Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flt-1 (fms-like tyrosine kinase-1), a receptor-type tyrosine kinase of sharing similar features with two other flt-family encoded proteins KDR/Flk-1 and Flt-4, has been recently identified as a receptor for Vascular Endothelial Growth Factor (VEGF) known to induce the proliferation of vascular endothelial cells. In this study, we demonstrate that Flt-1 encodes for a 180 kDa glycoprotein, binds VEGF with high affinity, undergoes autophosphorylation but does not generate any mitogenic response in transfected NIH3T3 fibroblasts. Interestingly, the immediate early gene c-myc was not induced, whereas the c-fos was induced very weakly in Flt-1 expressing NIH3T3 cells. A comparative analysis of the Flt-1 signal cascade in the environment of endothelial cells with that of Flt-1 expressing NIH3T3 cells showed that VEGF induced phosphorylation of PLC gamma and GAP complex on tyrosine in both type of cells. However, a strong activation of MAP kinases was observed only in endothelial cells. Further, different from many other receptor tyrosine kinases, tyrosine phosphorylation of Shc protein, an important adaptor for signal transduction from many receptor kinases, was very weak in both Flt-1-NIH3T3 cells and endothelial cells. These results suggest that Flt-1 kinase utilizes a unique signal transduction system in endothelial cells, and the activation of the Flt-1 kinase is insufficient to trigger a mitogenic response in NIH3T3 fibroblasts.
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PMID:A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. 782 66

The mechanism by which estradiol acts on cell multiplication is still unclear. Under conditions of estradiol-dependent growth, estradiol treatment of human mammary cancer MCF-7 cells triggers rapid and transient activation of the mitogen-activated (MAP) kinases, erk-1 and erk-2, increases the active form of p21ras, tyrosine phosphorylation of Shc and p190 protein and induces association of p190 to p21ras-GAP. Both Shc and p190 are substrates of activated src and once phosphorylated, they interact with other proteins and upregulate p21ras. Estradiol activates the tyrosine kinase/p21ras/MAP-kinase pathway in MCF-7 cells with kinetics which are similar to those of peptide mitogens. It is only after introduction of the human wild-type 67 kDa estradiol receptor cDNA that Cos cells become estradiol-responsive in terms of erk-2 activity. This finding, together with the inhibition by the pure anti-estrogen ICI 182 780 of the stimulatory effect of estradiol on each step of the pathway in MCF-7 cells proves that the classic estradiol receptor is responsible for the transduction pathway activation. Transfection experiments of Cos cells with the estradiol receptor cDNA and in vitro experiments with c-src show that the estradiol receptor activates c-src and this activation requires occupancy of the receptor by hormone. Our experiments suggest that c-src is an initial and integral part of the signaling events mediated by the estradiol receptor.
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PMID:Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. 863 62

