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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)

Ste5 is a Zn2+ finger-like protein thought to function before three kinases, Ste11 (a MEKK), Ste7 (a MEK), and Fus3 (a MAPK), in a conserved MAP kinase cascade required for mating in S. cerevisiae. Here, we present evidence that Ste5 forms a multikinase complex that joins these kinases for efficient Fus3 activation. By two-hybrid analysis, Ste11, Ste7, and Fus3 associate with different domains of Ste5, while Kss1, another MAPK, associates with the same domain as Fus3, thus implying that Ste5 simultaneously binds a MEKK, MEK, and MAPK. Ste5 copurifies with Ste11, Fus3, and a hypophosphorylated form of Ste7, and all four proteins cosediment in a glycerol gradient as if in a large complex. Ste5 also increases the amount of Ste11 complexed to Ste7 and Fus3 and is required for Ste11 to function. These results substantiate a novel signal transduction component that physically links multiple kinases within a single cascade.
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PMID:Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae. 806 90

MAP (mitogen-activated protein) kinases are serine/threonine protein kinases and mediate intracellular phosphorylation events linking various extracellular signals to different cellular targets. MAP kinase, MAP kinase kinase and MAP kinase kinase kinase are functional protein kinase units that are conserved in several signal transduction pathways in animals and yeasts. Isolation of all three components was also shown in plants and suggests conservation of a protein kinase module in all eukaryotic cells. In plants, MAP kinase modules appear to be involved in ethylene signaling and auxin-induced cell proliferation. Therefore, coupling of different extracellular signals to different physiological responses is mediated by MAP kinase cascades and appears to have evolved from a single prototypical protein kinase module which has been adapted to the specific requirements of different organisms.
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PMID:MAP kinases: universal multi-purpose signaling tools. 812 84

MEK is a family of dual specific protein kinases which activate the extracellular signal-regulated kinases by phosphorylation of threonine and tyrosine residues. MEK itself is activated via serine phosphorylation by upstream activator kinases, including c-raf, mos and MEK kinase. Here, we report the activation phosphorylation sites of human MEK1 and yeast STE7 kinase as determined by a combination of biochemical and genetic approaches. In human MEK1, substitution of either serine residue 218 or 222 with alanine completely abolished its activation by epidermal growth factor-stimulated Swiss 3T3 cell lysates or immunoprecipitated c-raf, suggesting that both serine residues are required for MEK1 activation. Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human MEK1 are the primary sites for phosphorylation by c-raf. These two serine residues are highly conserved in all members of the MEK family, including the yeast STE7 gene product, a MEK homolog in the yeast mating pheromone response pathway. Mutation of the corresponding residues in STE7 completely abolished the biological functions of this gene. These data demonstrate that MEK is activated by phosphorylation of two adjacent serine/threonine residues and this activation mechanism is conserved in the MEK family kinases.
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PMID:Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues. 813 46

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

Recently, it has been reported that Raf-1 kinase (Raf-1) has mitogen-activated protein kinase kinase kinase (MAPKKK) activity in various cells, although Raf-1 and MAP kinase kinase (MAPKK) can be phosphorylated by MAP kinase (MAPK) in vitro. Here we show that the maximal hyperphosphorylation of Raf-1 and MAPKK (10 min) was substantially achieved after the maximal activation of MAPKKK of Raf-1, MAPKK (2-5 min), and MAPK in Chinese hamster ovary cells overexpressing human insulin receptor (CHO-HIR cells) treated with insulin or 12-O-tetradecanoylphorbol-13-acetate (TPA). Moreover, we show that overexpression of MAPK in CHO-HIR cells resulted in enhanced hyperphosphorylation of Raf-1, MAPKK, and mammalian homolog of son of sevenless (mSos) after insulin or TPA stimulation as compared with parental cells. Furthermore, the maximal hyperphosphorylation of Raf-1 appears to be accompanied by a significant decrease in MAPKKK activity. These results suggest that 1) signals initiated by insulin and TPA converge on Raf-1 and activate its MAPKKK activity and 2) Raf-1, MAPKK, and mSos not only lie upstream of MAPK but also are phosphorylated by MAPK, directly or indirectly, and at least Raf-1 kinase activity might be down-regulated by this feedback mechanism.
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PMID:Feedback regulation of mitogen-activated protein kinase kinase kinase activity of c-Raf-1 by insulin and phorbol ester stimulation. 819 29

The mos protooncogene encodes a serine/threonine protein kinase that is only expressed at significant levels in germ cells. Recombinant malE-mos protein (Xenopus mos protooncogene fused in frame to the maltose binding protein of E. coli) activates MAP kinase in cell-free extracts prepared from Xenopus oocytes and eggs. Here we show that malE-mos immunoprecipitates from Xenopus extracts phosphorylate and activate MAP kinase kinase in vitro, indicating that mos can function as a MAP kinase kinase kinase. Moreover, ectopic expression of mos in mammalian somatic cells, that lack any endogenous mos protein, triggers the activation of MAP kinase in vivo. These results identify the mos protooncogene as a direct activator of the MAP kinase pathway, with the potential to activate this kinase cascade even in cells where normally there is no expression of mos.
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PMID:The protein kinase mos activates MAP kinase kinase in vitro and stimulates the MAP kinase pathway in mammalian somatic cells in vivo. 822 61

