Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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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)

Ras-induced malignant transformation requires Ras farnesylation, a lipid posttranslational modification catalyzed by farnesyltransferase (FTase). Inhibitors of this enzyme have been shown to block Ras-dependent transformation, but the mechanism by which this occurs remains largely unknown. We have designed FTI-276, a peptide mimetic of the COOH-terminal Cys-Val-Ile-Met of K-Ras4B that inhibited potently FTase in vitro (IC50 = 500 pM) and was highly selective for FTase over geranylgeranyltransferase I (GGTase I) (IC50 = 50 nM). FTI-277, the methyl ester derivative of FTI-276, was extremely potent (IC50 = 100 nM) at inhibiting H-Ras, but not the geranylgeranylated Rap1A processing in whole cells. Treatment of H-Ras oncogene-transformed NIH 3T3 cells with FTI-277 blocked recruitment to the plasma membrane and subsequent activation of the serine/threonine kinase c-Raf-1 in cells transformed by farnesylated Ras (H-RasF), but not geranylgeranylated, Ras (H-RasGG). FTI-277 induced accumulation of cytoplasmic non-farnesylated H-Ras that was able to bind Raf and form cytoplasmic Ras/Raf complexes in which Raf kinase was not activated. Furthermore, FTI-277 blocked constitutive activation of mitogen-activated protein kinase (MAPK) in H-RasF, but not H-RasGG, or Raf-transformed cells. FTI-277 also inhibited oncogenic K-Ras4B processing and constitutive activation of MAPK, but the concentrations required were 100-fold higher than those needed for H-Ras inhibition. The results demonstrate that FTI-277 blocks Ras oncogenic signaling by accumulating inactive Ras/Raf complexes in the cytoplasm, hence preventing constitutive activation of the MAPK cascade.
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PMID:Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. 759 20

Cysteine farnesylation of the Ras carboxyl terminal tetrapeptide CAAX motif (where C = cysteine, A = leucine, isoleucine, or valine, and X = methionine or serine) is required for Ras biological activity. In this report, we describe the effects of inhibitors of farnesyltransferase (FTase), the enzyme responsible for this lipid modification, on platelet-derived growth factor (PDGF) signaling in NIH-3T3 cells. In vitro, the CAAX peptidomimetic FTI-232 exhibits potent inhibition of FTase activity (IC50 = 150 nM) and its carboxyl-methylated counterpart, FTI-244, inhibits Ras processing in vivo. Treatment of NIH-3T3 cells with FTI-244 inhibits PDGF-induced DNA synthesis but not stimulation of mitogen-activated protein kinase (MAPK). However, FTI-244 significantly reduces PDGF-induced tyrosine phosphorylation levels of PDGF receptor (PDGFR) as well as its association with, and activation of, phosphatidylinositol-3-kinase (PI-3-K), a key enzyme in PDGF-induced mitogenesis.
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PMID:CAAX peptidomimetic FTI-244 decreases platelet-derived growth factor receptor tyrosine phosphorylation levels and inhibits stimulation of phosphatidylinositol 3-kinase but not mitogen-activated protein kinase. 766 49

Avian c-erbB is activated to a leukemia oncogene following truncation of its amino-terminal ligand-binding domain by retroviral insertion. The insertionally activated transcripts encode protein products which have constitutive tyrosine kinase activity and can induce erythroleukemia but not sarcomas. We have previously found that a valine-to-isoleucine point mutation at position 157 (V157I mutant) within the tyrosine kinase domain of this truncated erbB can dramatically activate the sarcomagenic potential of the oncogene and increase the kinase activity of this oncoprotein. This mutation lies at position 157 of the insertionally activated c-erbB product, affecting a highly conserved valine residue of the glycine loop involved in ATP binding and phosphate transfer. To investigate the functional importance of this residue in the catalytic activity of kinases, we have introduced at this position, by site-directed mutagenesis, codons representing the remaining 18 amino acid residues. Most of the mutants have diminished activity, with six of them completely devoid of kinase activity, indicating the sensitivity of this region to conformational changes. Some of these mutants displayed increased kinase activity and greater transforming potential in comparison with IA c-erbB, but none had levels as high as those of the V157I mutant. In general, the sarcomagenic potential of the various erbB mutants correlated with their autophosphorylation state and their ability to cause phosphorylation of MAP kinase. However, there are important exceptions such as the V157G mutant, which lacks enhanced autophosphorylation but is highly sarcomagenic. Studies of this and other autophosphorylation site mutants point to the existence of an autophosphorylation-independent pathway in sarcomagenesis. The requirement for leukemogenic potential is much less stringent and correlates with positivity of kinase activity. When the valine-to-isoleucine substitution was put in context of the full-length erbB protein, the mutation relaxed the ligand dependence and had a positive effect on the transforming potential of the full-length c-erbB.
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PMID:Modulation of erbB kinase activity and oncogenic potential by single point mutations in the glycine loop of the catalytic domain. 793 4

