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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vulval induction in Caenorhabditis elegans has helped define an evolutionarily conserved signal transduction pathway from receptor tyrosine kinases (RTKs) through the adaptor protein SEM-5 to RAS. One component present in other organisms, a guanine nucleotide exchange factor for Ras, has been missing in C.ELEGANS: To understand the regulation of this pathway it is crucial to have all positive-acting components in hand. Here we describe the identification, cloning and genetic characterization of C.ELEGANS: SOS-1, a putative guanine nucleotide exchanger for LET-60 RAS. RNA interference experiments suggest that SOS-1 participates in RAS-dependent signaling events downstream of LET-23 EGFR, EGL-15 FGFR and an unknown RTK. We demonstrate that the previously identified let-341 gene encodes SOS-1. Analyzing vulval development in a let-341 null mutant, we find an SOS-1-independent pathway involved in the activation of RAS signaling. This SOS-1-independent signaling is not inhibited by SLI-1/Cbl and is not mediated by PTP-2/SHP, raising the possibility that there could be another RasGEF.
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PMID:Caenorhabditis elegans SOS-1 is necessary for multiple RAS-mediated developmental signals. 1088 Apr 41

Midkine (MK) is a heparin-binding growth factor that promotes cell migration, cell growth and cell survival. The promotion of migration of inflammatory cells, especially macrophages, by MK is involved in formation of a vascular abnormality, i.e. neointima formation. MK-induced migration of peritoneal exudate macrophages was inhibited by heparin, chondroitin sulfate E and dermatan sulfate, but not by chondroitin sulfate D or chondroitin 6-sulfate. Digestion of macrophages with chondroitinase ABC as well as chondroitinase B decreased the migratory activity. However, heparitinase digestion showed only slight effects. These results indicated that a chondroitin sulfate, i.e. an E-type oversulfated structure with dermatan sulfate domain, is involved in MK-induced migration of macrophages. Although a chondroitin sulfate proteoglycan, receptor-type protein tyrosine phosphatase zeta (PTP zeta), participates in MK-induced migration of neurons and osteoblasts, PTP zeta was not detected in macrophages. The MK-induced migration was inhibited by PP1, wortomanin, PD 98059 and vanadate, indicating that the downstream signaling system, which includes Src, PI3 kinase and ERK as important components, is shared with other MK signaling systems in which PTP zeta is involved.
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PMID:Requirement of chondroitin sulfate/dermatan sulfate recognition in midkine-dependent migration of macrophages. 1192 7

Mitogen-activated protein kinases (MAPKs) mediate signaling from the cell membrane to the nucleus following their phosphorylation at conserved threonine and tyrosine residues within their activation loops. We show that protein tyrosine phosphatase epsilon (PTP epsilon) inhibits ERK1 and ERK2 kinase activity and reduces their phosphorylation; in agreement, ERK phosphorylation is increased in fibroblasts and in mammary tumor cells from mice genetically lacking PTP epsilon. PTP epsilon inhibits events downstream of ERKs, such as transcriptional activation mediated by Elk1 or by the serum response element. PTP epsilon also inhibits transcriptional activation mediated by c-Jun and C/EBP binding protein (CHOP) but not that mediated by the unrelated NFkB, attesting that it is broadly active within the MAPK family but otherwise specific. The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling. Slow induction of PTP epsilon and its lack of nuclear translocation following mitogenic stimulation suggest that PTP epsilon functions to prevent inappropriate activation and to terminate prolonged, rather than acute, activation of ERK in the cytosol.
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PMID:Protein tyrosine phosphatase epsilon inhibits signaling by mitogen-activated protein kinases. 1275 1

ERK MAP kinase plays a key role in relaying extracellular signals to transcriptional regulation. As different activity levels or the different duration of ERK activity can elicit distinct responses in one and the same cell, ERK has to be under strict positive and negative control. Although numerous genes acting positively in the ERK signaling pathway have been recovered in genetic screens, mutations in genes encoding negative ERK regulators appear underrepresented. We therefore sought to genetically characterize the dual-specificity phosphatase DMKP3. First, we established a novel assay to elucidate the substrate preferences of eukaryotic phosphatases in vivo and thereby confirmed the specificity of DMKP3 as an ERK phosphatase. The Dmkp3 overexpression phenotype characterized in this assay permitted us to isolate Dmkp3 null mutations. By genetic analysis we show that DMKP3 and the tyrosine phosphatase PTP-ER perform partially redundant functions on the same substrate, ERK. DMKP3 functions autonomously in a subset of photoreceptor progenitor cells in eye imaginal discs. In addition, DMKP3 function appears to be required in surrounding non-neuronal cells for ommatidial patterning and photoreceptor differentiation.
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PMID:The Drosophila dual-specificity ERK phosphatase DMKP3 cooperates with the ERK tyrosine phosphatase PTP-ER. 1281 May 95