Membrane phospholipids not only constitute structural membrane components, they also contain a wealth of biochemical information. They are the source of numerous lipid mediators (prostaglandins, leukotrienes, thromboxane, paf, lysophosphatidic acid and free fatty acids). These lipids act as second messengers inside the cell to modulate enzyme (e.g. PKC and GAP), ion channels (e.g. Ca2+ and K+) or the activity of factors regulating gene expression either at the transcriptional level (e.g. on the TNF alpha gene) or at the post-transcriptional level (e.g. on the GLUT4 transporter). The synthesis of lipid mediators results from the stimulation of phospholipase A2 (PLA2) activities. PLA2 cleaves membrane phospholipids to give rise to lysophospholipids and to free fatty acids from which second messengers are generated. More specifically, PLA2 provides the precursor for the eicosanoids, when the cleaved fatty acid is arachidonic acid, or for PAF, when the sn-1 position of the phospholipid is an alkyl ether linkage. Therefore, PLA2 is a key enzyme in the regulation of lipid mediators of inflammatory process. The purification and cloning of several PLA2s have demonstrated clear differences between secreted and intracellular PLA2. The secreted PLA2s are closely related proteins of low molecular weight (14 kDa) with calcium requirement in the mM range. They contain numerous bonds and retain the same amino-acids at the active site. In mammals, two types of secreted PLA2 have been identified: type I pancreatic PLA2 and type II inflammatory PLA2 which show 70% sequence homology. Recently, two others 14 kDa sPLA2 have been cloned which share also high homologies with type I and type II but contain respectively 6 and 8 disulpide bonds. In contrast, cellular PLA2s have higher molecular weights (40-110 kDa) and are either calcium independent or require microM amounts for activity. Cellular PLA2s preferentially act on sn-2-arachidonoyl phospholipids in vitro whereas sPLA2 do not display such selectivity in vitro. Both cellular and secreted PLA2s are involved in lipid mediator production. Cellular PLA2 can be activated by membrane receptors coupled to G proteins or by tyrosine kinase receptor, through the ras-raf1-MAP kinases network. Cellular PLA2s are thought to be involved in the initial production of lipid mediators after cell activation. Several lines of evidence suggest that secreted PLA2 is involved in the sustained production of lipid mediators in several cell types. These lines of evidence include the decrease in eicosanoid production by antibodies RNA of sPLA2. Furthermore, secreted PLA2s might trigger autocrine loops and proliferation responses through interaction with a specific receptor.
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PMID:[Diversity of phospholipases A2 and their functions]. 895 91

Ras proteins play a central role in the control of cellular proliferation. They are 189 amino acid monomeric GTP-binding proteins that cycle between an inactive GDP-bound and the active GTP-bound state, and carry a slow intrinsic GTPase activity. Ras proteins are activated by growth promoting signals incoming from receptor tyrosine kinases via SH2 domain and SH3 domain containing adapter proteins and the Ras exchange factor Sos, as well as from serpentine receptors via the beta gamma subunits of heterotrimeric G proteins and the Ras exchange factor Ras-GRF (or Cdc25). Proteins that can stimulate the GTPase activity of Ras (GAPs) ensure that following mitogenic stimulations, they return to their inactive GDP-bound state; amongst these proteins are p120-GAP, neurofibomin (the product of the susceptibility gene to type I neurofibromatosis), as well as the inositol 1,3,4,5-tetrakisphosphate-dependent GAPIP4BF. Several effectors have been identified that mediate the biological effects of Ras. The serine/threonine kinase Raf-1, as well as the closely related protein B-Raf, elicit the ERK cascade of MAP kinases. Phosphatidylinositol-3-OH kinase is involved in the activation of the Rac/Rho family proteins that play a role in the control of actin polymerisation, as well as in growth control, RalGDS, RGL and Rlf, are responsible for the activation of the Ras-related protein Ral. Recent evidence, using effector domain mutants of Ras, demonstrates that these pathways cooperate to elicit the growth promoting effects of Ras proteins.
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PMID:[Isoprenylated proteins and cell proliferation: regulators and effectors of Ras proteins]. 925 47

To address whether Ras can be activated by insulin in the PC12 cell line, proteins interacting with insulin receptor and IRS-1 molecules and their tyrosine phosphorylation were analyzed by immunoblotting following immunoprecipitation with antibodies. Tyrosine phosphorylation of the insulin receptor and IRS-1 was increased by insulin. Grb2 and Ras-GAP appeared in the immunoprecipitates by anti-insulin receptor and anti-IRS-1 from insulin-treated cells. In addition, PI 3-kinase was activated by insulin treatment in this cell line and Grb2, Ras-GAP, and MAP kinase were coprecipitated with Ras from both insulin-treated and NGF-treated cells. Analysis of MAP kinases from insulin-treated cells revealed that insulin, like NGF, increased tyrosine phosphorylation. However, activation of the MAP kinase by NGF lasted longer than activation by insulin. These results indicate that Ras can be activated by insulin in the PC12 cell line and that Ras activation is neither an accurate nor a plausible method of discriminating signals between proliferation and differentiation.
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PMID:Insulin activates Ras in the PC12 cell line. 926 35

