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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)

The mitogen-activated protein kinases (MAPKs) ERK-1 and ERK-2 are activated by a wide variety of oncogenes and extracellular stimuli. The MAPKs participate in a signalling cascade downstream of growth factor/cytokine receptors, Ras, Raf, and MEK. However, MAPK activation is more complicated than a simple linear pathway, and the evidence presented here supports a model of multiple, temporally distinct pathways converging on MAPK which are differentially utilized by various stimuli and cell types. In addition to MEK-dependent MAPK activation, we provide evidence for MEK-independent regulation of the MAPKs. Our results suggest that phosphatidylinositol-3-kinases (PI(3)K) or conventional protein kinase C isoforms (cPKCs) partially contribute to MEK-dependent activation. Importantly, we also find that PI3K and cPKCs play a major role in the MEK-independent, prolonged MAPK activation by platelet-derived growth factor signalling. This finding is of interest as the maintained activation of MAPK has been correlated by others to the regulation of cell proliferation and differentiation.
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PMID:Evidence for MEK-independent pathways regulating the prolonged activation of the ERK-MAP kinases. 913 64

PI3K was originally discovered as a lipid kinase involved in the phosphorylation of the inositol ring in position -3, leading to the synthesis of phosphatidyl-inositol-3-4 bisphosphate. The enzyme purified from rat liver is an heterodimer of two subunits of 85 and 110 KD respectively: it phosphorylates the D3 hydroxyl of phosphoinositides to produce phosphatidyl-inositol-3-phosphate. So far the function of the 3-phospho-inositide is unclear. It is likely that the entire phospholipid serves as a second messenger, since no phospholipase C has yet been found that can cleave the inositol group with a 3 phosphate residue. However the activation targets of this second messenger are still poorly known. Recently a novel/serine/theronine kinase was insolated by three groups and called differently RAC, PKB and AKT. It exhibits sequence homology with protein kinase A and C at the carboxyl terminal, whereas the aminoterminal domain has a plectrin homology. Activation of ATK is inhibited by wortmannin, a specific inhibitor of PI3K at very low concentrations. Furthermore inositol-3-phosphate can activate ATK in vitro. In addition very recently, a linkage of G-protein coupled receptors to the MAP kinase signalled pattern through PI3K has been discovered. But what is downstream of this pathway? 70S6 kinase is an attractive candidate since this kinase, involved in protein synthesis, is activated by AKT in vivo. Interestingly AKT is the cellular protooncogene of v-ATK and this implies that ATK induces a pathway of oncogenic transformation. AKT is inhibited by dominant negative mutants of ras and thus involved in the ras-raf-MAP kinase pathway. The role of PI3K is still indefinite but it must have a paramount importance in cell signalling since nearly all growth factor receptors recruit this enzyme and that the activity of fundamental growth factor receptors like PDGF, EGF and insulin are blocked by the specific inhibitor wortmannin, leading to the conclusion that the PI3K signal is much important in mitogenesis, protein synthesis, membrane ruffling, cell transformation and cell cycle progression.
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PMID:PI3K signal and DNA repair: a short commentary. 926 40

Wortmannin has been shown to be a non-competitive and irreversible inhibitor of PI3 kinase. For this reason, it has attracted considerable interest and it has been used, as a selective inhibitor of the PI3 kinase, for the study of signal transduction pathways in different systems including Xenopus oocytes. We show here that wortmannin itself is able to induce meiotic maturation at doses slightly higher that those required for complete inhibition of PI3 kinase. This effect was shown to be independent of the ability to inhibit PI3K since another unrelated PI3K inhibitor, LY294002, was unable to induce oocyte maturation at inhibitory concentrations for PI3 kinase. The mechanism for wortmannin-induced maturation involves the activation of maturation promoting factor (MPF) and MAP kinase activities in a time course that preceded the appearance of germinal vesicle breakdown. Thus, the pathway activated by wortmannin directly or indirectly affects other protein or proteins, besides PI3 kinase, responsible for its activity. This new target is placed independently or downstream of the PI3 kinase inhibition and upstream of protein synthesis. Moreover, the inhibition of either MPF or cAMP phosphodiesterase blocks wortmannin-induced maturation. We conclude that wortmannin may be a valuable tool for the study of the pathway leading to mitotic maturation of oocytes, but cannot be used as a specific PI3 kinase inhibitor.
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PMID:Wortmannin, an inhibitor of phosphatidyl-inositol 3-kinase, induces oocyte maturation through a MPF-MAPK-dependent pathway. 948 96