It has been demonstrated that signal transducer and activator of transcription-3 (STAT3) is activated after cerebral ischemia/reperfusion (I/R) in cortex and striatum. In this study, we investigated whether STAT3 was rapidly activated in hippocampus by cerebral ischemia without reperfusion in four-vessel occlusion (4-VO) model of Sprague-Dawley (SD) rats. The results showed that tyrosine phosphorylation and DNA binding activity of STAT3 was rapidly increased by ischemia. The p-STAT3 level in cytoplasm increased 5 min after occlusion and reached a peak at 10 min following ischemia (1.7 folds vs sham) by means of immunoblotting (IB). P-STAT3 in nucleus was gradually enhanced with its peak activity occurring at 30 min of ischemia (2.3 folds vs sham). Electrophoretic mobility shift assay (EMSA) with STAT3 probe demonstrated that DNA binding activity of STAT3 in nuclear extracts increased from 5 min and peaked at 30 min of ischemia (3.2 folds vs sham). These changes were prevented by genistein (a protein tyrosine kinase inhibitor) and antioxidant N-acetyl-L-cysteine (NAC), but promoted by sodium orthovanadate (a protein phosphatase inhibitor), which were administered to the SD rats 20 min before ischemia. These results indicate that the activation of STAT3 following cerebral ischemia may be modulated by PTK/PTP, and that this pathway may be of benefit to the adaptation of the hippocampal neurons to oxidative stress.
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PMID:Activation of STAT3 induced by cerebral ischemia in rat hippocampus and its possible mechanisms. 1281 99

The protozoan parasite of the genus Leishmania has developed strategies to evade host defence mechanisms. Leishmania (L.) parasites interfere with several signalling pathways to inhibit phagocyte functions. In the present study, we analysed possible alteration of MAPK activation during infection of human U937 cell line with Leishmania major parasites. Analysis of whole cell lysates by anti-phosphotyrosine immunoblotting, showed that the pattern of tyrosine phosphorylated proteins were different for undifferentiated, PMA differentiated and Leishmania major infected cells. Cell infection induces a decrease in tyrosine phosphorylation of several host cell proteins, including PMA-induced tyrosine phosphorylated proteins. Leishmania major also caused a time dependent inhibition of ERK2 phosphorylation which correlates with the inhibition of ERK activity. This Leishmania induced effect was blocked when the cells were treated with a PTP inhibitor, prior to infection. These results suggest that Leishmania major may interfere with MAPK mediated signal transduction of the host cell through the inhibition of ERK2 activation and that this effect may be mediated by induction of protein tyrosine phosphatases activities.
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PMID:Leishmania major induces deactivation of extracellular signal regulated kinases 2 in human U937 macrophage like cells. 1465 27

Prolactin (PRL) involvement in the regulation of luteal steroidogenesis in pigs during the early luteal phase and pregnancy is well documented. The intracellular mechanism of PRL action in steroidogenic cells, however, is not fully recognized yet. In the current study, we have tested the hypothesis that protein kinase C (PKC) and tyrosine kinases (PTK) as well as serine-threonine (PP) and tyrosine phosphatases (PTP) are involved in PRL signaling in luteal cells originated from the early corpora lutea (CL) of cyclic sows. Luteal cells (50 000 cells/ml M199) were incubated for 8 h (37 degrees C) with PRL (200 ng) and low density lipoproteins (LDL) to stimulate P(4) production. In addition, treatments included: PKC inhibitors--staurosporine and chelerythrine chloride; tyrosine kinase inhibitors--genistein and tyrphostin; serine-threonine phosphatase inhibitors--okadaic acid, cantharidin (inhibitors of PP1/2A) and cypermethrin (inhibitor of PP2B); and tyrosine phosphatase inhibitor--sodium orthovanadate. Moreover, after incubation (37 degrees C) with PRL (200 ng) for 2, 5, 10 or 20 min, luteal cells were homogenized and cytosolic as well as membrane fractions have been obtained. This was followed by partial purification of the subcellular fractions by DEAE-cellulose chromatography and determination of PKC activity by measuring the transfer of (32)P from [gamma-(32)P]ATP to histone III-S. In unstimulated porcine luteal cells the major proportion of PKC activity was present in the cytosol. Incubation of luteal cells with PRL resulted in a rapid, time dependent increase in the amount of PKC activity in the membrane fraction and a decrease in the amount of PKC activity in the cytosol fraction. PKC activity in the membrane fraction was maximal after 5 min of exposure the cells to PRL. Inhibitors of PKC and PTK suppressed PRL and LDL-induced P(4) production by porcine luteal cells. It is of interest that stimulated P(4) production was also reduced by inhibitors of PTP and PP1/2A (okadaic acid, cantharidin). In contrast, cypermethrin did not affect P(4) production stimulated by PRL and LDL. The results of the current study support the hypothesis that PKC and tyrosine kinases are intracellular mediators of PRL action in porcine luteal cells during the first days of the estrous cycle. The involvement of protein phosphatases in transmission of the PRL signal in early luteal cells in pigs is also suggested.
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PMID:Luteotrophic action of prolactin during the early luteal phase in pigs: the involvement of protein kinases and phosphatases. 1466 68