The maturation of female Schistosoma mansoni depends on pairing with a male which induces mitotic activities in the reproductive organs of the female worm. Since in other organisms cell proliferation is regulated by well-conserved signal transducing molecules, we looked for such molecules on immunoblots of schistosomes, using antibodies against conserved epitopes of Ras, GAP and MAP kinases. We identified all 3 molecules in schistosomes and found that they are developmentally regulated. Furthermore, there is evidence for their involvement in the male-directed maturation of the female.
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PMID:Identification of Ras, MAP kinases, and a GAP protein in Schistosoma mansoni by immunoblotting and their putative involvement in male-female interaction. 948 74

The mechanism by which estradiol (E2) acts on cell proliferation is still unclear. In this paper, we report the results of a series of experiments in an attempt to elucidate the effector pathway(s) involved in coupling the E2 receptors binding to cellular growth response in leiomyoma cells (LSMC). Under conditions of E2-dependent growth, E2 treatment of LSMC triggers rapid and transient activation of the MAP-kinase pathway. Interestingly, we demonstrate that the early downstream signal transduction events determined by E2-stimulation in quiescent LSMC, including the rapid protein tyrosine phosphorylation of a subset of intracellular proteins, such GAP, PI-3-K, and PLCgamma, and the concomitant activation of ancillary protein kinases, are related to E2-induced PDGF secretion. Moreover, we identify the PDGF, alone or in association with other growth factors, as the main growth factor involved in the proliferation response of LSMC to E2 stimulation. The addition of neutralizing antibodies anti-PDGF was able to inhibit the mitogenic activity present in LSMC conditioned media samples. On the other hand, E2 did not affect the constitutive expression as well as the ligand affinity of PDGF receptors on LSMC plasmamembrane. Cell treatment with the antiestrogen ICI 182780 correlate both with a perturbation of E2-induced transductional circuit and with the disappearance of the mitogenic factor, PDGF, in LSMC conditioned media; the latter therefore, represents the main autocrine mediator of cell growth modulation, upregulated by E2 and down-regulated by antiestrogenic compound. Our experiments suggest that growth factor secretion is an initial and integral part of the signaling events mediated by the estradiol receptors, not related, at least in part, to E2 transcriptional modulation.
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PMID:17-beta estradiol elicits an autocrine leiomyoma cell proliferation: evidence for a stimulation of protein kinase-dependent pathway. 1116 81

Coculture with stromal cells tends to maintain normal hematopoietic progenitors and their leukemic counterparts in an undifferentiated, proliferative state. An example of this effect is seen with megakaryocytic differentiation, wherein stromal contact renders many cell types refractory to potent induction stimuli. This inhibitory effect of stroma on megakaryocytic differentiation correlates with a blockade within hematopoietic cells of protein kinase C-epsilon (PKC-epsilon) up-regulation and of extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase activation, both of which have been implicated in promoting megakaryocytic differentiation. In this study K562DeltaRafER.5 cells, expressing an estradiol-responsive mutant of the protein kinase Raf-1, were used to determine the relevance and stage of ERK/MAPK pathway blockade by stromal contact. Activation of DeltaRafER by estradiol overrode stromal blockade of megakaryocytic differentiation, implicating the proximal stage of the ERK/MAPK pathway as a relevant control point. Because stromal contact blocked delayed but not early ERK activation, the small guanosine triphosphatase (GTPase) Rap1 was considered as a candidate inhibitory target. Activation assays confirmed that Rap1 underwent sustained activation as a result of megakaryocytic induction, as previously described. As with ERK activation, stromal contact selectively blocked delayed but not early Rap1 activation, having no effect on Ras activation. Enforced expression of either wild-type Rap1 or the GTPase (GAP) resistant mutant Rap1 V12 failed to override stromal inhibition, suggesting that the inhibitory mechanism does not involve GAP up-regulation but rather may target upstream guanine nucleotide exchange factor (GEF) complexes. Accordingly, coimmunoprecipitation demonstrated stromally induced alterations in a protein complex associated with c-Cbl, a scaffolding factor for Rap1-GEF complexes.
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PMID:Stromal inhibition of megakaryocytic differentiation is associated with blockade of sustained Rap1 activation. 1239 69

