Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bidirectional signalling, i.e. simultaneous signalling through a receptor as well as its cell surface-bound ligand has been identified for several members of the TNF and TNF receptor family members. Reverse signalling through the ligands offers the advantage of an immediate feed-back and a more precise fine tuning of biological responses. Little is known about the molecular nature of reverse signalling through the ligands. CD137 ligand, member of the TNF family is expressed on monocytes and induces activation, migration, prolongation of survival and proliferation of monocytes. Here we show that reverse signalling by CD137 ligand is mediated by protein tyrosine kinases, p38 mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1,2, MAP/ERK kinase (MEK), Phosphoinositide-3-kinase (PI3-K) and protein kinase A (PKA) but not by protein kinase C (PKC). This study also shows that reverse signalling relies on the same signal transduction molecules as signalling through classical receptors and is in its nature not different from it.
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PMID:Signal transduction mechanisms of CD137 ligand in human monocytes. 1785 13

Neuropilin-1 (Np-1), a receptor for semaphorin 3A and vascular endothelial growth factor, is expressed at high levels in pancreatic ductal adenocarcinoma (PDAC). To assess the potential role of Np-1 in PDAC, COLO-357 pancreatic cancer cells, which express relatively low levels of Np-1, were stably transfected with the Np-1 cDNA. Np-1 overexpression was associated with enhanced cell invasiveness in response to hepatocyte growth factor (HGF), and this effect was abolished by small interfering RNA-mediated down-regulation of c-Met. Conversely, in PANC-1 pancreatic cancer cells, which express relatively high levels of Np-1, suppression of endogenous Np-1 completely abolished HGF-mediated cell invasion. To determine which pathways are involved in Np-1-mediated facilitation of c-Met-dependent cell invasiveness, the effects of HGF on signaling were examined next in sham-transfected and Np-1-overexpressing COLO-357 cells. HGF actions on c-Met tyrosine phosphorylation and p38 mitogen-activated protein kinase (MAPK) activation were increased in Np-1-overexpressing COLO-357 cells by comparison with HGF effects in sham-transfected cells. SB203580, an inhibitor of p38 MAPK, suppressed HGF-induced invasion in Np-1-overexpressing cells, whereas U0126, a MAP/extracellular signal-regulated kinase kinase inhibitor, was without effect. PP2, a Src inhibitor, and LY294002, a phosphatidylinositol 3-kinase inhibitor, also suppressed HGF-induced invasion in these cells. Immunoprecipitation studies revealed that Np-1 associated with c-Met, but not with epidermal growth factor receptor, family members. Confocal microscopy indicated that this association occurred on the plasma membrane and that HGF promoted the internalization of Np-1-c-Met complex, leading to its perinuclear localization. These findings indicate that Np-1 is required for efficient activation of c-Met-dependent pathways that promote cell invasiveness.
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PMID:Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. 1797 73

The intracellular signaling pathways mediating the neurotrophic actions of pituitary adenylate cyclase-activating polypeptide (PACAP) were investigated in human neuroblastoma SH-SY5Y cells. Previously, we showed that SH-SY5Y cells express the PAC(1) and VIP/PACAP receptor type 2 (VPAC(2)) receptors, and that the robust cAMP production in response to PACAP and vasoactive intestinal peptide (VIP) was mediated by PAC(1) receptors (Lutz et al. 2006). Here, we investigated the ability of PACAP-38 to differentiate SH-SY5Y cells by measuring morphological changes and the expression of neuronal markers. PACAP-38 caused a concentration-dependent increase in the number of neurite-bearing cells and an up-regulation in the expression of the neuronal proteins Bcl-2, growth-associated protein-43 (GAP-43) and choline acetyltransferase: VIP was less effective than PACAP-38 and the VPAC(2) receptor-specific agonist, Ro 25-1553, had no effect. The effects of PACAP-38 and VIP were blocked by the PAC(1) receptor antagonist, PACAP6-38. As observed with PACAP-38, the adenylyl cyclase activator, forskolin, also induced an increase in the number of neurite-bearing cells and an up-regulation in the expression of Bcl-2 and GAP-43. PACAP-induced differentiation was prevented by the adenylyl cyclase inhibitor, 2',5'-dideoxyadenosine (DDA), but not the protein kinase A (PKA) inhibitor, H89, or by siRNA-mediated knock-down of the PKA catalytic subunit. PACAP-38 and forskolin stimulated the activation of extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAP; p38 MAP kinase) and c-Jun N-terminal kinase (JNK). PACAP-induced neuritogenesis was blocked by the MEK1 inhibitor PD98059 and partially by the p38 MAP kinase inhibitor SB203580. Activation of exchange protein directly activated by cAMP (Epac) partially mimicked the effects of PACAP-38, and led to the phosphorylation of ERK but not p38 MAP kinase. These results provide evidence that the neurotrophic effects of PACAP-38 on human SH-SY5Y neuroblastoma cells are mediated by the PAC(1) receptor through a cAMP-dependent but PKA-independent mechanism, and furthermore suggest that this involves Epac-dependent activation of ERK as well as activation of the p38 MAP kinase signaling pathway.
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PMID:PACAP-38 induces neuronal differentiation of human SH-SY5Y neuroblastoma cells via cAMP-mediated activation of ERK and p38 MAP kinases. 1799 38

