling attenuates prostate cancer cell growth in animal models. The nature of intracellular signaling pathways mediating mitogenic effects of GPCRs in prostate cancer is poorly defined, although the G protein-dependent activation of the Ras-to-mitogen-activated protein kinase pathway has emerged as a critical regulatory event. Activated GPCRs may also exert their mitogenic effects in the prostate by activating the androgen receptor.
 ...
PMID:G proteins in cancer: the prostate cancer paradigm. 1473 86

Because of their central role in the cellular response to growth factors, assays of MAP kinase activity are commonly used in pharmaceutical screening efforts aimed at detecting chemical modifiers of growth regulatory pathways. As our understanding of the complexity of signal transduction networks expands, however, it is becoming apparent that previously unappreciated temporal and contextual factors have profound effects on MAP kinase function. This is exemplified by recent studies of the regulation of the ERK1/2 MAP kinase cascade by GPCRs. Depending on receptor and cell type, GPCR stimulation of ERK1/2 can reflect a heterogenous array of signaling events. Activation of second messenger-dependent protein kinases and cross talk between GPCRs and receptor or nonreceptor tyrosine kinases can all induce ERK1/2 activation. Furthermore, a growing body of data indicates that the mechanism of ERK1/2 activation is a major determinant of ERK1/2 function. Activation of a nuclear pool of ERK1/2 as a consequence of cross talk between GPCRs and growth factor receptor tyrosine kinases may provide a mitogenic stimulus. In contrast, activation of ERK1/2 in localized pools on the membrane or confined to endosomal vesicles through the utilization of focal adhesions or beta-arrestins as "scaffolds" may spatially constrain ERK1/2 activity and favor the phosphorylation of nonnuclear ERK substrates. Findings such as these suggest that screening strategies that use single readouts of MAP kinase activity or function are likely to miss important signaling events, and point to the need for a multidimensional approach to MAP kinase-based screening efforts.
 ...
PMID:Signaling in time and space: G protein-coupled receptors and mitogen-activated protein kinases. 1509 Jan 98

HHV-8-GPCR is a chemokine-like receptor encoded by KSHV, the etiologic agent of KS. HHV-8-GPCR is constitutively active. Although it is homologous to mammalian CXCR2, it binds CXC and CC chemokines. Structure-function analysis showed that chemokines bind primarily to the amino terminus whereas signaling occurs in the absence of: the amino terminus, which is, therefore, not a tethered agonist. In in vitro systems, HHV-8-GPCR signals via multiple transduction pathways including, activation of phospholipase C and PKC, inhibition of adenylyl cyclase, activation of nuclear factor-kappaB; activation PI 3-kinase, p42/44 MAPK and Akt/PKB, and activation of JNK/SAPK, p38 MAPK and RAFTK. HHV-8-GPCR is important in the HHV-8 life cycle because HHV-8-GPCR-deficient viruses do not replicate in response to chemokines and exhibit, less efficient reactivation from latency. Although the role of HHV-8-GPCR in the pathogenesis of KS has not been defined, expression of HHV-8-GPCR resulted in the development of angioproliferative, KS-like tumors in transgenic mice. As endothelial cells may be targets of HHV-8 infection, HHV-8-GPCR has been studied in endothelial cells in vitro in which it affects cell adhesion and migration, increases cell survival, and stimulates secretion of proinflammatory cytokines and proangiogenic factors. Based on these findings and the observation that HHV-8-GPCR is expressed in only a few endothelial- like "spindle cells" within KS lesions, we propose that HHV-8-GPCR is involved in KS pathogenesis by stimulating secretion of proinflammatory/proangiogenic factors that act in a paracrine fashion to cause tumorigenesis.
 ...
PMID:Insights into the viral G protein-coupled receptor encoded by human herpesvirus type 8 (HHV-8). 1520 3