The receptor kinase activity associated with the epidermal growth factor (EGF) receptor and platelet-derived growth factor (PDGF) receptor plays an important role in ligand-induced signaling events. The effect of specific, synthetic chemical inhibitors of PDGF- and EGF-mediated receptor tyrosine autophosphorylation on receptor signaling were examined in NIH 3T3 cells overexpressing PDGF or EGF receptors. Specific inhibition of ligand-dependent receptor autophosphorylation, PI3K activation, mitogen-activated protein kinase (MAPK) activation, cyclin E-associated kinase activity and cell proliferation was measured after treatment of cells with these inhibitors. A synthetic PDGF receptor kinase inhibitor exhibited specific inhibitory properties when tested for PDGF-induced receptor autophosphorylation, MAPK activity, PI3K activation, entry into S phase and cyclin E-associated kinase activity. A synthetic EGF receptor kinase inhibitor showed selective inhibitor properties when tested for EGF-induced receptor autophosphorylation, MAPK activation, PI3K activation, entry into S phase and cyclin E-associated kinase activity. In both cases, these compounds were found to be effective as inducers of growth arrest and accumulation of cells in the G1 phase of the cell cycle after ligand treatment. However, at high concentrations, the EGF receptor kinase inhibitor was observed to exhibit some nonspecific effects as demonstrated by attenuation of PDGF-induced receptor autophosphorylation and cell cycle progression. This demonstrates that it is critical to use the lowest concentration of such an inhibitor that will alter the response under investigation, to have confidence that the conclusions derived from the use of such inhibitor are valid. We conclude that these experimental parameters signify useful end points to measure the relative selectivity of tyrosine kinase inhibitors that affect receptor-mediated signal transduction.
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PMID:Inhibition of platelet-derived growth factor and epidermal growth factor receptor signaling events after treatment of cells with specific synthetic inhibitors of tyrosine kinase phosphorylation. 958 Jun 35

STAT proteins become activated upon tyrosine and serine phosphorylation, are subsequently translocated from the cytosol to the nucleus where they exert DNA-binding activity. Several STAT binding consensus motifs have been identified in the promoters of distinct genes. These consensus elements mediate STAT recruitment and influence the kind of STAT proteins that are bound at a specific promoter site. Recent structure function analyses have revealed conserved amino terminal sequences to be crucial for phosphatase dependent deactivation of the STAT proteins. To date an increasing amount of data is available concerning the on- and off-regulation of STAT activity. Considerable convergence as well as crosstalk has been shown between the JAK-STAT pathway and the MAPK, RAS, PI3K, PKC, and PKA involving pathways. Moreover, the nature of the genes that are regulated by STAT proteins as well as the cell functions that result from STAT activation are of great current interest. Understanding the critical functional role of STAT mediated signalling events as well as their regulation by interfering pathways provides new insights into the mechanisms involved in malignant cell proliferation.
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PMID:The JAK-STAT pathway: signal transduction involved in proliferation, differentiation and transformation. 961 75

