Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogen-activated protein (MAP) kinase pathways include a three-kinase cascade terminating in a MAP kinase family member. The middle kinase in the cascade is a MAP/extracellular signal-regulated kinase (ERK) kinase or MEK family member and is highly specific for its MAP kinase target. The first kinase in the cascade, a MEK kinase (MEKK), is characterized by its ability to activate one or more MEK family members. A two-plasmid bacterial expression system was employed to express active forms of the following MEK and MAP kinase family members: ERK1, ERK2, alpha-SAPK, and p38 and their upstream activators, MEK1, -2, -3, and -4. In each kinase module, the upstream activator, a constitutively active mutant of MEK1 or MEKK1, was expressed from a low copy plasmid, while one or two downstream effector kinases were expressed from a high copy plasmid with different antibiotic resistance genes and origins of replication. Consistent with their high activity, ERK1 and ERK2 were doubly phosphorylated on Tyr and Thr, were recognized by an antibody specific to the doubly phosphorylated forms, and were inactivated by either phosphoprotein phosphatase 2A or phosphotyrosine phosphatase type 1. Likewise, activated p38 and alpha-stress-activated protein kinase could also be inactivated by either phosphatase, and alpha-stress-activated protein kinase was recognized by an antibody specific to the doubly phosphorylated forms. These three purified, active MAP kinases have specific activities in the range of 0.6-2.3 micromol/min/mg. Coexpression of protein kinases with their substrates in bacteria is of great value in the preparation of numerous phosphoproteins, heretofore not possible in procaryotic expression systems.
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PMID:Reconstitution of mitogen-activated protein kinase phosphorylation cascades in bacteria. Efficient synthesis of active protein kinases. 911 Sep 99

T cell activation requires the import of NF-AT transcription factors to the nucleus, a process promoted by calcineurin-dependent dephosphorylation and inhibited by poorly understood protein kinases. Here, we report the identification of two protein kinases that oppose NF-AT4 nuclear import. Casein kinase Ialpha directly binds and phosphorylates NF-AT4, resulting in the inhibiton of NF-AT4 nuclear translocation. MEKK1 indirectly suppresses NF-AT4 nuclear import by stabilizing the interaction between NF-AT4 and CKIalpha. CKIalpha thus acts to establish an intramolecular masking of the nuclear location signal on NF-AT4, while MEKK1 augments this mechanism, and may further provide a link to signal transduction pathways regulating NF-AT4.
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PMID:Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1. 963 Feb 28

Previously we implicated c-Jun N-terminal kinase (JNK) as an element that is involved in signal integration during co-stimulation of T lymphocytes. This pathway has now been traced to an upper level, comprising MAPKK SEK1/MKK4/JNKK1 which, similarly to JNK, must receive input both from the TCR and CD28. A large portion of this input is probably integrated at the level of the Rho-family protein CDC42 which, here, activates SEK1 and JNK to the level reached by TCR and CD28 stimulation. We have identified another putative SEK/ JNK pathway regulator, PKCtheta, which in contrast to CDC42, activates SEK and JNK maximally only in conjunction with a calcium signal delivered through calcineurin. Signals originating at the TCR and CD28 may travel down the JNK pathway via PKCtheta, calcineurin, CDC42, MEKK1 and SEK1.
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PMID:Co-stimulation-dependent activation of a JNK-kinase in T lymphocytes. 971 Feb 10

We have previously reported that the activation of resting human immature peripheral blood T (PBT) lymphocytes is associated with the loss of retinoid X receptor alpha (RXRalpha) expression. In the present study, we have demonstrated that, unlike resting cells, activation of cycling human mature PBT lymphocytes, and T lymphocyte leukemia cell lines is accompanied by the accumulation of RXRalpha mRNA and protein. Interestingly, cyclosporin A further augmented RXRalpha expression, indicating the involvement of calcineurin pathways in the process. 9-cis retinoic acid inhibited the accumulation, suggesting that retinoids can regulate the synthesis of their own receptors during T cell activation. Transfection analysis in Jurkat cells, using RXRE-dependent reporter assays, showed that RXRalpha accumulated during T cell activation was transcriptionally inactive. To investigate the mechanism of such inhibition, the role of two mitogen-activated protein kinase pathways, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), in modulating RXRE-dependent transcription, was explored. The expression of constitutively active MAP/ERK kinase kinase 1 (MEKK1) inhibited RXRE-dependent transcription, whereas dominant negative MEKK1 increased the transcription, indicating the involvement of JNK signaling pathways in the process. In contrast, expression of constitutively active MEK1, which activates ERK pathway, enhanced RXRE-dependent activation. When both were activated simultaneously, JNK pathway was dominant over ERK pathway and resulted in inhibition of RXRE-mediated transcription. These data demonstrate a dual regulatory control of RXRalpha expression during the activation of resting and cycling T lymphocytes and indicate a dynamic balance between JNK and ERK pathways in modulating RXRE-mediated transactivation.
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PMID:Accumulation of RXR alpha during activation of cycling human T lymphocytes: modulation of RXRE transactivation function by mitogen-activated protein kinase pathways. 1103 54

