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)

Both MAP kinases and the protein kinase p74raf-1 are activated by many growth factors in a c-ras-dependent manner and by oncogenic p21ras. We were therefore interested in determining the relationship between MAP kinases and raf. The MAP kinase ERK2 is activated by expression of oncogenically activated raf, independently of cellular ras. Overexpressed p74raf-1 potentiates activation of ERK2 by EGF and TPA. MAP kinase kinase inactivated by phosphatase 2A treatment is phosphorylated and reactivated by incubation with p74raf-1 immunoprecipitated from phorbol ester-treated cells. We conclude that raf protein kinase is upstream of MAP kinases and is either a MAP kinase kinase kinase or a MAP kinase kinase kinase kinase.
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PMID:Activation of the MAP kinase pathway by the protein kinase raf. 133 Mar 21

We have studied in cultured rat astroglial cells MAP kinases, known for their role in intracellular signal transduction. The MAP kinase activity was stimulated by growth factors (FGFb, FGFa, EGF, PDGF, and IGF1), by a phorbol ester (TPA) activating-protein kinase C (PKC), by a neuropeptide (endothelin-1), and by a neuromediator (carbachol). Astrocytes pretreated for 18 h with TPA were still stimulated by growth factors and endothelin, suggesting that down-regulated isoforms of PKC are not involved in MAP kinase activation. In contrast, the small effect of carbachol was suppressed by TPA pretreatment. Astrocytes contained two proteins (p41 and p44) recognized by MAP kinase antibody. These proteins were phosphorylated on tyrosine residues in the cytosols of stimulated astrocytes. The kinetics of MAP kinase activation by FGFb and IGF1 were very different. FGFb promoted a rapid activation of MAP kinase (about 10 min) plus a prolonged phase that lasted at least 12 h. IGF1 produced only a rapid transient peak of activation at about 20 min. Hence, extracellular signals might generate different effects in astrocytes by differentially modulating the MAP kinase cascade. On a Mono Q column the growth factor-stimulated MAP kinase activity was separated into two peaks containing p41 and p44. Stimulation of astrocytes altered the elution pattern of p44 as a result of its phosphorylation. An ATP-dependent MAP kinase activator (MW = 40-45 kDa) was found in fractions of FGFb-stimulated cells which were not retained on Mono Q column, indicating the existence of a MAP kinase kinase (MEK) in astrocytes. C-Raf, identified in other cells as a MAP kinase kinase kinase, was also present in astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:MAP kinase cascade in astrocytes. 816 69

MEK kinases (MEKKs) 1, 2, 3 and 4 are members of sequential kinase pathways that regulate MAP kinases including c-Jun NH2-terminal kinases (JNKs) and extracellular regulated kinases (ERKs). Confocal immunofluorescence microscopy of COS cells demonstrated differential MEKK subcellular localization: MEKK1 was nuclear and in post-Golgi vesicular-like structures; MEKK2 and 4 were localized to distinct Golgi-associated vesicles that were dispersed by brefeldin A. MEKK1 and 2 were activated by EGF, and kinase-inactive mutants of each MEKK partially inhibited EGF-stimulated JNK activity. Kinase-inactive MEKK1, but not MEKK2, 3 or 4, strongly inhibited EGF-stimulated ERK activity. In contrast to MEKK2 and 3, MEKK1 and 4 specifically associated with Rac and Cdc42 and kinase-inactive mutants blocked Rac/Cdc42 stimulation of JNK activity. Inhibitory mutants of MEKK1-4 did not affect p21-activated kinase (PAK) activation of JNK, indicating that the PAK-regulated JNK pathway is independent of MEKKs. Thus, in different cellular locations, specific MEKKs are required for the regulation of MAPK family members, and MEKK1 and 4 are involved in the regulation of JNK activation by Rac/Cdc42 independent of PAK. Differential MEKK subcellular distribution and interaction with small GTP-binding proteins provides a mechanism to regulate MAP kinase responses in localized regions of the cell and to different upstream stimuli.
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PMID:MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42. 930 38