We have shown previously that LPPs (lipid phosphate phosphatases) reduce the stimulation of the p42/p44 MAPK (p42/p44 mitogen-activated protein kinase) pathway by the GPCR (G-protein-coupled receptor) agonists S1P (sphingosine 1-phosphate) and LPA (lysophosphatidic acid) in serum-deprived HEK-293 cells [Alderton, Darroch, Sambi, McKie, Ahmed, N. J. Pyne and S. Pyne (2001) J. Biol. Chem. 276, 13452-13460]. In the present study, we now show that this can be blocked by pretreating HEK-293 cells with the caspase 3/7 inhibitor, Ac-DEVD-CHO [N-acetyl-Asp-Glu-Val-Asp-CHO (aldehyde)]. Therefore LPP2 and LPP3 appear to regulate the apoptotic status of serum-deprived HEK-293 cells. This was supported further by: (i) caspase 3/7-catalysed cleavage of PARP [poly(ADP-ribose) polymerase] was increased in serum-deprived LPP2-overexpressing compared with vector-transfected HEK-293 cells; and (ii) serum-deprived LPP2- and LPP3-overexpressing cells exhibited limited intranucleosomal DNA laddering, which was absent in vector-transfected cells. Moreover, LPP2 reduced basal intracellular phosphatidic acid levels, whereas LPP3 decreased intracellular S1P in serum-deprived HEK-293 cells. LPP2 and LPP3 are constitutively co-localized with SK1 (sphingosine kinase 1) in cytoplasmic vesicles in HEK-293 cells. Moreover, LPP2 but not LPP3 prevents SK1 from being recruited to a perinuclear compartment upon induction of PLD1 (phospholipase D1) in CHO (Chinese-hamster ovary) cells. Taken together, these data are consistent with an important role for LPP2 and LPP3 in regulating an intracellular pool of PA and S1P respectively, that may govern the apoptotic status of the cell upon serum deprivation.
 ...
PMID:Regulation of cell survival by lipid phosphate phosphatases involves the modulation of intracellular phosphatidic acid and sphingosine 1-phosphate pools. 1596 Jun 10

We have previously shown that the PDGFbeta receptor uses a classical GPCR-mediated pathway in order to induce efficient activation of p42/p44 MAPK in response to PDGF. We therefore, considered the possibility that GTPase accelerating proteins (RGS proteins), which regulate GPCR signalling, modulate PDGFbeta receptor-mediated signal transmission. Several lines of evidence were obtained to support functional interaction between the PDGFbeta receptor and RGS12 in HEK 293 and airway smooth muscle cells. Firstly, the over-expression of the RGS12 PDZ/PTB domain N-terminus or RGS12 PTB domain reduced the PDGF-induced activation of p42/p44 MAPK. Secondly, the RGS12 PDZ/PTB domain N-terminus and RGS12 PDZ domain can form a complex with the PDGFbeta receptor. Therefore, the results presented here provide the first evidence to support the concept that the PDZ/PTB domain N-terminus and/or the PTB domain of RGS12 may modulate PDGFbeta receptor signalling. In airway smooth muscle cells, over-expressed recombinant RGS12 and the isolated PDZ/PTB domain N-terminus co-localised with PDGFbeta receptor in cytoplasmic vesicles. To provide additional evidence for a role of the PDZ/PTB domain N-terminus, we used RGS14. RGS14 has the same C-terminal domain architecture of an RGS box, tandem Ras-binding domains (RBDs) and GoLoco motif as RGS12, but lacks the PDZ/PTB domain N-terminus. In this regard, RGS14 exhibited a different sub-cellular distribution compared with RGS12, being diffusely distributed in ASM cells. These findings suggest that RGS12 via its PDZ/PTB domain N-terminus may regulate trafficking of the PDGFbeta receptor in ASM cells.
 ...
PMID:The effect of RGS12 on PDGFbeta receptor signalling to p42/p44 mitogen activated protein kinase in mammalian cells. 1621 5


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