At 8-12 weeks post axotomy, unusual distal processes (UDPs) with axon-like structural (uniform diameter, tortuous) and molecular (growth-associated protein [GAP]43, absence of microtubule-associated protein [MAP]2a/b immunoreactivity) features emerge from distal motoneuron dendrites (Rose et al. [2001] Eur J Neurosci 13:1166-1176). In this study, we determine the time course of molecular and morphological changes associated with the formation of axons from dendrites. Motoneurons innervating neck muscles in the adult cat were permanently axotomized for 2, 4, 20, or 35 weeks and intracellularly stained with Neurobiotin. Computer-assisted reconstructions were used to map the location of MAP2a/b and GAP-43 immunoreactivity. At 2 and 4 weeks post axotomy, all UDPs had short appendages, giving them an arboreal appearance. They were immunoreactive for GAP-43 and lacked immunostaining for MAP2a/b. Axon-like UDPs were not seen until 8-12 weeks post axotomy. By 20 and 35 weeks post axotomy, some axon-like UDPs acquired morphological features of axons with synaptic connections (right-angled branching, bouton-like specializations). GAP-43 immunoreactivity was not detected in any axotomized motoneurons by 20 weeks post axotomy, whereas all UDPs remained devoid of MAP2a/b immunoreactivity even at 35 weeks post axotomy. These molecular changes accompanied structural modifications to proximal regions of "dendrites" giving rise to UDPs. The distance from the ends of the UDPs to the soma did not change. Thus, all UDPs begin as simple, arboreal structures with molecular features of growing axons, but over a period of 35 weeks, some UDPs slowly acquire morphological and molecular features of motoneuron axons with synaptic connections. These results suggest a new modus operandi for axonal growth and the establishment of new synaptic connections after injury.
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PMID:The temporal sequence of morphological and molecular changes in axotomized feline motoneurons leading to the formation of axons from the ends of dendrites. 1464 82

Reactive oxygen species (ROS) are a continuous hazard in eukaroytic cells by their ability to cause damage to biomolecules, in particular to DNA. Previous data indicated that the cytosolic serine peptidase tripeptidyl-peptidase II (TPPII) translocates into the nucleus of most tumor cell lines in response to gamma-irradiation and ROS production; an event that promoted p53 expression as well as caspase-activation. We here observed that nuclear translocation of TPPII was dependent on signaling by MAP kinases, including p38MAPK. Further, this was caused by several types of DNA-damaging drugs, a DNA cross-linker (cisplatinum), an inhibitor of topoisomerase II (etoposide), and to some extent also by nucleoside-analogues (5-fluorouracil, hydroxyurea). In the minority of tumor cell lines where TPPII was not translocated into the nucleus in response to DNA damage we observed reduced intracellular ROS levels, and the expression levels of redox defense systems were increased. Further, treatment with the ROS-inducer gamma-hexa-chloro-cyclohexane (gamma-HCH, lindane), an inhibitor of GAP junctions, restored nuclear translocation of TPPII in these cell lines upon gamma-irradiation. Moreover, blocking nuclear translocation of TPPII in etoposide-treated cells, by using a peptide-derived inhibitor (Z-Gly-Leu-Ala-OH), attenuated expression of gamma-H2AX in gamma-irradiated melanoma cells. Our results indicated a role for TPPII in MAPK-dependent DNA damage signaling.
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PMID:MAP kinase-signaling controls nuclear translocation of tripeptidyl-peptidase II in response to DNA damage and oxidative stress. 2064


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