The immunosuppressive effects of cyclosporin A (CsA) and FK506 are mediated through binding to immunophilins. Here we show that FK506-FKBP complex suppresses the activation of JNK and p38 pathways at a level upstream of mitogen-activated protein kinase (MAPK) kinase kinase (MAPKK-K) besides the calcineurin-NFAT pathway. A238L, a viral gene product that binds to immunophilin, also blocks activation of both pathways. In contrast, direct inhibitors of calcineurin, Cabin 1 and FR901725, suppress the activation of NFAT but not the JNK or p38 pathway. We further demonstrate that co-expression of a constitutively active NFAT and a constitutively active MEKK1 renders the interleukin-2 promoter in Jurkat T lymphocytes resistant to CsA and FK506, whereas Jurkat cells expressing a constitutively active NFAT alone are still sensitive to CsA or FK506. Therefore, CsA and FK506 exert their immunosuppressive effects through targeting both the calcineurin-dependent NFAT pathway and calcineurin-independent activation pathway for JNK and p38.
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PMID:Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation. 1125 83

Human neutrophil accumulation in inflammatory foci is essential for the effective control of microbial infections. Although exposure of neutrophils to cytokines such as tumor necrosis factor-alpha (TNFalpha), generated at sites of inflammation, leads to activation of MAPK pathways, mechanisms responsible for the fine regulation of specific MAPK modules remain unknown. We have previously demonstrated activation of a TNFalpha-mediated JNK pathway module, leading to apoptosis in adherent human neutrophils (Avdi, N. J., Nick, J. A., Whitlock, B. B., Billstrom, M. A., Henson, P. M., Johnson, G. L., and Worthen, G. S. (2001) J. Biol. Chem. 276, 2189-2199). Herein, evidence is presented linking regulation of the JNK pathway to p38 MAPK and the Ser/Thr protein phosphatase-2A (PP2A). Inhibition of p38 MAPK by SB 203580 and M 39 resulted in significant augmentation of TNFalpha-induced JNK and MKK4 (but not MKK7 or MEKK1) activation, whereas prior exposure to a p38-activating agent (platelet-activating factor) diminished the TNFalpha-induced JNK response. TNFalpha-induced apoptosis was also greatly enhanced upon p38 inhibition. Studies with a reconstituted cell-free system indicated the absence of a direct inhibitory effect of p38 MAPK on the JNK module. Neutrophil exposure to the Ser/Thr phosphatase inhibitors okadaic acid and calyculin A induced JNK activation. Increased phosphatase activity following TNFalpha stimulation was shown to be PP2A-associated and p38-dependent. Furthermore, PP2A-induced dephosphorylation of MKK4 resulted in its inactivation. Thus, in neutrophils, p38 MAPK, through a PP2A-mediated mechanism, regulates the JNK pathway, thus determining the extent and nature of subsequent responses such as apoptosis.
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PMID:A role for protein phosphatase-2A in p38 mitogen-activated protein kinase-mediated regulation of the c-Jun NH(2)-terminal kinase pathway in human neutrophils. 1218 63

Intracellular calcium levels can have profound effects on muscle biology via alterations in gene expression. In particular, intracellular calcium levels increase during muscle activation and are thought to underlie fast-to-slow shifts in muscle gene expression. In the present work, we determined that increased intracellular calcium has a significant effect on the activity of the adult fast myosin heavy chain (MyHC) promoters in the order of MyHC IIa>> IId/x > IIb. We have identified the pathways by which the calcium signal mediates increased activation of the MyHC IIa promoter. Inhibition of calcineurin or calcium-calmodulin kinase greatly attenuates ionophore-induced activation of the MyHC IIa promoter, whereas protein kinase C inhibitors have no effect. Inhibition and overexpression studies with members of the mitogen-activated protein kinase family reveal roles for MEK1/MEK2 and MEKK1, but not p38 or phosphatidylinositol 3-kinase. Downstream mediators of these effects are the activities of the MEF-2 and NFAT transcription factors, whose binding sites in the MyHC IIa promoter are required for calcium-induced activation of the MyHC IIa promoter.
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PMID:Intracellular calcium and myosin isoform transitions. Calcineurin and calcium-calmodulin kinase pathways regulate preferential activation of the IIa myosin heavy chain promoter. 1223 57

