Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cross-linking of the high-affinity IgE receptor (FcepsilonRI) on mast cells with IgE and multivalent antigen triggers mitogen-activated protein (MAP) kinase activation and cytokine gene expression. We report here that MAP kinase kinase 4 (MKK4) gene disruption does not affect either MAP kinase activation or cytokine gene expression in response to cross-linking of FcepsilonRI in embryonic stem cell-derived mast cells. MKK7 is activated in response to cross-linking of FcepsilonRI, and this activation is inhibited by MAP/ERK kinase (MEK) kinase 2 (MEKK2) gene disruption. In addition, expression of kinase-inactive MKK7 in the murine mast cell line MC/9 inhibits c-Jun NH(2)-terminal kinase (JNK) activation in response to cross-linking of FcepsilonRI, whereas expression of kinase-inactive MKK4 does not affect JNK activation by this stimulus. However, FcepsilonRI-induced activation of the tumor necrosis factor-alpha (TNF-alpha) gene promoter is not affected by expression of kinase-inactive MKK7. We describe an alternative pathway by which MEKK2 activates MEK5 and big MAP kinase1/extracellular signal-regulated kinase 5 in addition to MKK7 and JNK, and interruption of this pathway inhibits TNF-alpha promoter activation. These findings suggest that JNK activation by antigen cross-linking is dependent on the MEKK2-MKK7 pathway, and cytokine production in mast cells is regulated in part by the signaling complex MEKK2-MEK5-ERK5.
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PMID:Role of MEKK2-MEK5 in the regulation of TNF-alpha gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells. 1127 63

Mitogen-activated protein kinase (MAPK) cascades play essential roles in the transduction of extracellular signals to cytoplasmic and nuclear effectors. The MAPK kinase kinase MEKK2 is essential for activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 5 (ERK5). These pathways are important for expression of specific cytokine genes in mast cells following cross-linking of the high-affinity IgE receptor (FcepsilonRI). A consequence of ERK5 activation is activation of the transcriptional factor myocyte enhancing factor-2C (MEF2C), leading to increased c-Jun expression. We have investigated the role of MEF2C activation in mast cells and demonstrated that it requires sequential activation of the signaling cascade of MEKK2-MEK5-ERK5. Following phosphorylation of MEF2C, activated MEF2C regulates transcription of c-Jun but not TNF-alpha. Inhibition of ERK5, MEK5 activation or activation of MEKK2-deficient mast cells was associated with inhibition of MEF2C phosphorylation and a decrease in c-Jun expression. Thus, these data define an activation module, MEKK2-MEK5-ERK5-MEF2C in the transcriptional activation of c-Jun in mast cells following FcepsilonRI cross-linking. These results demonstrate the novel and important, MEKK2-dependent role of MEF2C in induction of c-Jun expression in mast cells activated through FcepsilonRI, a pathway distinct from that involving MEKK2-MEK5-ERK5 in the regulation of mast cell cytokine production.
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PMID:MEF2C regulates c-Jun but not TNF-alpha gene expression in stimulated mast cells. 1451 74

Mitogen-activated protein kinase (MAPK) cascades are central components of the intracellular signaling networks used by eukaryotic cells to respond to a wide spectrum of extracellular stimuli. An MAPK is activated by an MAPK kinase, which in turn is activated by an MAPK kinase kinase (MAP3K). However, little is known about the molecular aspects of the regulation and activation of large numbers of MAP3Ks that are crucial in relaying upstream receptor-mediated signals through the MAPK cascades to induce various physiological responses. In this study, we identified a novel MEKK2-interacting protein, Mip1, that regulates MEKK2 dimerization and activation by forming a complex with inactive and nonphosphorylated MEKK2. In particular, Mip1 prevented MEKK2 activation by blocking MEKK2 dimer formation, which in turn blocked JNKK2, c-Jun N-terminal kinase 1 (JNK1), extracellular signal-regulated kinase 5, and AP-1 reporter gene activation by MEKK2. Furthermore, we found that the endogenous Mip1-MEKK2 complex was dissociated transiently following epidermal growth factor stimulation. In contrast, the knockdown of Mip1 expression by siRNA augmented the MEKK2-mediated JNK and AP-1 reporter activation. Together, our data suggest a novel model for MEKK2 regulation and activation.
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PMID:Mip1, an MEKK2-interacting protein, controls MEKK2 dimerization and activation. 1598 11