Although a large number of signalling cascades are known to be activated downstream of NCAM, only little is known regarding the hierarchical relationship between the involved molecules in the individual cascades and the level of cross talk between the cascades. Here, we evaluated the requirement of putative upstream signalling cascades for the phosphorylation of the kinases extracellular signal-regulated kinase (ERK) and Akt and the transcription factor cyclic adenosine monophosphate (cAMP) response-element binding protein (CREB) following stimulation of NCAM in rat cerebellar granule neurons with an NCAM ligand, the C3d peptide. NCAM-mediated ERK phosphorylation depended on activation of the fibroblast growth factor receptor (FGFR), Src-family kinases, MEK (MAP and ERK kinase) and G(0)/G(i)-proteins, whereas NCAM-mediated CREB phosphorylation depended on the activity of Src-family kinases and MEK. NCAM-specific Akt phosphorylation depended on cyclic guanosine monophosphate (cGMP) and phosphatidylinositide 3-kinase (PI3K). All three phosphorylation events were independent of activation of the signalling molecules phospholipase C, protein kinase C, protein kinase A, and CamKII, which all have been demonstrated previously to be involved in NCAM signalling. For comparison, we also evaluated the role of upstream signalling cascades on fibroblast growth factor 2 (FGF2)-mediated phosphorylation of ERK, Akt, and CREB and found that FGF2 required the activity of both FGFR and Src-family kinases for phosphorylation of ERK, Akt, and CREB. MEK was required for phosphorylation of ERK and CREB, but not Akt, whereas G(0)/G(i)-proteins were necessary for phosphorylation of Akt and CREB, and cGMP was necessary for Akt phosphorylation. We thus demonstrate that even though NCAM and FGF2 have many signalling features in common, and even though both are known to activate FGFR, there are a number of differences in the intracellular signalling network activated by the NCAM ligand C3d and the FGFR ligand FGF2.
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PMID:Relative role of upstream regulators of Akt, ERK and CREB in NCAM- and FGF2-mediated signalling. 1865 13

Alzheimer disease (AD) is a chronic neurodegenerative disease that is characterized by progressive memory loss. Pathological markers of AD include neurofibrillary tangles, accumulation of amyloid-beta plaques, neuronal loss, and inflammation. The exact events that lead to the neuronal dysfunction and loss are not completely understood. However, pro-inflammatory cytokines, such as interleukin-1beta, interleukin-6, and tumor necrosis factor alpha, are increased in AD, along with gene expression of major histocompatibility complex (MHC) class II molecules and macrophage migration inhibitory factor (MIF). MHC class II molecules are found in microglia of the brain, while MIF is found in both microglia and neurons of the hypothalamus, hippocampus, and cortex. MIF is not only a lymphocyte mediator but also a pituitary factor with endocrine properties and can mediate phosphorylation of the extracellular signal-regulated kinase-1/2 MAP kinases pathway. In this study, we looked at CD74, an integral membrane protein that acts as both a chaperone for MHC class II molecules as well as a receptor binding site for MIF. CD74 was recently found to be increased in microglia in AD cases compared to age-matched controls, but has not been reported in neurons. In our analysis, immunohistochemistry revealed a significant increase in CD74 primarily in neurofibrillary tangles, amyloid-beta plaques, and microglia. This is the first finding to our knowledge that CD74 is increased in neurons of AD cases compared to age-matched control cases.
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PMID:Expression of CD74 is increased in neurofibrillary tangles in Alzheimer's disease. 1878 68