Negative selection is the process whereby immature thymocytes expressing TCRs with high affinity for self-peptide:MHC complexes are induced to undergo apoptosis. The transcriptional events that occur as a result of TCR signaling during negative selection are not well-characterized. Using oligonucleotide arrays, we have identified 33 genes that exhibit changes in RNA levels in CD4(+)CD8(+) thymocytes during negative selection in vivo. Of 18 genes that have been further characterized, 13 are regulated in response to stimulation with Ag or anti-CD3 and anti-CD28 Abs ex vivo, indicating that these genes are regulated independently of activation of the peripheral immune system. These data also support the idea that anti-CD3/CD28-mediated thymocyte apoptosis is a valid model for negative selection in vivo. A detailed examination of the regulation of many of the identified genes in response to treatment with dexamethasone or gamma-radiation or in response to anti-CD3/anti-CD28 stimulation in the presence of pharmacological inhibitors of mitogen-activated protein kinase kinase kinase 1, p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase, calcineurin, and cyclin-dependent kinase 2 has facilitated the elucidation of a map of the transcriptional events that occur downstream of the TCR. These studies support a model whereby similar signal transduction pathways are activated by stimuli that induce positive and negative selection and are consistent with the idea that the balance between opposing proapoptotic and antiapoptotic pathways determines cell fate. The data presented in this study also suggest that calcineurin functions to amplify TCR signals by promoting sustained increases in the levels of specific transcripts.
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PMID:Characterization of transcriptional regulation during negative selection in vivo. 1284 48

CREB is a prototypic bZIP transcription factor and a master regulator of glucose metabolism, synaptic plasticity, cell growth, apoptosis, and tumorigenesis. Transducers of regulated CREB activity (TORCs) are essential transcriptional coactivators of CREB and an important point of regulation on which various signals converge. In this study, we report on the activation of TORC1 through MEKK1-mediated phosphorylation. MEKK1 potently activated TORC1, and this activation was independent of downstream effectors MEK1/MEK2, ERK2, JNK, p38, protein kinase A, and calcineurin. MEKK1 induced phosphorylation of TORC1 both in vivo and in vitro. Expression of the catalytic domain of MEKK1 alone in cultured mammalian cells sufficiently caused phosphorylation and subsequent activation of TORC1. MEKK1 physically interacted with TORC1 and stimulated its nuclear translocation. An activation domain responsive to MEKK1 stimulation was mapped to amino acids 431-650 of TORC1. As a physiological activator of CREB, interleukin 1alpha triggered MEKK1-dependent phosphorylation of TORC1 and its consequent recruitment to the cAMP response elements in the interleukin 8 promoter. Taken together, our findings suggest a new mechanism for regulated activation of TORC1 transcriptional coactivator and CREB signaling.
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PMID:Activation of TORC1 transcriptional coactivator through MEKK1-induced phosphorylation. 1878 53

To improve contractile function, the myocardium undergoes hypertrophic growth without myocyte proliferation in response to both pathologic and physiologic stimulation. Various membrane-bound receptors and intermediate signal transduction pathways regulate the induction of cardiac hypertrophy, but the cardioprotective regulatory pathways or effectors that antagonize cardiac hypertrophy remain poorly understood. Here we identify the small GTPase Cdc42 as a signaling intermediate that restrained the cardiac growth response to physiologic and pathologic stimuli. Cdc42 was specifically activated in the heart after pressure overload and in cultured cardiomyocytes by multiple agonists. Mice with a heart-specific deletion of Cdc42 developed greater cardiac hypertrophy at 2 and 8 weeks of stimulation and transitioned more quickly into heart failure than did wild-type controls. These mice also displayed greater cardiac hypertrophy in response to neuroendocrine agonist infusion for 2 weeks and, more remarkably, enhanced exercise-induced hypertrophy and sudden death. These pathologies were associated with an inability to activate JNK following stimulation through a MEKK1/MKK4/MKK7 pathway, resulting in greater cardiac nuclear factor of activated T cells (NFAT) activity. Restoration of cardiac JNK signaling with an Mkk7 heart-specific transgene reversed the enhanced growth effect. These results identify what we believe to be a novel antihypertrophic and protective cardiac signaling pathway, whereby Cdc42-dependent JNK activation antagonizes calcineurin-NFAT activity to reduce hypertrophy and prevent transition to heart failure.
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PMID:Cdc42 is an antihypertrophic molecular switch in the mouse heart. 1974 Dec 99


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