The receptor-type form of protein tyrosine phosphatase epsilon (RPTP) is among the few tyrosine phosphatases that can support the transformed phenotype of tumor cells. Accordingly, cells from mammary epithelial tumors induced by activated Neu in mice genetically lacking RPTP appear morphologically less transformed and exhibit reduced proliferation. The effect of RPTP in these cells is mediated at least in part by its ability to activate Src, the prototypic member of a family of related kinases. We show here that RPTP is a physiological activator of two additional Src family kinases, Yes and Fyn. Activities of both kinases are inhibited in mammary tumor cells lacking RPTP, and phosphorylation at their C-terminal inhibitory tyrosines is increased. In agreement, opposite effects on activities and phosphorylation of Yes and Fyn are observed following increased expression of PTP. RPTP also forms stable complexes with either kinase, providing physical opportunity for their activation by RPTP. Surprisingly, expression of Yes or of Fyn does not rescue the morphological phenotype of RPTP-deficient tumor cells in contrast with the strong ability of Src to do so. We conclude that RPTP activates Src, Yes, and Fyn, but that these related kinases play distinct roles in Neu-induced mammary tumor cells.
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PMID:Protein tyrosine phosphatase epsilon activates Yes and Fyn in Neu-induced mammary tumor cells. 1498 May 17

Fibroblast growth factor (FGF)-1 and -2 have potent biological activities implicated in malignant tumor development. Their autocrine and nonautocrine activity in tumor progression of carcinoma was investigated in the NBT-II cell system. Cells were manipulated to either produce and be autocrine for FGF-1 or -2 or to only produce but not respond to these factors. The autocrine cells are highly invasive and tumorigenic and the determination of specific targets of FGF/fibroblast growth factor receptor (FGFR) signaling was assessed. In vitro studies showed that nonautocrine cells behave like epithelial parental cells, whereas autocrine cells have a mesenchymal phenotype correlated with the overexpression of urokinase plasminogen activator receptor (uPAR), the internalization of E-cadherin, and the redistribution of beta-catenin from the cell surface to the cytoplasm and nucleus. uPAR was defined as an early target, whereas E-cadherin and the leukocyte common antigen-related protein-tyrosine phosphatase (LAR-PTP) were later targets of FGF signaling, with FGFR1 activation more efficient than FGFR2 at modulating these targets. Behavior of autocrine cells was consistent with a decrease of tumor-suppressive activities of both E-cadherin and LAR-PTP. These molecular analyses show that the potential of these two growth factors in tumor progression is highly dependent on specific FGFR signaling and highlights its importance as a target for antitumor therapy.
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PMID:Targets of fibroblast growth factor 1 (FGF-1) and FGF-2 signaling involved in the invasive and tumorigenic behavior of carcinoma cells. 1528 42

NK (natural killer) cells are lymphocytes of the innate immune system that are involved in early defense mechanisms against foreign cells as well as autologous cells that are undergoing various forms of stress, such as microbial infection (viral, bacterial, or parasitic), tumor transformation, or nonmalignant activation. NK cell activation is controlled by a dynamic balance between complementary and antagonist pathways that are initiated when they bind a cell targeted for destruction. The Natural Killer Cell Signaling Pathway illustrates the signals produced by the activating cell surface receptors that initiate PTK (protein tyrosine kinase)-dependent pathways through their noncovalent association with transmembrane signaling adaptors that harbor ITAMs (immunoreceptor tyrosine-based activation motifs). This Connections Map also describes the mechanism by which these positive pathways are antagonized by intracytoplasmic PTPs (protein tyrosine phosphatases) that are activated upon engagement of cell surface receptors with intracytoplasmic ITIMs (immunoreceptor tyrosine-based inhibition motifs). The tyrosine phosphorylation status of several signaling components that are substrates for both PTKs and PTPs is thus key to the propagation of the NK cell effector pathways. Additional cell surface receptors that are not directly coupled to ITAMs also participate in NK cell activation, such as NKG2D (which is noncovalently associated with the DAP10 transmembrane signaling adaptor), adhesion molecules, and cytokine receptors. Understanding the integration of these signals into the "canonical" PTK-PTP equilibrium represents the future challenge for the elucidation of NK cell effector signaling pathways.
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PMID:Natural killer cell receptor signaling pathway. 1601 3


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