Oncogenic activating mutations in the cytosolic serine/threonine kinase, BRAF, have been reported in a variety of neoplasms. BRAF relays signals from membrane-bound RAS downstream through the MAP/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) signaling pathway. The presence of BRAF activating mutations suggests the importance of the MAP/ERK kinase pathway for tumor growth and points to possible therapeutic interventions. Recently, BRAF mutations were reported to characterize a series of prostate adenocarcinomas. In this study, we used DNA melting analysis with high-resolution technology to screen a series of 93 prostate carcinomas for BRAF mutations. None were found. This suggests that BRAF mutations may not play an important role in the oncogenesis or therapy of prostate adenocarcinoma.
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PMID:Lack of BRAF activating mutations in prostate adenocarcinoma: a study of 93 cases. 1898 52

To elucidate the involvement of the noradrenergic system in the regulation of spinal microglial activity, we examined the effects of noradrenaline (NA) on the phosphorylation of three MAP kinases (extracellular signal-regulated kinase (ERK), p38, or c-Jun N-terminal kinase (JNK)) stimulated by ATP in rat cultured spinal microglia using Western blotting. ATP (100 microM) quickly induced the phosphorylation of three MAP kinases and MKK3/6, which are upstream kinases of p38. Under these conditions, NA inhibited only the ATP-stimulated phosphorylation of p38 in a time (30-60 min)- and dose (10-100 microM)-dependent manner, but did not affect those of ERK, JNK, or MKK3/6. The inhibitory action of NA was completely reversed by pretreatment with propranolol, an antagonist for beta-adrenoceptors, or both atenolol and ICI118551, selective antagonists for beta1 and beta2, respectively. Treatment with dibutyryl cAMP or the selective activator of PKA mimicked the inhibitory effect of NA. Furthermore, treatment with KT5720, an inhibitor of protein kinase A, completely blocked the action of NA. These data suggest that NA could control the activation of p38 through the beta1/2-adrenergic pathways, which include the production of cAMP and the activation of PKA. Simultaneously, we found that NA also markedly inhibited the ATP-induced increase in the expression of tumor necrosis factor (TNF)-alpha mRNA through beta-adrenergic pathways. Furthermore, preincubation with either actinomycin D or cyclohexamide, general inhibitors of transcription or protein synthesis, respectively, almost completely blocked the inhibitory action of NA on the ATP-stimulated phosphorylation of p38. These results suggest that de novo synthesis of certain factors by NA through beta-adrenoceptors would participate in the modulation of p38 activity. Thus, the inhibitory system via beta1/2-adrenergic pathways in spinal microglia appears to have an important role in the modulation of microglial functions through the downregulation of p38 activity.
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PMID:Noradrenaline reduces the ATP-stimulated phosphorylation of p38 MAP kinase via beta-adrenergic receptors-cAMP-protein kinase A-dependent mechanism in cultured rat spinal microglia. 1952 13

