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)

We demonstrated recently that in renal epithelial cells from collecting ducts of Madin-Darby canine kidneys (MDCK), Na(+),K(+), Cl(-) cotransport is inhibited up to 50% by ATP via its interaction with P(2Y) purinoceptors (Biochim. Biophys. Acta 1998. 1369:233-239). In the present study we examined which type of renal epithelial cells possesses the highest sensitivity of Na(+),K(+),Cl(-) cotransport to purinergic regulation. We did not observe any effect of ATP on Na(+),K(+),Cl(-) cotransport in renal epithelial cells from proximal and distal tubules, whereas in renal epithelial cells from rabbit and rat collecting ducts ATP decreased the carrier's activity by approximately 30%. ATP did not affect Na(+),K(+),Cl(-) cotransport in C7 subtype MDCK cells possessing the properties of principal cells but led to approximately 85% inhibition of this carrier in C11-MDCK cells in which intercalated cells are highly abundant. Both C7- and C11-MDCK exhibited ATP-induced IP(3) and cAMP production and transient elevation of [Ca(2+)](i). In contrast to the above-listed signaling systems, ATP-induced phosphorylation of ERK and JNK MAP kinases was observed in C11-MDCK only. Thus, our results reveal that regulation of renal Na(+),K(+),Cl(-) cotransport by P(2Y) receptors is limited to intercalated cells from collecting ducts and indicate the involvement of the MAP kinase cascade in purinergic control of this ion carrier's activity.
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PMID:Purinergic modulation of Na(+),K(+),Cl(-) cotransport and MAP kinases is limited to C11-MDCK cells resembling intercalated cells from collecting ducts. 1056 92

There are at least three distinct MAP kinase signaling modules in mammalian cells, distinguished by the family of kinases (Erk, SAPK/JNK, or p38) that is ultimately activated. Many input signals activate multiple MAP kinase cascades, and the mechanisms that control the specificity of signal output are not well understood. We show that SEK1/MKK4, a MAP kinase kinase proposed to activate SAPK/JNK, is a very potent inhibitor of p54 SAPK beta/JNK3 both in vitro and in vivo if present at equimolar or higher ratios. In contrast SEK can activate SAPK when present in substoichiometric amounts, but this activation is slow, consistent with the rate-limiting step in activation being the dissociation of an inactive SEK:SAPK complex. The N-terminal unique region of SEK is both necessary and partially sufficient for inhibition of SAPK, and is also necessary for activation of SAPK by SEK in vitro. We have also used the p38 MAP kinase and its activator MKK6 to examine the regulatory relationships among different kinases involved in stress responses. We show using purified kinases that inhibitory activity is specific for the combination of SEK and SAPK: SEK can activate but not inhibit p38, and MKK6 can activate but not inhibit SAPK beta and p38. These results reveal a potential mechanism for regulating stress-activated kinases, adding to a growing body of evidence suggesting that MAP kinases are controlled by relatively stable interactions with their activators.
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PMID:Concentration-dependent positive and negative regulation of a MAP kinase by a MAP kinase kinase. 1059 70

MAP kinases have been established to be key regulators of cellular signal transduction systems and are conserved from baker's yeast to human beings. Until now, three major types of mammalian MAP kinases (ERK, p38, and JNK/SAPK) have been reported and extensively studied. Advancement of genomic research as well as homology cloning techniques has revealed that there are several other protein kinase families that are structurally modestly related to those conventional MAP kinases. Indeed, most of them possess the TXY motif characteristic to MAP kinases in their activation loop, and can be regarded as members of the MAP kinase superfamily, yet some of them show closest overall similarity to Cdks. These kinases, all of mammalian origin, include MAK, MRK, MOK, p42KKIALRE, p56KKIAMRE, NLK, DYRK/Mnb, and Prp4. Although most of their physiological roles remain unknown, recent progress starts shedding some light on their functions.
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PMID:Distantly related cousins of MAP kinase: biochemical properties and possible physiological functions. 1060 Apr 95