Neurons cultured from neonatal rat hypothalamus and brainstem contain many angiotensin II (Ang II) type 2 (AT2) receptors, and we previously determined that activation of these sites elicited a stimulation of serine/threonine phosphatase 2A (PP2A). Here, we have investigated the effects of Ang II on neuronal mitogen-activated protein (MAP) kinases, potential targets for PP2A. Using in-gel kinase assays and immunoprecipitation analyses we have shown that Ang II (10 nM-1 microM) elicits significant increases in p44(MAPK) (Erk1) and p42(MAPK) (Erk2) activities in cultured neurons, mediated via Ang II type 1 (AT1) receptors. This stimulatory effect of Ang II on Erk1 and Erk2 activities was potentiated by blockade of AT2 receptors with (S)-1-[4-(dimethylamino)-3-methylphenyl]methyl-5-(diphenylacetyl)- 4, 5,6,7-tetrahydro-1H-imidazo[4,5-C]pyridine-6-carboxylic acid (PD 123319, 1 microM). Furthermore, the AT2 receptor agonist N-alpha-nicotinoyl-Tyr-Lys-(N-alphaCBZ-Arg)-His-Pro-Ile-OH (CGP42112A) (10-50 nM) caused significant decreases in neuronal Erk1 and Erk2 activities, which were abolished by PD 123319 (1 microM) and by the PP2A inhibitor okadaic acid (3 nM). This indicates that AT1 and AT2 receptors have opposite actions on Erk1 and Erk2 activities in neonatal neurons. Since MAP kinases are involved in the regulation of growth/differentiation and apoptosis, our data may provide an intracellular basis for modulatory effects of Ang II receptors on these processes.
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PMID:Mitogen-activated protein kinases in rat brain neuronal cultures are activated by angiotensin II type 1 receptors and inhibited by angiotensin II type 2 receptors. 866 75

We have cloned a novel protein kinase from human cerebellum and named it LZK (leucine zipper-bearing kinase). The LZK cDNA encoded a 966-amino acid polypeptide that contains a kinase catalytic domain and double leucine/isoleucine zippers separated by a short spacer region. The amino acid sequence of the kinase catalytic domain was a hybrid between those in serine/threonine and tyrosine protein kinases, indicating that LZK belongs to the subfamily of the mixed lineage kinase (MLK) family. The kinase catalytic domain of LZK was most similar to DLK (Holtzman, L. B., Merritt, S.E., and Fan, G. (1994) J. Biol. Chem. 269, 30808-30817), MUK (Hirai, S., Izawa, M., Osada, S., Spyrou, G., and Ohno, S. (1996) Oncogene 12, 641-650), and ZPK (Reddy, U. R., and Presure, D. (1994) Biochem. Biophys. Res. Commun. 202, 613-620), which belong to the same subfamily of the MLK family. However, besides the kinase catalytic domain and double leucine/isoleucine zippers, there was no significant homology with known proteins. The recombinant LZK autophosphorylated in the presence of ATP and divalent cations, and exhibited serine/threonine kinase catalytic activity. Northern blot analysis revealed that LZK is expressed most strongly in the pancreas, with a pattern that differs from other MLKs. Expression of LZK in COS7 cells induced phosphorylation of c-Jun and activation of JNK-1, indicating the association of LZK in the c-Jun amino-terminal kinase/stress-activated protein kinase pathway. The expressed LZK was detected primarily in the membrane fraction, suggesting that LZK interacts with other cellular components in vivo.
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PMID:Molecular cloning and functional expression of a cDNA encoding a new member of mixed lineage protein kinase from human brain. 935 28