Secreted proteins such as growth factors, cytokines, and chemokines play important roles in tumor development. Through expression microarray and bioinformatic analysis, we discovered a novel secreted protein, neuroblastoma-derived secretory protein (NDSP). The NDSP gene is found on chromosome 1q25.2 and encodes a 167 amino acid protein with a putative signal peptide. Using real-time PCR and immunoblotting, we find that NDSP is specifically overexpressed in neuroblastoma at much higher levels than other adult and pediatric malignancies and normal tissues. NDSP is an 18-kDa protein that can be secreted by NDSP-transfected HEK-293T cells, as well as, neuroblastoma cell lines endogenously expressing NDSP. Inhibiting NDSP expression in neuroblastoma cell lines with retrovirally transduced NDSP small hairpin interfering RNA, sh-NDSP, results in decreased cellular proliferation and colony formation. We also find inhibited extracellular signal-regulated kinase (ERK)1/2 phosphorylation in the sh-NDSP cell line. Treating the parental cell line with MAP/ERK kinase 1/2 inhibitors, which diminish ERK1/2 phosphorylation, results in decreased cell proliferation. Culturing these transduced cells with recombinant NDSP, reintroducing NDSP overexpression in the knockdown cell line, or inducing Ras oncogene overexpression for constitutive ERK1/2 activation results in a reversal of the growth-inhibited phenotype and proliferation rates similar to the control cells. In addition, reintroduction of NDSP overexpression in the sh-NDSP cell line results in ERK1/2 phosphorylation similar to control. We conclude that NDSP is specifically overexpressed in neuroblastoma and actively secreted from tumor cells. Furthermore, NDSP serves as a growth factor for neuroblastoma tumor cells through activation of the ERK-mediated proliferation pathway.
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PMID:Neuroblastoma-derived secretory protein is a novel secreted factor overexpressed in neuroblastoma. 1967 56

Gastric cancer is a deadly disease for which current therapeutic options are extremely limited. Vascular endothelial growth factor receptors and platelet-derived growth factor receptors regulate gastric cancer cell proliferation, invasion, and tumor angiogenesis. In the present study, we report that sorafenib therapy effectively inhibited tumor growth and angiogenesis in tumor xenografts. These were associated with reduction in the phosphorylation of vascular endothelial growth factor receptor-2 Tyr951, c-Kit Tyr568/570, platelet-derived growth factor receptor-beta Tyr1021, and Akt Ser473 and Thr308, down-regulation of positive cell cycle regulators, increased apoptosis, and up-regulation of p27. Sorafenib treatment also caused up-regulation of p-c-Raf Ser338 and p-extracellular signal-regulated kinase (ERK) Thr202/Tyr204 in gastric cancer xenografts. The combination of sorafenib and MAP/ERK kinase inhibitor AZD6244 enhances the effectiveness of each compound alone. Potential effect of sorafenib/AZD6244 included increase in proapoptotic Bim. Our data show that MAP/ERK kinase inhibition enhances the antitumor activity of sorafenib in vivo, supporting a rationale for multitargeted suppression of the angiogenesis and ERK signaling network in gastric cancer therapy.
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PMID:AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer. 1972 82

Tissue factor (TF) is the principal trigger of the coagulation cascade and involved in arterial thrombus formation. Platelet-derived growth factor CC (PDGF-CC) is a recently discovered member of the PDGF family released upon platelet activation. This study assesses the impact of PDGF-CC on TF expression in human cells. PDGF-CC concentration-dependently induced TF expression by 2.5-fold in THP-1 cells, by 2.0-fold in human peripheral blood monocytes, by 1.4-fold in vascular smooth muscle cells, and by 2.6-fold in microvascular endothelial cells, but did not affect TF expression in aortic endothelial cells. A similar pattern was observed with PDGF-BB. In contrast, PDGF-AA did not alter TF expression in THP-1 cells. TF whole cell activity was induced following stimulation with PDGF-BB and PDGF-CC in THP-1 cells. Real-time polymerase chain reaction revealed that PDGF-CC induced TF mRNA. PDGF-CC transiently activated p42/44 MAP kinase [extracellular signal-regulated kinase (ERK)], while phosphorylation of the MAP kinases c-Jun NH(2)-terminal kinase (JNK) and p38 remained unaffected. PD98059, a specific inhibitor of ERK phosphorylation, but not the p38 inhibitor SB203580 or the JNK inhibitor SP600125 prevented PDGF-CC induced TF expression in a concentration-dependent manner. The effect of PDGF-CC was antagonized by both PDGF receptor alpha and PDGF receptor beta neutralizing antibodies; in contrast, PDGF-BB was only inhibited by PDGF receptor beta blocking antibody. PDGF receptor alpha and PDGF receptor beta inhibition prevented PDGF-CC-induced ERK phosphorylation. PDGF-CC induces TF expression via activation of alpha/beta receptor heterodimers and an ERK-dependent signal transduction pathway.
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PMID:PDGF-CC induces tissue factor expression: role of PDGF receptor alpha/beta. 1979 51


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