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)

We have shown that FGF (basic or acidic) is mitogenic for quiescent hamster lung fibroblasts (CCL39 line). It is active alone but is much more efficient in synergistic combinations with G-protein-activating agents. When used alone, FGF appears to exert its mitogenic effects without involving any of the major G-protein-mediated signaling pathways. It causes no significant hydrolysis of phosphoinositides, it does not alter the activity of adenylate cyclase, and its mitogenicity is insensitive to pertussis toxin. It therefore seems likely that all pleiotropic actions of FGF are primarily mediated by the intrinsic protein tyrosine kinase of its receptors. However, FGF, acting through its receptor tyrosine kinase, and thrombin, acting through G-protein-coupled receptors, induce a common set of early responses detected within seconds or minutes at the level of membranes, cytoplasm, and nuclei. Typical examples of early responses are activation of Na/H antiporter and Na/K/Cl cotransporter, phosphorylation of ribosomal protein S6, and increased transcription of early-immediate genes (c-fos, c-jun, and c-myc). Not only various classes of growth factors acting via distinct transducing mechanisms activate common targets, but also their synergistic effects on reinitiation of DNA synthesis is reflected on the early responses. How does the coordination of these signaling events take place? A partial answer to this question is illustrated in Figure 6 in which "switch kinases" play the role of integrators of multiple extracellular signals. Raf and, perhaps more convincingly, MAP kinases that are activated by dual phosphorylation on tyrosine and threonine residues are potential good candidates for this integration. This hypothetical scheme could therefore explain, in part, the coordination and the synergy commonly observed in the mitogenic response. The synergy could be generated at the level of MAP kinases simply by dual activating phosphorylations. With the recent cloning of MAP kinases, these questions will be more easily addressed. Another important gap that will have to be filled in future studies is the identification of all the members of the kinase cascade. When used in synergistic combinations with G-protein-activating agents, FGF does exert in contrast some effects on the G-protein-mediated pathways. It potentiates the G-protein-mediated activations of both PIP2-PLC and adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mitogenic effects of fibroblast growth factors in cultured fibroblasts. Interaction with the G-protein-mediated signaling pathways. 166 81

Human monoblastoid leukemia U937 cells differentiate to monocyte/macrophage upon treatment with phorbol ester, 12-o-tetradecanoylphorbol-13-acetate (TPA). Previous studies, including our own, have demonstrated that drug-induced differentiation of leukemia cells is associated with genetic and enzymatic activations of protein tyrosine phosphatases (PTPases). In this study, to further investigate a relationship between PTPase activation and leukemic differentiation, we established TPA-resistant U937 variant UT16 cells. Unlike known TPA-resistant cells whose resistance is mainly due to lack or down modulation of protein kinase C (PKC), UT16 cells showed TPA-induced activation of PKC, Raf-1, and ERK/MAP kinases similar to the parental U937 cells. Interestingly, however, UT16 cells exhibited altered binding activity of AP-1 complexes, decreased ability to induce c-jun and c-fos gene expressions, and failure to differentiate to a monocytic lineage. Based on these observations, UT16 cells could be considered a novel type of TPA-resistant cell. Among UT16 cells, most of TPA-inducible PTPase genes, PTP-1C, PTP-MEG2, P19-PTP, HPTP epsilon, and PTP-U1, did not respond to TPA. Consistently, TPA increased PTPase enzymatic activity in U937 but not in UT16 cells. Taken together, activation of PTPases is well correlated with TPA-induced differentiation of U937 cells. These findings indicate that gene expression and enzymatic activity of some PTPase isozymes described here are regulated by a TPA-mediated signaling event and are likely to be used as biomarkers for the monocytic differentiation of myeloid leukemia cells.
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PMID:Phorbol ester-resistant monoblastoid leukemia cells with a functional mitogen-activated protein kinase cascade but without responsive protein tyrosine phosphatases. 747 24