c-Jun N-terminal protein kinase (JNK), a member of the mitogen-activated protein (MAP) kinase family, regulates gene expression in response to various extracellular stimuli. JNK is activated by JNK-activating kinase (JNKK1 and JNKK2), a subfamily of the dual specificity MAP kinase kinase (MEK) family, through phosphorylation on threonine (Thr) 183 and tyrosine (Tyr) 185 residues. The physiological functions of the JNK pathway, however, are not completely understood. A major obstacle is the lack of specific and activated kinase components that can stimulate the JNK pathway in the absence of any stimulus. Here we show that fusion of JNK1 to its upstream activator JNKK2 resulted in its constitutive activation. In HeLa cells, the JNKK2-JNK1 fusion protein showed significant JNK activity, which was comparable with that of JNK1 activated by many stimuli and activators, including EGF, TNF-alpha, anisomycin, UV irradiation, MEKK1, and small GTP binding proteins Rac1 and Cdc42Hs. Immunoblotting analysis indicated that JNK1 was phosphorylated by JNKK2 in the fusion protein on both Thr(183) and Tyr(185) residues. Like JNKK2, the JNKK2-JNK1 fusion protein was highly specific for the JNK pathway and did not activate either p38 or ERK2. Transient transfection assays demonstrated that the JNKK2-JNK1 fusion protein was sufficient to stimulate c-Jun transcriptional activity in the absence of any stimulus. Immunofluorescence analysis revealed that the JNKK2-JNK1 fusion protein was predominantly located in the nucleus of transfected HeLa cells. These results indicate that the JNKK2-JNK1 fusion protein is a constitutively active Jun kinase, which will facilitate the investigation of the physiological roles of the JNK pathway.
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PMID:The JNKK2-JNK1 fusion protein acts as a constitutively active c-Jun kinase that stimulates c-Jun transcription activity. 1050 43

The effects of EGFR signaling on retinol metabolism were evaluated in the squamous cell carcinoma cell lines defective in LRAT. In a 24-h incubation, the presence of EGF resulted in a 20-25% increase in retinyl ester accumulation. Assessment of retinol esterification and retinyl ester utilization (hydrolysis), in cell cultures and in cell homogenates, revealed that the increase in retinyl ester mass was the result of a reduction in retinyl ester hydrolysis. When grown in the absence of EGF, the cultures used about 40% of their retinyl esters, compared to about 21% in cultures grown with EGF. This effect of EGF was blocked by an EGF receptor-neutralizing antibody, an EGF receptor tyrosine-kinase inhibitor (PD153035), and a specific inhibitor of MEK kinase influencing the mitogen-activated protein kinase (MAPK) cascade (PD98059). Both transcription and translation were required, suggesting that signaling from the EGF receptor through the MAPK cascade controls the expression of modulators or inhibitors of the retinyl ester hydrolase(s). Thus EGFR signaling can alter the intracellular concentration of retinol by suppressing the access to the retinyl ester pool. Similar EGF effects were seen in cultures of normal keratinocytes.
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PMID:Epidermal growth factor signaling pathway influences retinoid metabolism by reduction of retinyl ester hydrolase activities in normal and malignant keratinocytes. 1073 2

Ca(2+)-sensitive tyrosine kinase Pyk2 was shown to be involved in angiotensin (Ang) II-mediated activation of extracellular signal-regulated kinase (ERK) via transactivation of epidermal growth factor receptor (EGF-R). In this study, we tested the involvement of Pyk2 and EGF-R in Ang II-induced activation of JNK and c-Jun in cardiac fibroblasts. Ang II markedly stimulated JNK activities, which were abolished by genistein and intracellular Ca(2+) chelators but partially by protein kinase C depletion. Inhibition of EGF-R did not affect Pyk2 and JNK activation by Ang II. Stable transfection with a dominant negative (DN) mutant for Pyk2 (PKM) completely blocked JNK activation by Ang II. DN mutants of Rac1 (DN-Rac1) and MEK kinase (DN-MEKK1) also abolished it, whereas those of Cdc42, RhoA, and Ha-Ras had no effect. Induction of c-Jun gene transcription by Ang II was abolished in PKM, DN-Rac1, and DN-MEKK1, in which Ang II-induced binding of ATF2/c-Jun heterodimer to the activator protein-1 sequence at -190 played a key role. These results suggest that 1) in cardiac fibroblasts activation of JNK and c-Jun by Ang II is initiated by Pyk2-dependent signalings but not by downstream signals of EGF-R or Ras, 2) Rac1 but not Cdc42 is required for JNK activation by Ang II upstream of MEKK1, and 3) ATF-2/c-Jun binding to the activator protein-1 sequence at -190 plays a key role for induction of c-Jun gene by Ang II.
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PMID:Angiotensin II initiates tyrosine kinase Pyk2-dependent signalings leading to activation of Rac1-mediated c-Jun NH2-terminal kinase. 1085 8

Herein, we define how MEKK1, a MAPK kinase kinase, regulates cell migration. MEKK1 is associated with actin fibers and focal adhesions, localizing MEKK1 to sites critical in the control of cell adhesion and migration. EGF-induced ERK1/2 activation and chemotaxis are inhibited in MEKK1-/- fibroblasts. MEKK1 deficiency causes loss of vinculin in focal adhesions of migrating cells, increased cell adhesion and impeded rear-end detachment. MEKK1 is required for activation of the cysteine protease calpain and cleavage of spectrin and talin, proteins linking focal adhesions to the cytoskeleton. Inhibition of ERK1/2 or calpain, but not of JNK, mimics MEKK1 deficiency. Therefore, MEKK1 regulates calpain-mediated substratum release of migrating fibroblasts.
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PMID:MEKK1 regulates calpain-dependent proteolysis of focal adhesion proteins for rear-end detachment of migrating fibroblasts. 1283 96