The growth rate of rodent embryonic neuroblasts and human neuroblastoma cell lines is regulated in part by autocrine or paracrine actions of neuropeptides of the family that includes vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), and pituitary adenylate cyclase-activating peptide (PACAP). These peptides act via seven transmembrane G-protein-linked receptors coupled to cAMP elevation, phospholipase C activation, intracellular Ca2+ release, and/or of mitogen-activated protein (MAP) kinase activation. Here we investigated the action of these peptides on the mouse neuroblastoma cell line Neuro2a. PHI and VIP inhibited proliferation at concentrations as low as 10(-13) M and 10(-10) M, respectively. In contrast, PACAP action was biphasic, with stimulation occurring at subnanomolar doses and inhibition at higher doses. Peptide actions were studied further by measuring cAMP and ERK1/2 MAP kinase activity and by assessing 3H-thymidine incorporation in conjunction with a panel of signal transduction pathways inhibitors. The data obtained indicated that the PHI-inhibitory and PACAP-stimulatory activities were mediated by corresponding changes in activity of the MAP kinase pathway and independent of protein kinase A (PKA) or protein kinase C (PKC). In contrast, the inhibitory actions of VIP and PACAP were specifically blocked by antagonists of PKA. Northern blot analysis revealed gene expression for only the PACAP-preferring (PAC1) receptor. However, binding experiments using 125I-labeled PACAP27, PHI, and VIP, demonstrated the presence of PACAP-preferring sites, bivalent VIP/PACAP sites, and PHI-binding sites that did not interact with VIP. The studies demonstrate potent regulatory actions of PACAP, PHI, and VIP on neuroblastoma cell proliferation which appear to be mediated by multiple subsets of receptors which differentially couple to MAP kinase and PKA signaling pathways.
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PMID:Differential effects of peptide histidine isoleucine (PHI) and related peptides on stimulation and suppression of neuroblastoma cell proliferation. A novel VIP-independent action of PHI via MAP kinase. 967 97

PC12 cells are well characterized for their ability to differentiate into neuronal-like cells when challenged with nerve growth factor. It has been reported that the calpain and proteasome inhibitor N-acetyl-Leu-Leu-norleucinal (CI) is also able to induce neurite outgrowth in PC12 cells. In this study, we report that the inhibitor of proteasomal chymotrypsin-like activity, carbobenzoxy-Ile-Glu-(O-tert-butyl)-Ala-Leu-aldehyde (PSI), can also induce differentiation of PC12 cells. Induction of neurite outgrowth with PSI, CI, or its close analogue, carbobenzoxy-Leu-Leu-leucinal (MG132), was associated with stress-activated protein kinase (SAPK) activation. Neurite formation induced by protease inhibition was independent of mitogen-activated protein kinase/extracellular signal-regulated kinase, p38/reactivating kinase, or phosphatidylinositol 3-kinase activities. The exact mechanism by which protease inhibition activates SAPKs remains to be elucidated; however, our results suggest that the SAPK signal transduction cascade may be an alternative and/or parallel pathway in the regulation of neuronal differentiation.
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PMID:Activation of stress-activated protein kinases correlates with neurite outgrowth induced by protease inhibition in PC12 cells. 1003 79

Shc and IRS-1 (and their relatives) are cytoplasmic docking proteins that possess phosphotyrosine-binding (PTB) domains, through which they bind specific activated receptor tyrosine kinases (RTK). The subsequent phosphorylation of Shc or IRS-1 creates binding sites for the SH2 domains of multiple signaling proteins, leading to the activation of intracellular biochemical pathways. The PTB domains of Shc and IRS-1 both recognize autophosphorylation sites in RTKs with the consensus sequence NPXpY, but show distinct abilities to bind stably to RTKs such as the TrkA nerve growth factor receptor and the insulin receptor. In vitro analysis has suggested that residues N-terminal to the NPXpY motif may determine the affinity with which phosphopeptide ligands are recognized by the Shc and IRS-1 PTB domains. Unlike IRS-1, the Shc PTB domain binds poorly to the insulin-receptor (IR) beta subunit in vitro, owing to its low affinity for the NPXpY autophosphorylation site at Tyr 960 of the IR. As a consequence, Shc does not bind stably to the activated IR in cells. We show that substitution of Ser 955, five residues N-terminal to the Tyr 960 autophosphorylation site (the -5 position), with Ile alters the target specificity of the IR such that it stably associates with Shc in insulin-stimulated cells. A triple substitution of the -5, -8 and -9 residues relative to Tyr 960 of the IR to the corresponding amino acids found in the Shc PTB domain binding site of TrkA results in even stronger binding of the IR to Shc in vivo. The variant IRs with enhanced ability to bind Shc showed an increased ability to activate the MAPK pathway in response to insulin stimulation. These results demonstrate that subtle differences in residues N-terminal to NPXpY autophosphorylation sites determine the ability of RTKs to bind specific PTB domain proteins in vivo, and thus modify the signaling properties of activated receptors.
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PMID:Re-engineering the target specificity of the insulin receptor by modification of a PTB domain binding site. 1034 Mar 78