Sodium butyrate (SB), a naturally occurring short-chain fatty acid, was investigated for its therapeutic value as an antiproliferative agent for vascular smooth muscle cells (SMCs). At 5-mmol/L concentration, SB had no significant effect on rat SMC proliferation. However, at the same concentration, SB inhibited platelet-derived growth factor (PDGF)-AA-, -AB-, and -BB-induced proliferation of SMCs. Exposure of SMCs to PDGF-BB resulted in activation of receptor intrinsic tyrosine kinase activity and autophosphorylation of beta-PDGF-receptor (beta-PDGFR). The activated beta-PDGFR physically associated and phosphorylated signaling molecules such as ras-GTPase activating protein (GAP) and phospholipase C gamma (PLC gamma). SB, in the absence of PDGF-BB, caused neither beta-PDGFR tyrosine phosphorylation nor phosphorylation and association of GAP and PLC gamma with beta-PDGFR. PDGF-BB-enhanced activation of receptor intrinsic tyrosine kinase activity and autophosphorylation of tyrosine residues of beta-PDGFR were unaffected by SB irrespective of whether SMCs were preincubated with SB before exposure to PDGF-BB plus SB or incubated concomitantly with PDGF-BB plus SB. Likewise, phosphorylation and association of GAP and PLC gamma with PDGF-BB-activated beta-PDGFR were unaffected. In addition, SB did not block PDGF-BB-stimulated, PLC gamma-mediated production of inositol triphosphate. Similarly, PDGF-BB-induced beta-PDGFR degradation was unaffected when SMCs were exposed to PDGF-BB plus SB, and SB by itself had no influence on beta-PDGFR degradation. Unlike beta-PDGFR kinase activity, mitogen-activated protein kinase (MAP-kinase) activity was stimulated by SB by about 2.7-fold. Exposure of SMCs to PDGF-BB caused an approximately 11.4-fold increase in MAP-kinase activity and this increase in activity was not significantly affected when cells were coincubated with PDGF-BB and SB (10.3-fold). However, pretreatment of SMCs with SB for 30 minutes and subsequent incubation in PDGF-BB plus SB abolished most of the PDGF-BB-induced MAP-kinase activity (4.6-fold). Transcription of growth response genes such as c-fos, c-jun, and c-myc were induced by PDGF-BB, and their induction was suppressed, particularly c-myc, by incubating SMCs with PDGF-BB plus SB. Similarly, preincubation of cells with SB for 30 minutes and subsequent incubation in PDGF-BB plus SB diminished PDGF-BB-induced transcription of c-fos, c-jun, and c-myc. However, SB by itself had no significant effect on c-fos, c-jun, and c-myc transcription.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sodium butyrate inhibits platelet-derived growth factor-induced proliferation of vascular smooth muscle cells. 748 53

Growth hormone (GH) plays a central role in regulating growth and intermediary metabolism in vertebrates, although the mechanisms by which GH initiates these actions are largely unknown. The GH receptor, a member of the cytokine receptor superfamily, does not demonstrate homology with any known tyrosine kinases. However, addition of GH to cells in vitro has been shown to stimulate tyrosine phosphorylation of various intracellular proteins including mitogen-activated protein kinases (MAP kinases) and the newly described Janus kinase, JAK2. Subsequent steps in GH-mediated signal transduction have not been delineated. In the present study, we have examined early events in GH action in vivo. Hypophysectomized juvenile male rats were treated with GH for 15, 30, or 60 min. Rat liver whole cell and nuclear extracts were prepared and analyzed via SDS-polyacrylamide gel electrophoresis and Western blotting techniques. GH rapidly stimulated the tyrosine phosphorylation of at least 8 nuclear proteins of 205, 91, 83, 80, 65, 53, 44, and 42 kDa, and caused the dephosphorylation of a single approximately 149-kDa protein. Using specific antibodies, we have identified three of these nuclear phosphoproteins as 42- and 44-kDa MAP kinases, and as STAT91, a 91-kDa component of the interferon-stimulated gene factor-3 protein complex. One consequence of the activation of STAT91 in the nucleus is the appearance of GH-stimulated DNA binding activity, as assessed by gel-mobility shift assay using an oligonucleotide containing a c-sis-inducible element from the c-fos promoter. These results show that nuclear protein tyrosine phosphorylation is a prominent early event in GH action in vivo and demonstrate a link between GH-stimulated signal transduction and target gene expression.
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PMID:Rapid changes in nuclear protein tyrosine phosphorylation after growth hormone treatment in vivo. Identification of phosphorylated mitogen-activated protein kinase and STAT91. 751 Jun 76