Two p53-null T lymphoma cell lines proved to be highly sensitive to inhibition of gene expression. With either actinomycin D or cycloheximide, apoptosis commenced within 2 h, as indicated by loss of membrane integrity, degradation of certain proteins (including the phosphatase calcineurin) and DNA fragmentation. These effects were ablated by co-expression of Bcl-2 or co-incubation with the caspase inhibitor Z-VAD-fmk. These results suggest that the apoptotic machinery is in place in these cells but held in check by an unknown labile protein, which probably acts upstream of Bcl-2. Although cycloheximide can activate the JNK or p38 MAP kinases in some cells, neither was implicated here. However, disruption of phosphoinositide 3-kinase signaling may be involved, because the cells were also sensitive to wortmannin. The high sensitivity of the p53-null lymphoma cells to inhibitors of gene expression suggests that such inhibitors might prove useful in the cytotoxic therapy of certain tumors.
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PMID:Interference with gene expression induces rapid apoptosis in p53-null T lymphoma cells. 1063 38

Human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins interact with CD4 and chemokine receptors on T cells to deliver signals that trigger either activation, anergy, or apoptosis. However, the molecular mechanisms driving these responses remain poorly understood. In this study we demonstrate that apoptosis is induced upon HIV-1 envelope binding to the chemokine receptor CXCR4. Cells expressing a mutant form of CXCR4 with a C-terminal deletion were also sensitive to HIV-1 envelope-mediated apoptosis, indicating that the cytoplasmic tail of CXCR4 is not required to induce the apoptotic pathway. The specificity of this process was analyzed using several inhibitors of gp120-CD4-CXCR4 interaction. Monoclonal antibodies directed against the gp120-binding site on CD4 (ST4) and against CXCR4 (MAB173) prevented the apoptotic signal in a dose-dependent manner. The cell death program was also inhibited by SDF-1alpha, the natural ligand of CXCR4, and by suramin, a G protein inhibitor that binds with a high affinity to the V3 loop of HIV-1 gp120 envelope protein. These results highlight the role played by gp120-binding on CXCR4 to trigger programmed cell death. Next, we investigated the intracellular signal involved in gp120-induced apoptosis. This cell death program was insensitive to pertussis toxin and did not involve activation of the stress- and apoptosis-related MAP kinases p38(MAPK) and SAPK/JNK but was inhibited by a broad spectrum caspase inhibitor (z-VAD.fmk) and a relatively selective inhibitor of caspase 3 (z-DEVD.fmk). Altogether, our results demonstrate that HIV induces a caspase-dependent apoptotic signaling pathway through CXCR4.
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PMID:Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type 1 envelope glycoprotein (gp120). 1070 41

Vav and PKCtheta play an early and important role in the TCR/CD28-induced stimulation of MAP kinases and activation of the IL-2 gene. Vav is also essential for actin cytoskeleton reorganization and TCR capping. Here, we report that PKCtheta function was selectively required in a Vav signaling pathway that mediates the TCR/CD28-induced activation of JNK and the IL-2 gene and the upregulation of CD69 expression. Vav also promoted PKCtheta translocation from the cytosol to the membrane and cytoskeleton and induced its enzymatic activation in a CD3/CD28-initiated pathway that was dependent on Rac and on actin cytoskeleton reorganization. These findings reveal that the Vav/Rac pathway promotes the recruitment of PKCtheta to the T cell synapse and its activation, essential processes for T cell activation and IL-2 production.
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PMID:A novel functional interaction between Vav and PKCtheta is required for TCR-induced T cell activation. 1071 81

The c-Jun N-terminal kinases (JNKs, also called stress activated protein kinases. SAPKs) and p38 kinases constitute together with extracellular signal-regulated kinases (ERKs) the family of MAP kinases. Whereas the functions of JNKs under physiological conditions are largely unknown, there is raising evidence that JNKs are potent effectors of apoptosis or degeneration of neurons in vitro and in the brain. The activation of the inducible transcription factor c-Jun by N-terminal phosphorylation is a central event in JNK-mediated degenerative processes that depend on de novo protein synthesis. At the post-translational level, cytoplasmic degenerative actions of JNKs might comprise inhibition of Bcl-2 and steroid hormone-receptor signaling or hyperphosphorylation of tau; and at transcriptional level, JNKs might trigger the induction of the apoptotic effectors p53 and Fas-Ligand by phosphorylation of c-Jun. The role of p38 is the nervous system is poorly understood, but its activation is also considered as part of the neuronal stress response. This review informs about the genetic processing, the regulation of activity and the biochemical actions of JNK and p38 isoforms in general. In the second part, we summarize the findings on expression and activation of JNKs and p38 under neurodegenerative condition. A particular focus is also put on the putative function of JNK under physiological conditions and for neuroprotection.
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PMID:JNK and p38 stresskinases--degenerative effectors of signal-transduction-cascades in the nervous system. 1075 64