Constitutive activating mutations of the TSHR gene, have been detected in about 30 per cent of hyperfunctioning human thyroid adenomas and in a minority of differentiated thyroid carcinomas. The mutations activating the TSHR gene(s) in the thyroid carcinomas, were located at the codon 623 changing an Ala to a Ser (GCC-->TCC) or in codon 632 changing a Thr to Ala or Ile (ACC-->GCC or ACC-->ATC). In order to study if the constitutively activated TSHR gene(s) has played a role in the determination of the malignant phenotype presented by these tumors, we investigated: (1) the transforming capacity after transfection of mouse 3T3 cells, of a TSHR cDNA activated by an Ala-->Ser mutation in codon 623 or an Thr-->Ile mutation in codon 632 and (2) the pathway(s) eventually responsible(s) for the malignant phenotype of the cells transformed by these constitutively activated TSHR cDNAs. Our results show that (1) the TSHR(M623) or (M632) cDNAs give rise to 3T3 clones presenting a fully neoplastic phenotype (growth in agar and nude mouse tumorigenesis); this phenotype was weaker in the cells transformed by the 632 cDNA; (2) suggest that the fully transformed phenotype of our 3T3 cells, may be the consequence of the additive effect of the activation of at least two different pathways: the cAMP pathway through G(alpha)s and the Ras dependent MAPK pathway through G(beta)gamma and PI3K and (3) show that the PI3K isoform playing a key role as an effector in the MAPK pathway activation in our 3T3-transformed cells is PI3Kgamma. Signaling from PI3Kgamma to MAPK appears to require in our murine cellular system a tyrosine kinase (still not characterized), Shc, Grb2, Sos, Ras and Raf. It is proposed that the constitutively activated TSHR genes detected in the thyroid carcinomas, may have played an oncogenic role, participating in their development through these two pathways.
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PMID:Role of the cAMP and MAPK pathways in the transformation of mouse 3T3 fibroblasts by a TSHR gene constitutively activated by point mutation. 1103 7

Using an in vitro chromatin assembly assay in Xenopus egg extract, we show that cyclin E binds specifically and saturably to chromatin in three phases. In the first phase, the origin recognition complex and Cdc6 prereplication proteins, but not the minichromosome maintenance complex, are necessary and biochemically sufficient for ATP-dependent binding of cyclin E--Cdk2 to DNA. We find that cyclin E binds the NH(2)-terminal region of Cdc6 containing Cy--Arg-X-Leu (RXL) motifs. Cyclin E proteins with mutated substrate selection (Met-Arg-Ala-Ile-Leu; MRAIL) motifs fail to bind Cdc6, fail to compete with endogenous cyclin E--Cdk2 for chromatin binding, and fail to rescue replication in cyclin E--depleted extracts. Cdc6 proteins with mutations in the three consensus RXL motifs are quantitatively deficient for cyclin E binding and for rescuing replication in Cdc6-depleted extracts. Thus, the cyclin E--Cdc6 interaction that localizes the Cdk2 complex to chromatin is important for DNA replication. During the second phase, cyclin E--Cdk2 accumulates on chromatin, dependent on polymerase activity. In the third phase, cyclin E is phosphorylated, and the cyclin E--Cdk2 complex is displaced from chromatin in mitosis. In vitro, mitogen-activated protein kinase and especially cyclin B--Cdc2, but not the polo-like kinase 1, remove cyclin E--Cdk2 from chromatin. Rebinding of hyperphosphorylated cyclin E--Cdk2 to interphase chromatin requires dephosphorylation, and the Cdk kinase-directed Cdc14 phosphatase is sufficient for this dephosphorylation in vitro. These three phases of cyclin E association with chromatin may facilitate the diverse activities of cyclin E--Cdk2 in initiating replication, blocking rereplication, and allowing resetting of origins after mitosis.
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PMID:Cyclin E uses Cdc6 as a chromatin-associated receptor required for DNA replication. 1125 26


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