When quiescent dog thyroid epithelial cells in primary culture are stimulated for 48 h with thyrotropin (TSH), forskolin acting through cAMP, or with cAMP-independent mitogens including epidermal growth factor (EGF), hepatocyte growth factor (HGF), and a tumor promoting phorbol ester (TPA), only 30-60% of cells progress through the cell cycle. A more general growth response requires the combination of EGF and TSH or forskolin. In this study we ask whether this intercellular heterogeneity in mitogen sensitivity could depend on a similar heterogeneity at early stages of the mitogenic stimulation process, i.e., at the levels of p42/p44 MAP kinase nuclear translocation and c-Fos protein appearance. We used indirect immunofluorescence microscopy with photometric quantitation and corroborated data using Western blotting. We analyzed the double staining of c-Fos and p42/p44 MAP kinases, since the nuclear translocation of these MAP kinases has been suggested as a key step for the stimulation of c-fos transcription. (i) EGF and HGF induced c-Fos accumulation and MAP kinase translocation in variable fractions of the cell population that corresponded to their relative potency as mitogens. c-Fos appearance and MAP kinase translocation poorly correlated in individual cells. Many cells accumulated c-Fos without any detectable p42/p44 MAP kinase translocation. The heterogeneity of proliferative responses to EGF could be due to the lack of c-Fos or MAP kinase responsiveness of many cells. (ii) TPA induced c-Fos accumulation and MAP kinase translocation within the whole cell population, which did not explain the heterogeneity of the growth response to this factor and showed that these events are not sufficient to elicit DNA synthesis, (iii) TSH and forskolin induced a weak c-Fos accumulation in only a minority of cells but, as previously shown, no p42/p44 MAP kinase phosphorylation and translocation. An important c-Fos expression was thus dispensable for the strong DNA synthesis stimulation exerted by cAMP-dependent mitogens. (iv) Forskolin potentiated the EGF effect on c-Fos expression but not on p42/p44 MAP kinase phosphorylation and translocation. This reflected the fact that EGF induced c-Fos accumulation in 90% of cells in the presence of forskolin but in 30-50% of cells in its absence. This kind of potentiation, which specifically implies an increase in the fraction of responding cells, is termed "generalization" in the present study.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Intercellular heterogeneity of early mitogenic events: cAMP generalizes the EGF effect on c-Fos protein appearance but not on MAP kinase phosphorylation and nuclear translocation in dog thyroid epithelial cells. 758 41

The c-fos serum response element (SRE) forms a ternary complex with the transcription factors SRF (serum response factor) and TCF (ternary complex factor). By itself, SRF can mediate transcriptional activation induced by serum, lysophosphatidic acid, or intracellular activation of heterotrimeric G proteins. Activated forms of the Rho family GTPases RhoA, Rac1, and CDC42Hs also activate transcription via SRF and act synergistically at the SRE with signals that activate TCF. Functional Rho is required for signaling to SRF by several stimuli, but not by activated CDC42Hs or Rac1. Activation of the SRF-linked signaling pathway does not correlate with activation of the MAP kinases ERK, SAPK/JNK, or MPK2/p38. Functional Rho is required for regulated activity of the c-fos promoter. These results establish SRF as a nuclear target of a novel Rho-mediated signaling pathway.
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PMID:The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. 2478 41

