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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The expression of the human CL100 gene and its mouse homologue 3CH134 is increased up to 40-fold in fibroblasts exposed to oxidative/heat stress and growth factors. CL100 is a member of an expanding family of protein tyrosine phosphatases with amino acid sequence similarity to a Tyr/Ser-protein phosphatase encoded by the late H1 gene of vaccinia virus. Here we show that the CL100 phosphatase, expressed and purified in bacteria, rapidly and potently inactivates recombinant MAP kinase in vitro by the concomitant dephosphorylation of both its phosphothreonine and phosphotyrosine residues. Furthermore, CL100 suppresses the [val12] ras-induced activation of MAP kinase in a cell-free system from Xenopus oocytes. Both activities are abolished by mutagenesis of the highly conserved cysteine (Cys-258) within the phosphatase active site. In contrast to the vaccinia H1 phosphatase, CL100 shows no measurable catalytic activity towards a number of other substrate proteins modified on serine, threonine or tyrosine residues. Our results demonstrate that CL100 is a dual specificity phosphatase and indicate that MAP kinase is one of its physiological targets. CL100 may be the first example of a new class of protein phosphatases responsible for modulating the activation of MAP kinase following exposure of quiescent cells to growth factors and further implicates MAP kinase activation/deactivation in the cellular response to stress.
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PMID:The human CL100 gene encodes a Tyr/Thr-protein phosphatase which potently and specifically inactivates MAP kinase and suppresses its activation by oncogenic ras in Xenopus oocyte extracts. 839 41

Mitogen-activated protein (MAP) kinases Raf-1, pp60src, and p21ras all play important roles in the transfer of signals from the cell surface to the nucleus. We have used the baculovirus/Sf9 insect cell system to elucidate the regulatory relationships between pp60v-src, p21v-ras, MAP kinase (p44erk1/mapk), and Raf-1. In Sf9 cells, p44erk1/mapk is activated by coexpression with either v-Raf or a constitutively activated form of Raf-1 (Raf22W). In contrast, p44erk1/mapk is activated to only a limited extent by coexpression with either Raf-1 or p21v-ras alone. This activation of p44erk1/mapk is greatly enhanced by coexpression with both p21v-ras and Raf-1. Since we have previously shown that p21v-ras stimulates Raf-1 activity, the activation of p44erk1/mapk by p21v-ras may occur exclusively via a Raf-1-dependent pathway. However, a dominant-inhibitory mutant of Raf-1 (Raf301) does not block the activation of p44erk1/mapk by p21-v-ras. Further, pp60v-src, which activates Raf-1 at least as effectively as p21v-ras, fails to enhance p44erk1/mapk activity greatly when coexpressed with Raf-1. These data suggest that activation of p44erk1/mapk by p21v-ras may occur via both Raf-1-dependent and Raf-1-independent pathways.
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PMID:Raf-1 and p21v-ras cooperate in the activation of mitogen-activated protein kinase. 839 Jun 81

Transforming growth factor beta 1 (TGF beta 1) is a potent inhibitor of epithelial cell growth, although the mechanism of growth inhibition remains unknown. We report here a critical relationship between cellular p21ras activity and TGF beta 1 action. Microinjection of oncogenic Ha-ras protein into TGF beta 1-arrested mink lung epithelial cells overcomes TGF beta 1 growth inhibition and allows progression into S phase. Cells released from TGF beta 1 inhibition following microinjection with anti-p21ras antibody, on the other hand, remain TGF beta 1-arrested and do not enter S phase, indicating a requirement for p21ras activity. These biological data are substantiated biochemically in that TGF beta 1 is shown to decrease the activation state of endogenous p21ras, as measured by the level of GTP-bound p21ras. In addition, the phosphorylation and kinase activity of mitogen-activated protein kinase, which depends upon cellular ras activity, is elevated in cells which have been released from growth arrest by TGF beta 1. Together these data demonstrate the involvement of p21ras activity in TGF beta 1-induced growth inhibition and suggest that the inhibitor controls proliferation by modulating the activity of p21ras.
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PMID:Release from G1 growth arrest by transforming growth factor beta 1 requires cellular ras activity. 840 89

Raf-1 is a serine/threonine kinase which is essential in cell growth and differentiation. Tyrosine kinase oncogenes and receptors and p21ras can activate Raf-1, and recent studies have suggested that Raf-1 functions upstream of MEK (MAP/ERK kinase), which phosphorylates and activates ERK. To determine whether or not Raf-1 directly activates MEK, we developed an in vitro assay with purified recombinant proteins. Epitope-tagged versions of Raf-1 and MEK and kinase-inactive mutants of each protein were expressed in Sf9 cells, and ERK1 was purified as a glutathione S-transferase fusion protein from bacteria. Raf-1 purified from Sf9 cells which had been coinfected with v-src or v-ras was able to phosphorylate kinase-active and kinase-inactive MEK. A kinase-inactive version of Raf-1 purified from cells that had been coinfected with v-src or v-ras was not able to phosphorylate MEK. Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. We conclude that MEK is a direct substrate of Raf-1 and that the activation of MEK by Raf-1 is due to phosphorylation by Raf-1, which is sufficient for MEK activation. We also tested the ability of protein kinase C to activate Raf-1 and found that, although protein kinase C phosphorylation of Raf-1 was able to stimulate its autokinase activity, it did not stimulate its ability to phosphorylate MEK.
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PMID:Reconstitution of the Raf-1-MEK-ERK signal transduction pathway in vitro. 841 57