Shear stress differentially activates extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) by mechanisms involving Galphai2 and Gbeta/gamma proteins, respectively, in bovine aortic endothelial cells (BAEC). The early events in this signaling mechanism by which G proteins regulate ERK and JNK in response to shear stress have not been defined. Here we show that BAEC endogenously express a G protein-dependent form of phosphatidylinositol 3-kinase, PI3Kgamma, and its activity is stimulated by shear stress. PI3Kgamma activity was measured in vitro using BAEC that were transiently transfected with an epitope-tagged PI3Kgamma (vsv-PI3Kgamma). Exposure of BAEC to shear stress rapidly and transiently stimulated the activity of vsv-PI3Kgamma (maximum by 15 s, with a return to basal after 1-min exposure to 5 dyn/cm2 shear stress). Activity of vsv-PI3Kgamma was stimulated by shear stress intensities as low as 0.5 dyn/cm2. Treatment of BAEC with an inhibitor of PI3K, wortmannin, inhibited shear-dependent activation of JNK but had no effect on that of ERK. Furthermore, expression of a kinase-inactive mutant (PI3KgammaK799R) in BAEC inhibited the shear-dependent activation of JNK but not ERK. Taken together, these results suggest that PI3Kgamma selectively regulates the shear-sensitive JNK pathway. This differential and novel signaling pathway may be responsible for coordinating various mechanosensitive events in endothelial cells.
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PMID:Phosphatidylinositol 3-kinase gamma mediates shear stress-dependent activation of JNK in endothelial cells. 981 99

To determine whether potentiation of cell survival is an intrinsic function among the insulin receptor tyrosine kinase (RTK) family, we compared the ability of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-IR) cytoplasmic tails to attenuate apoptosis. Expression and activation of IGF-IR, in interleukin-3 (IL-3)-dependent 32Dcl.3 cells, prevents death under conditions of IL-3 withdrawal. In contrast, a chimeric receptor comprising the extracellular portion of IGF-IR fused to the cytoplasmic tail of IR (chIR) fails to promote cell survival when activated with ligand. Both chIR and IGF-IR exhibit comparable levels of enzymatic activity as evidenced by their ability to autophosphorylate and transphosphorylate the shc protein in vivo. Both chIR and IGF-IR can activate the MAPK signal transduction pathway; however, neither RTK is capable of promoting mitogenesis in the absence of IRS proteins. Structure function analysis of the IR cytoplasmic tail reveals that replacing the COOH-terminal 94 amino acids of the IR cytoplasmic tail with the comparable sequence from IGF-IR confers full antiapoptotic function. Furthermore, mutation of only two amino acids within IR, Phe-1264 and His-1265 to tyrosine (chIR/YY) is sufficient to impart a cell survival activity comparable to wild-type IGF-IR. Amino acid residues Phe-1264 and His-1265 of IR are in a region comparable to Tyr-1250 and Tyr-1251 within human IGF-IR. The amino acid sequence of IR from other species contains at least one tyrosine residue in this region, suggesting that differences in antiapoptotic function we observed may represent a characteristic unique to human members of this RTK family. The ability of IGF-IR or chIR/YY to prevent apoptosis is not blocked by addition of the PI3K inhibitor wortmannin. These studies define a critical region responsible for mediating cell survival through a novel interaction that is independent of mitogenesis.
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PMID:Identification of structural characteristics that contribute to a difference in antiapoptotic function between human insulin and insulin-like growth factor 1 receptors. 983 Dec 46

Phosphoinositide kinases (PI3Ks) play an important role in mitogenic signaling and cell survival, cytoskeletal remodeling, metabolic control and vesicular trafficking. Here we summarize the structure-function relationships delineating the activation process of class I PI3Ks involving various domains of adapter subunits, Ras, and interacting proteins. The resulting product, PtdIns(3,4,5)P3, targets Akt/protein kinase B (PKB), Bruton's tyrosine kinase (Btk), phosphoinositide-dependent kinases (PDK), integrin-linked kinase (ILK), atypical protein kinases C (PKC), phospholipase Cgamma and more. Surface receptor-activated PI3Ks function in mammals, insects, nematodes and slime mold, but not yeast. While many members of the class II family have been identified and characterized biochemically, it is presently unknown how these C2-domain containing PI3Ks are activated, and which PI substrate they phosphorylate in vivo. PtdIns 3-P is produced by Vps34p/class III PI3Ks and operates via the PtdIns 3-P-binding proteins early endosomal antigen (EEA1), yeast Vac1p, Vps27p, Pip1p in lysosomal protein targeting. Besides the production of D3 phosphorylated lipids, PI3Ks have an intrinsic protein kinase activity. For trimeric GTP-binding protein-activated PI3Kgamma, protein kinase activity seems to be sufficient to trigger mitogen-activated protein kinase (MAPK). Recent disruption of PI3K genes in slime mold, Caenorhabditis elegans, Drosophila melanogaster and mice further underlines the importance of PI3K signaling systems and elucidates the role of PI3K signaling in multicellular organisms.
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PMID:Structure and function of phosphoinositide 3-kinases. 983 78