The alternative splicing of the mek5 gene gives rise to two isoforms. MEK5beta lacks an extended N terminus present in MEK5alpha. Comparison of their activities led us to identify a novel mitogen-activated protein kinase (MAPK) docking site in the N terminus of MEK5alpha that is distinct from the consensus motif identified in the other MAPK kinases. It consists of a cluster of acidic residues at position 61 and positions 63 to 66. The formation of the MEK5/extracellular signal-regulated kinase 5 (ERK5) complex is critical for MEK5 to activate ERK5, to increase transcription via MEF2, and to enhance cellular survival in response to osmotic stress. Certain mutations in the ERK5 docking site that prevent MEK5/ERK5 interaction also abrogate the ability of MEKK2 to bind and activate MEK5. However, the identification of MEK5alpha mutants with selective binding defect demonstrates that the MEK5/ERK5 interaction does not rely on the binding of MEK5alpha to MEKK2 via their respective PB1 domains. Altogether these results establish that the N terminus of MEK5alpha is critical for the specific organization of the components of the ERK5 signaling pathway.
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PMID:A novel mitogen-activated protein kinase docking site in the N terminus of MEK5alpha organizes the components of the extracellular signal-regulated kinase 5 signaling pathway. 1626 May 99

Calcineurin is a serine/threonine protein phosphatase that plays a critical role in many physiologic processes such as T-cell activation, skeletal myocyte differentiation, and cardiac hypertrophy. We previously showed that active MEKK3 is capable of stimulating calcineurin/nuclear factor of activated T-cells (NFAT) signaling in cardiac myocytes through phosphorylation of modulatory calcineurin-interacting protein 1 (MCIP1). However, the protein kinases that function downstream of MEKK3 to mediate MCIP1 phosphorylation and the mechanism of MCIP1-mediated calcineurin regulation have not been defined. Here, we show that MEK5 and big MAP kinase 1 (BMK1) function downstream of MEKK3 in a signaling cascade that induces calcineurin activity through phosphorylation of MCIP1. Genetic studies showed that BMK1-deficient mouse lung fibroblasts failed to mediate MCIP1 phosphorylation and activate calcineurin/NFAT in response to angiotensin II, a potent NFAT activator. Conversely, restoring BMK1 to the deficient cells restored angiotensin II-mediated calcineurin/NFAT activation. Thus, using BMK1-deficient mouse lung fibroblast cells, we provided the genetic evidence that BMK1 is required for angiotensin II-mediated calcineurin/NFAT activation through MICP1 phosphorylation. Finally, we discovered that phosphorylated MCIP1 dissociates from calcineurin and binds with 14-3-3, thereby relieving its inhibitory effect on calcineurin activity. In summary, our findings reveal a previously unrecognized essential regulatory role of mitogen-activated protein kinase signaling in calcineurin activation through the reversible phosphorylation of a calcineurin-interacting protein, MCIP1.
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PMID:Protein kinase-mediated regulation of calcineurin through the phosphorylation of modulatory calcineurin-interacting protein 1. 1641 48