xPAK1, a probable effector of stress activated MAP-kinase SAPK1/JNK activation and cytoskeletal dynamics, was found to be ubiquitously expressed within the Xenopus laevis ear and lateral line system during the development and differentiation of these organs. xPAK1 expression was very strong in the otic placode from its condensation, and expression continued in the otic vesicle up until stage 35/36, after which it abruptly ceased. At stage 29/30 expression occurred specifically in the epithelium of the otic vesicle, which includes the prospective sensorial epithelium. Expression of xPAK1 was also observed in the lateral line system from stage 35/36, at which stage the lateral line primordia have begun to migrate from the region of the otic vesicle. Lateral line expression continued at least until stage 37/38, at which time xPAK1 was noted in association with the differentiating lateral line organs. To our knowledge, xPAK1 is the first ubiquitous lateral line marker that is also expressed in the ear. In the context of previous studies, our data suggest that xPAK1 either plays a role in the differentiation of the mechano-sensors of the auditory system or in the formation of the otic vesicle epithelium and the lateral line primordia.
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PMID:The cytoskeletal effector xPAK1 is expressed during both ear and lateral line development in Xenopus. 1079 83

The effects of pituitary and extrapituitary prolactin include cellular proliferation and differentiation. PC12 cells was used as a model to delineate respective signaling of prolactin. Prolactin acted as a mitogen for undifferentiated PC12 cells, as measured by significant increases in bromodeoxyuridine incorporation and in cell numbers, with an efficacy equal to epidermal growth factor. Both the long and short form of the prolactin receptor was expressed, yet only the long isoform was tyrosine-phosphorylated upon agonist binding. Functional prolactin receptor signaling was further demonstrated in the activation of JAK2 and phosphorylation activation of the transcription factors Stat1, -3, and -5a. Surprisingly, prolactin stimulated a sustained activation of Raf-B, without activation of the MAP kinases ERK1 or -2. Instead, in solid phase kinase assays using a glutathione S-transferase-c-Jun fusion protein (amino acids 1-79) as the substrate, a significant activation of the mitogen-activated protein Janus kinase (c-Jun N-terminal kinase; JNK) was observed. The prolactin-induced activation of JNK was prolonged and accompanied by a significant increase in c-Jun mRNA abundance and c-Jun protein synthesis. Moreover, analysis of bromodeoxyuridine incorporation at the single cell level revealed that epidermal growth factor-dependent incorporation was inhibited by PD98059 and independent of SB203580, whereas prolactin-induced incorporation was ERK and mitogen-activated protein kinase p38 independent but was abolished with JNK inhibition by 30 microm SB203580. Our studies suggest that prolactin may have a role in the growth of PC12 cells, where it stimulates concurrent mitogenic and differentiation-promoting signaling pathways.
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PMID:Prolactin-induced cell proliferation in PC12 cells depends on JNK but not ERK activation. 1080 11

This study examines the involvement of RNA and protein synthesis in the modulation of apoptosis in vascular smooth muscle cells (VSMC) by intracellular monovalent cations. In VSMC transfected with E1A adenovirus (VSMC-E1A), inversion of the [Na(+)](i)/[K(+)](i) ratio by an inhibitor of the Na(+),K(+) pump, ouabain, prevented the development of apoptosis triggered by serum withdrawal. Inhibition of apoptosis by ouabain was abolished by inhibitors of RNA and protein synthesis, actinomycin D, and cycloheximide, respectively. In VSMC-E1A, incubation with ouabain for 4 and 24 hours augmented RNA synthesis by 20% to 50% and 3-fold to 4-fold, respectively. In quiescent VSMC, the effect of ouabain and serum on RNA synthesis was additive. Ouabain did not affect the level of phosphorylation of ERK, JNK, and p38 MAP kinases and blocked apoptosis independent of the presence of the MAPK kinase inhibitors PD98059 and SB 202190. Equimolar substitution of NaCl with KCl in the incubation medium abolished the effect of ouabain on intracellular Na(+) and K(+) concentration, apoptosis, and RNA synthesis. Thus, our results demonstrate that the antiapoptotic effect of the inverted [Na(+)](i)/[K(+)](i) ratio is mediated by MAPK-independent induction of de novo synthesis of RNA species encoding inhibitor(s) of programmed cell death.
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PMID:Inversion of the intracellular Na(+)/K(+) ratio blocks apoptosis in vascular smooth muscle cells by induction of RNA synthesis. 1081 65


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