With the aim of interrupting the growth factor-stimulated Ras signaling pathway at the level of the Grb2-Sos interaction, a peptidimer, made of two identical proline-rich sequences from Sos linked by a lysine spacer, was designed using structural data from Grb2 and a proline-rich peptide complexed with its SH3 domains. The peptidimer affinity for Grb2 is 40 nM whereas that of the monomer is 16 microM, supporting the dual recognition of both Grb2 SH3 domains by the dimer. At 50 nM, the peptidimer blocks selectively Grb2-Sos complexation in ER 22 (CCL 39 fibroblasts overexpressing epidermal growth factor receptor) cellular extracts. The peptidimer specifically recognizes Grb2 and does not interact with PI3K or Nck, two SH3 domain-containing adaptors. The peptidimer was modified to enter cells by coupling to a fragment of Antennapedia homeodomain. At 10 microM, the conjugate inhibits the Grb2-Sos interaction (100%) and MAP kinase (ERK1 and ERK2) phosphorylation (60%) without modifying cellular growth of ER 22 cells. At the same concentration, the conjugate also inhibits both MAP kinase activation induced by nerve growth factor or epidermal growth factor in PC12 cells, and differentiation triggered by nerve growth factor. Finally, when tested for its antiproliferative activity, the conjugate was an efficient inhibitor of the colony formation of transformed NIH3T3/HER2 cells grown in soft agar, with an IC50 of around 1 microM. Thus, the designed peptidimers appear to be interesting leads to investigate signaling and intracellular processes and for designing selective inhibitors of tumorigenic Ras-dependent processes.
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PMID:A Sos-derived peptidimer blocks the Ras signaling pathway by binding both Grb2 SH3 domains and displays antiproliferative activity. 987 27

The scatter factor/hepatocyte growth factor regulates scattering and morphogenesis of epithelial cells through activation of the MET tyrosine kinase receptor. In particular, the noncatalytic C-terminal tail of MET contains two autophosphorylation tyrosine residues, which form a multisubstrate-binding site for several cytoplasmic effectors and are thought to be essential for signal transduction. We show here that a MET receptor mutated on the four C-terminal tyrosine residues, Y1311F, Y1347F, Y1354F, and Y1363F, can induce efficiently a transcriptional response and cell scattering, whereas it cannot induce cell morphogenesis. Although the mutated receptor had lost its ability to recruit and/or activate known signaling molecules, such as GRB2, SHC, GAB1, and PI3K, by using a sensitive association-kinase assay we found that the mutated receptor can still associate and phosphorylate a approximately 250-kDa protein. By further examining signal transduction mediated by the mutated MET receptor, we established that it can transmit efficient RAS signaling and that cell scattering by the mutated MET receptor could be inhibited by a pharmacological inhibitor of the MEK-ERK (MAP kinase kinase-extracellular signal-regulated kinase) pathway. We propose that signal transduction by autophosphorylation of the C-terminal tyrosine residues is not the sole mechanism by which the activated MET receptor can transmit RAS signaling and cell scattering.
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PMID:The multisubstrate docking site of the MET receptor is dispensable for MET-mediated RAS signaling and cell scattering. 1006 3


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