Nuclear factor kappaB-inducing kinase (NIK) is a member of the MAP kinase kinase kinase family that was first identified as a component of the TNF-R1-induced NF-kappaB activation pathway (TNF, tumor necrosis factor; nuclear factor kappaB, NF-kappaB). Gene knockout study, however, suggests that NIK is dispensable for TNF-R1- but required for lymphotoxin-beta receptor-induced NF-kappaB activation. A NIK kinase inactive mutant is a potent inhibitor of NF-kappaB activation triggered by various stimuli, suggesting that NIK is involved in a broad range of NF-kappaB activation pathways. To unambiguously identify signaling pathways that NIK participates in, we screened antibody arrays for proteins that are associated with NIK. This effort identified ErbB4, one of the EGF/heregulin receptors, and Grb7, an adapter protein associated with ErbB4 (ErbB, epidermal growth factor receptor family protein; EGF, epidermal growth factor; Grb, growth factor receptor bound). Coimmunoprecipitation experiments demonstrated that NIK interacted with Grb7, as well as Grb10 and Grb14, but not Grb2. Domain mapping experiments indicated that the central GM domain of Grb7 was sufficient for its interaction with NIK. Coimmunoprecipitation experiments also indicated that Grb7 and NIK could be simultaneously recruited into signaling complexes of all known EGF/heregulin receptors, including EGFR, ErbB2, ErbB3, and ErbB4. In reporter gene assays, NIK could potentiate Grb7, ErbB2/ErbB4, and EGF-induced NF-kappaB activation. A NIK kinase inactive mutant could block ErbB2/ErbB4 and EGF-induced NF-kappaB activation. Moreover, EGF/heregulin receptors activated NF-kappaB in wild-type, but not NIK-/- embryonic fibroblasts. Our findings suggest that NIK is a component of the EGF/heregulin receptor signaling complexes and involved in NF-kappaB activation triggered by these receptors.
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PMID:NIK is a component of the EGF/heregulin receptor signaling complexes. 1285 71

The cell interactions that specify the spatial pattern of vulval precursor cell (VPC) fates differ between the nematodes Oscheius tipulae CEW1 and Caenorhabditis elegans. In the former, the centered pattern of fates is obtained by two successive inductions from the gonadal anchor cell, whereas in the latter, a single inductive step by the anchor cell (EGF-Ras-MAP kinase pathway) can act as a morphogen and is reinforced by lateral signaling between the vulval precursors (Notch pathway). We performed a genetic screen for vulva mutants in O. tipulae CEW1. Here we present the mutants that specifically affect the vulval induction mechanisms. Phenotypic and epistatic analyses of these mutants show that both vulval induction steps share common components, one of which appears to be MEK kinase(s). Moreover, the inductive pathway (including MEK kinase) influences the competence of the vulval precursor cells and more strikingly their division pattern as well, irrespective of their vulval fate. Finally, a comparison of vulval mutant phenotypes obtained in C. elegans and O. tipulae CEW1 highlights the evolution of vulval induction mechanisms between the two species.
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PMID:The two steps of vulval induction in Oscheius tipulae CEW1 recruit common regulators including a MEK kinase. 1469 57

The ERK5 signaling cascade acts through sequential activation of MEKK2/3, MEK5 and ERK5 and transmits signals to a variety of stress and mitogenic related targets. In this study we examined the subcellular localization of the components of the ERK5 cascade and found that in resting, as well as in EGF-stimulated HeLa and Rat-1 cells, endogenous ERK5 is localized mainly in the nucleus. This location is different from the previously described location of exogenous ERK5, in the cytosol of resting cells, which is confirmed in this study. The reason for the different localization could be a saturation of anchoring moieties by the endogenous ERK5. Indeed, in situ detergent extraction analysis using Nonidet P-40, revealed that ERK5 is bound to detergent resistant moieties in the nucleus, while the exogenous protein fails to interact with those anchors. The upstream activator MEK5 is also localized in the nucleus both before and after EGF stimulation and is resistant to NP-40 extraction in resting cells. ERK5 remains bound to these nuclear moieties even after stimulation, while MEK5 is detached from the anchors but remains localized in the nucleus. Unlike ERK5 and MEK5, their upstream activator MEKK2 is localized mainly in the cytosol of resting cells, and translocates into the nucleus upon EGF stimulation, allowing transmission of signals to the nuclear MEK5. The nuclear localization of MEK5 and ERK5 is different from that of ERK1/2 and MEK1/2 in resting cells, indicating that each MAPK cascade uses distinct mechanisms to transmit extracellular signals to their nuclear targets.
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PMID:MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation. 1507 38


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