Mitogen-activated protein kinases (MAPKs) are rapidly phosphorylated and activated in response to various extracellular stimuli in many different cell types. Such regulation of MAPK results from sequential activation of a series of protein kinases. The kinases that phosphorylate MAPKs, the MAP kinase kinases (MEKs) are also activated by phosphorylation. MEKs are related in sequence to the yeast protein kinases Byr1 (from Schizosaccharomyces pombe) and Ste7 (from Saccharomyces cerevisiae), which function in the pheromone-induced signaling pathway that results in mating. Byr1 and Ste7 are in turn regulated by the protein kinases Byr2 and Ste11. The amino acid sequence of the mouse homolog of Byr2 and Ste11, denoted MEKK (MEK kinase), was elucidated from a complementary DNA sequence encoding a protein of 672 amino acid residues (73 kilodaltons). MEKK was expressed in all mouse tissues tested, and it phosphorylated and activated MEK. Phosphorylation and activation of MEK by MEKK was independent of Raf, a growth factor-regulated protein kinase that also phosphorylates MEK. Thus, MEKK and Raf converge at MEK in the protein kinase network mediating the activation of MAPKs by hormones, growth factors, and neurotransmitters.
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PMID:A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. 838 2

Virtually all mitogens lead to the rapid activation of one or more mitogen-activated protein (MAP) kinases. In almost all cases, mitogen-activated surface signaling complexes transmit an essential signal via ras on to a protein kinase cascade that involves the serine/threonine kinase raf. Raf appears to be a MAP kinase kinase kinase, activating MAP kinase kinase which, in turn, activates MAP kinase. Among the targets of MAP kinase are other kinases, nuclear transcription factors and other proteins with roles in cell cycle activation. Both G0-arrested somatic cells and G2-arrested oocytes use many of the same signaling mechanisms to break cell cycle arrest; this is a useful concept in light of newly developed cell-free systems from quiescent oocytes that can be used to study signal transduction in vitro.
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PMID:MAP kinase and the activation of quiescent cells. 838 66

Activation of tyrosine kinase receptors causes mitogen-activated protein (MAP) kinase stimulation via a pathway involving p21ras, p74raf-1 (acting as a MAP kinase kinase kinase), and MAP kinase kinases; however, the pathway by which heterotrimeric G-protein-coupled receptors activate MAP kinases is undefined. Since there are several MAP kinase kinase kinases it has been suggested that p74raf-1 may only couple tyrosine kinase receptors to MAP kinase activation. We therefore investigated the requirement for p21ras and p74raf-1 in G-protein receptor-mediated MAP kinase activation. Lysophosphatidic acid stimulates MAP kinase via a pertussis toxin-sensitive pathway, which is blocked by dominant negative Ras. Lysophosphatidic acid-stimulated MAP kinase activation is potentiated by overexpression of p74raf-1 and blocked by expression of a dominant negative Raf protein comprising the N-terminal 259 amino acids. We conclude that lysophosphatidic acid activates MAP kinases by a G-protein-coupled pathway that requires both p21ras and p74raf-1.
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PMID:Lysophosphatidic acid stimulates mitogen-activated protein kinase activation via a G-protein-coupled pathway requiring p21ras and p74raf-1. 840 93

Plasma membrane-enriched fractions were prepared from human embryonic retinal cells transformed with either adenovirus E1A and oncogenic ras DNA, or E1A and E1B DNA. Ras comprised 5-10% of the membrane protein from the E1A/ras transformed cells, whereas the membranes from E1A/E1B transformed cells did not overexpress Ras. The membranes from E1A/ras cells contained MAP kinase kinase kinase (MAPKKK) activity, even after washing in 0.5 M NaCl, whereas the membranes from E1A/E1B cells did not. Neither membrane fraction contained MAP kinase kinase or MAP kinase activity after washing with 0.5M NaCl. Immunoblotting experiments revealed about 10-fold more c-Raf in the membranes from E1A/ras cells than from E1A/E1B cells, and 50-60% of the MAPKKK activity in Triton X100-solubilised membranes from E1A/ras cells was immunoprecipitated with anti-Raf antibodies. A striking enrichment of c-Raf in the plasma membranes of E1A/ras cells was also demonstrated by immunocytochemistry, where it was co-localized with Ras. The MAPKKK activity in E1A/ras membranes was unaffected by incubation with protein phosphatases or by inclusion of protein phosphatase inhibitors during isolation, nor was it activated by GTP-Ras or inhibited by GDP-Ras. The results support the view that Ras and c-Raf interact with one another, but that neither c-Raf phosphorylation nor its interaction with GTP-Ras are alone sufficient for activation. The identification of MAPKKK activity in the membranes of ras-transformed cells may prove useful in elucidating the mechanism by which Raf is activated by Ras.
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PMID:Specific association of activated MAP kinase kinase kinase (Raf) with the plasma membranes of ras-transformed retinal cells. 841 21


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