The ability of the receptor for the hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) to function in non-hematopoietic cells is unknown. NIH3T3 fibroblasts were transfected with cDNAs encoding the alpha and beta subunit of the human GM-CSF receptor and a series of stable transformants were isolated that bound GM-CSF with either low (KD = 860 - > 1000 pM) or high affinity (KD = 20-80 pM). Low affinity receptors were not functional. However, the reconstituted high affinity receptors were found to be capable of activating a number of signal transduction pathways, including tyrosine kinase activity, phosphorylation of Raf-1, and the transient induction of c-fos and c-myc mRNAs. The activation of protein tyrosine phosphorylation by GM-CSF in NIH3T3 cells was rapid (< 1 min) and transient (peaking at 5-20 min) and resulted in the phosphorylation of proteins of estimated molecular weights of 42, 44, 52/53 and 58-60 kDa. Some of these proteins co-migrated with proteins from myeloid cells that were phosphorylated on tyrosine residues in response to GM-CSF. In particular, p42 and p44 were identified as mitogen-activated protein kinases (MAP kinases), and the phosphorylation on tyrosine residues of p42 and p44 MAP kinases occurred at the same time as the phosphorylation of Raf-1. However, despite evidence for activation of many mitogenic signal transduction molecules, GM-CSF did not induce significant proliferation of transfected NIH3T3 cells. These results suggest that murine fibroblasts contain signal transducing molecules that can effectively interact with the human GM-CSF receptor, and that are sufficient to activate at least some of the same signal transduction pathways this receptor activates in myeloid cells, including activation of one or more tyrosine kinase(s). However, the level of activation of signal transduction is either below a threshold of necessary activity or at least one mitogenic signal necessary for proliferation is missing.
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PMID:The human granulocyte-macrophage colony-stimulating factor receptor is capable of initiating signal transduction in NIH3T3 cells. 768 77

MAP kinase (mitogen activated protein kinase) represents a ubiquitously expressed family of kinases whose long term activation via phosphorylation is essential for the mitogenic response in fibroblasts. Two family members, p42 and p44 MAP kinase are cytosolic proteins in quiescent cells, but become nuclear following mitogenic stimulation. Inactivation of MAP kinases occurs via a specific phosphatase, MKP-1. Hence, we examined the localisation of this phosphatase, to determine the cellular site of MAP kinase inactivation. Transient transfection of CCL39 fibroblasts with epitope-tagged MKP-1 showed the protein to be entirely nuclear in both quiescent and mitogen stimulated cells, whereas a catalytically inactive mutant in which the essential cysteine was mutated to serine (MKP-1CS) was predominately cytoplasmic and again serum stimulation failed to alter the protein's localisation. Expression of either wild type or inactive MKP-1 did not alter the cytosolic localisation of p44 MAP kinase in quiescent cells nor the ability of MAP kinase to translocate to the nucleus following mitogen stimulation. Expression of wild type MKP-1 inhibited serum stimulated early (c-fos promoter) and late (dhfr promoter) transcriptional events as well as entry into S-phase. This inhibition was reversed by the co-expression of an active MAP kinase. We conclude that in the continual expression of MKP-1, the cellular localisation of MAP kinase is unaffected and that inactivation of MAP kinase by MKP-1 is a nuclear process leading to the inhibition of cell division.
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PMID:Constitutive MAP kinase phosphatase (MKP-1) expression blocks G1 specific gene transcription and S-phase entry in fibroblasts. 776 Oct 91

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

Irradiation of HeLa cells with short-wavelength ultraviolet light (UVC) induces the modification and activation of the preexisting transcription factors c-Fos-c-Jun (AP-1) and TCF/Elk-1, as well as the protein synthesis independent transcriptional activation of the c-fos and c-jun genes. This response to UVC is mediated via obligatory cytoplasmic signal transduction, involving Ras and Raf, Src, and MAP kinases. The UVC response is inhibited by prior down-modulation of growth factor receptor signaling upon growth factor prestimulation, by suramin (an inhibitor of receptor activation) or by expression of a dominant negative epidermal growth factor (EGF) receptor mutant. These data suggest the involvement of several growth factor receptors in the UVC response. Indeed, UVC induces the suramin-inhibitable immediate tyrosine phosphorylation of the EGF receptor.
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PMID:Involvement of growth factor receptors in the mammalian UVC response. 792 65


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