MEKK2, MEK5, and extracellular signal-regulated kinase 5 (ERK5) are members of a three-kinase cascade for the activation of ERK5. MEK5 is the only MAP2K to express a PB1 domain, and we have shown that it heterodimerizes with the PB1 domain of MEKK2. Here we demonstrate the MEK5 PB1 domain is a scaffold that also binds ERK5, functionally forming a MEKK2-MEK5-ERK5 complex. Reconstitution assays and CFP/YFP imaging (fluorescence resonance energy transfer [FRET]) measuring YFP-MEKK2/CFP-MEK5 and CFP-MEK5/YFP-ERK5 interactions define distinct MEK5 PB1 domain binding sites for MEKK2 and ERK5, with a C-terminal extension of the PB1 domain contributing to ERK5 binding. Stimulus-dependent CFP/YFP FRET in combination with mutational analysis was used to define MEK5 PB1 domain residues critical for the interaction of MEKK2/MEK5 and MEK5/ERK5 required for activation of the ERK5 pathway in living cells. Fusion of the MEK5 PB1 domain to the N terminus of MEK1 confers ERK5 regulation by a MAP2K normally regulating only ERK1/2. The MEK5 PB1 domain confers stringent MAP3K regulation of ERK5 relative to more promiscuous MAP3K control of ERK1/2, JNK, and p38.
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PMID:PB1 domain-dependent signaling complex is required for extracellular signal-regulated kinase 5 activation. 1650 87

Cells integrate signals to select the appropriate response from an array of possible outcomes. Signal integration causes the reorganization of signaling pathways by undescribed events. To analyze the molecular changes in signaling pathways that elicit different responses, we focused on the interaction between cyclic AMP (cAMP) and growth factors. We show that the activation of extracellular signal-regulated kinase 5 (ERK5), but not ERK1/2, by growth factors is disrupted by cAMP through cAMP-dependent protein kinase (PKA). Activation of MEKK2, a mitogen-activated protein (MAP) kinase kinase kinase upstream of ERK5 that is required for growth factor activation of ERK5, is also disrupted by PKA. Transcription of c-Jun is induced by ERK5, and like ERK5, c-Jun induction is also blocked by cAMP. Transcription from the serum response element, like activation of ERK1/2, is not blocked by cAMP. Collectively, these results support a model in which cAMP shapes the growth factor-induced cellular response through PKA-dependent uncoupling of selected MAP kinase cascades from activating signals.
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PMID:Cyclic AMP selectively uncouples mitogen-activated protein kinase cascades from activating signals. 1658 79

The extracellular signal-regulated kinase 5 (ERK5) is activated in neurons of the central nervous system by neurotrophins including brain-derived neurotrophic factor (BDNF). Although MEK5 is known to mediate BDNF stimulation of ERK5 in central nervous system neurons, other upstream signaling components have not been identified. Here, we report that BDNF induces a sustained activation of ERK5 in rat cortical neurons and activates Rap1, a small GTPase, as well as MEKK2, a MEK5 kinase. Our data indicate that activation of Rap1 or MEKK2 is sufficient to stimulate ERK5, whereas inhibition of either Rap1 or MEKK2 attenuates BDNF activation of ERK5. Furthermore, BDNF stimulation of MEKK2 is regulated by Rap1. Our evidence also indicates that Ras and MEKK3, a MEK5 kinase in non-neuronal cells, do not play a significant role in BDNF activation of ERK5. This study identifies Rap1 and MEKK2 as critical upstream signaling molecules mediating BDNF stimulation of ERK5 in central nervous system neurons.
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PMID:Brain-derived neurotrophic factor activates ERK5 in cortical neurons via a Rap1-MEKK2 signaling cascade. 1700 42

Extracellular signal-regulated kinase 5 (ERK5) is also known as big MAPK (BMK1) or MAPK7. ERK5 is 115 kDa in mass and therefore larger than the other MAPKs such as ERK1/2, JNK, and p38. Like other MAPKs, ERK5 is ubiquitously expressed in mammalian cells and is part of a three kinase cascade involving a MAPK kinase (MEK5) and MAPK kinase kinase (primarily MEKK2 and MEKK3). ERK5 is important for proliferative responses to growth factors like epidermal growth factor and stress responses such as hyperosmolarity. Upon stimulation, ERK5 rapidly translocates to the nucleus for the control of transcription. ERK5 is also critical for maintenance of vascular integrity and endothelial cell survival. In this chapter, we define methods used to measure the activation of ERK5 using different biochemical and cell-based assays.
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PMID:Activity assays for extracellular signal-regulated kinase 5. 2081 78