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

Vulval induction in C. elegans is controlled by a highly conserved signaling pathway similar to the RTK-Ras-MAPK cascade in mammals. By screening for suppressors of the Multivulva phenotype caused by an activated let-60 ras allele, we isolated mutations in a gene, ksr-1, that acts as a positive modifier of vulval induction and is required for at least two other let-60 ras-mediated processes. Although ksr-1 mutations do not perturb vulval induction in an otherwise wild-type background, they have very strong effects on vulval induction in genetic backgrounds where Ras pathway activity is constitutively activated or compromised, suggesting that ksr-1 activity is required for maximal stimulation of vulval fates by the Ras pathway. Genetic epistasis analysis suggests that ksr-1 acts downstream of or in parallel to let-60 ras. We cloned ksr-1 and have shown that it encodes a novel putative protein kinase related to the Raf family of Ser/Thr kinases.
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PMID:The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction. 852 6

The STP-C488 oncogene of herpesvirus saimiri has transforming activity independent of the rest of the viral genome. We now demonstrate that STP-C488 associates with cellular ras in transformed cells. Mutations that disrupted this association with ras disrupted the transforming ability of the STP-C488 oncogene. Binding assays showed that STP-C488 was capable of competing with raf-1 for binding to ras. Expression of STP-C488 activated the ras signaling pathway as evidenced by a two- to fourfold increase in the ratio of ras-GTP to ras-GDP and by the constitutive activation of mitogen-activated protein kinase. Consistent with an activation of signaling through ras, STP-C488 expression induced ras-dependent neurite outgrowth in PC12 cells. STP-C488 is the first virus-encoded protein shown to achieve oncogenic transformation via association with cellular ras.
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PMID:Association of the viral oncoprotein STP-C488 with cellular ras. 852 15

We have examined whether activation of MAP kinases [or extracellular signal-regulated kinases (ERKs)] is required for the survival of rat sympathetic neurons by comparing the actions of three survival factors whose survival-promoting actions can be blocked by neutralizing Fab fragments to p21 ras (Nobes and Tolkovsky, 1995, Eur. J. Neurosci., 7, 344-350), nerve growth factor (NGF), the cytokines ciliary neurotrophic factor (CNTF) and leukaemia inhibitory factor (LIF), and the cyclic AMP analogue 4-(8-chlorophenylthio)cAMP (CPTcAMP). NGF-induced survival was accompanied by an intense (15- to 30-fold) and steady (> 24 h) activation of p44 and p42 ERKs which waned rapidly (t1/2 approximately 30 min) upon NGF withdrawal. However, concentrations of NGF that induced a weak (4- to 5-fold) stimulation of the ERKs were not sufficient to maintain long-term survival. Moreover, prolonged and intense stimulation of the ERKs by NGF for up to 15.5 h was unable to confer long-term survival, since withdrawal of NGF after this time resulted in neuronal death that was kinetically indistinguishable from the death of neurons that had not been exposed to NGF. By contrast, CNTF and LIF continued to support survival for up to 3 days after eliciting only transient (< 30 min and 1 h respectively) activation of p44 and p42 ERKs, while CPTcAMP induced survival for several days without any measurable activation of the ERKs. Taken together, these data suggest that ERK activation per se is neither necessary nor sufficient for survival and that alternative pathways exist for effecting long-term survival of rat sympathetic neurons.
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PMID:Activation of p44 and p42 MAP kinases is not essential for the survival of rat sympathetic neurons. 854 72

Interaction of cells with extracellular matrix via integrin adhesion receptors plays an important role in a wide range of cellular: functions, for example cell growth, movement, and differentiation. Upon interaction with substrate, integrins cluster and associate with a variety of cytoplasmic proteins to form focal complexes and with the actin cytoskeleton. Although the intracellular signals induced by integrins are at present undefined, it is thought that they are mediated by proteins recruited to the focal complexes. It has been suggested, for example, that after recruitment to focal adhesions p125FAK can activate the ERK1/2 MAP kinase cascade. We have previously reported that members of the rho family of small GTPases can trigger the assembly of focal complexes when activated in cells. Using microinjection techniques, we have now examined the role of the extracellular matrix and of the two GTP-binding proteins, rac and rho, in the assembly of integrin complexes in both mouse and human fibroblasts. We find that the interaction of integrins with extracellular matrix alone is not sufficient to induce integrin clustering and focal complex formation. Similarly, activation of rho or rac by extracellular growth factors does not lead to focal complex formation in the absence of matrix. Focal complexes are only assembled in the presence of both matrix and functionally active members of the rho family. In agreement with this, the interaction of integrins with matrix in the absence of rho/rac activity is unable to activate the ERK1/2 kinases in Swiss 3T3 cells. In fact, ERK1/2 can be activated fully by growth factors in the absence of matrix and it seems unlikely, therefore, that the adhesion dependence of fibroblast growth is mediated through the ras/MAP kinase pathway. We conclude that extracellular matrix is not sufficient to trigger focal complex assembly and subsequent integrin-dependent signal transduction in the absence of functionally active members of the rho family of GTPases.
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PMID:The assembly of integrin adhesion complexes requires both extracellular matrix and intracellular rho/rac GTPases. 855 52


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