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)

The tumor suppressor p16/CDKN2A/INK4a gene is frequently mutated, mostly by homozygous deletions in high-grade gliomas. Although the p16 protein suppresses cell proliferation primarily through inhibition of cell-cycle progression at the G1 phase, other phenotypic changes in glioma cells associated with p16INK4a alterations have not been fully described. To determine the roles of p16 alterations in glioma formation, we have established ecdysone-driven inducible p16 expression in the human glioblastoma cell line CL-4, which were derived from p16-null U87MG cells. Here we show that exogenous p16 expression in CL-4 cells results in morphological changes, with large and flattened cytoplasm, which are associated with increased formation of cytoplasmic actin-stress fibers and vinculin accumulation in the focal adhesion contacts. Adhesion of CL-4 cells to extracellular matrix proteins, such as laminin, fibronectin, and type IV collagen, significantly increased upon exogenous p16 expression, which correlated with increased expression of integrin alpha5 and alphav. Expression of a small GTP-binding protein, Rac, also decreased. Following epidermal growth factor stimulation, phosphorylation of MAP kinases ERK1 and 2 and induction of an early immediate gene product, c-Fos, were significantly reduced in CL-4 cells with p16 expression. These results suggest that the tumor suppressor p16 may exert its antitumor effects through modulation of multiple aspects of glioblastoma phenotypes, including proliferation, invasiveness, and responsiveness to extracellular growth stimuli.
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PMID:Phenotypic changes associated with exogenous expression of p16INK4a in human glioma cells. 1190 77

It is well established that mechanical forces can regulate cell growth and guide tissue remodeling, yet little is known about how mechanical signals act at the cell surface membrane to produce biochemical changes in the cell. To explore this question, I used a mouse embryonic F9 vinculin-deficient cell line (gamma229), which, unlike wild-type cells, shows no fibronectin-dependent cell spreading. The wild-type cell line exhibited a twofold increase in area over four hours. I observed (i) an earlier rise in intracellular free calcium from approximately 0.2 to approximately 3 microm in wild-type compared with gamma229 cells, thus similar calcium levels after 4 h; (ii) an initial higher ratio of p-MAP/MAP-Kinase for gamma229, but similar FA-Kinase activation; and (iii) a marginal change in intracellular pH [pH](i) in both F9 cell lines. When I applied controlled local stresses directly to integrin receptors using RGD-coated magnetic beads, they displaced to a lesser extent in wild-type than in gamma229 cells. Both F9 cell lines showed a small stress-dependent rise in [Ca2+]i levels and similar PKA-c activity. In summary, the mechanical linkage of integrin-vinculin-cytoskeleton seemed not to be essential for chemical signal transduction.
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PMID:The coupling of vinculin to the cytoskeleton is not essential for mechano-chemical signaling in F9 cells. 1199 56

Mn is a neurotoxin that leads to a syndrome resembling Parkinson's disease after prolonged exposure to high concentrations. Our laboratory has been investigating the mechanism by which Mn induces neuronal cell death. To accomplish this, we have utilized rat pheochromocytoma (PC12) cells as a model since they possess much of the biochemical machinery associated with dopaminergic neurons. Mn, like nerve growth factor (NGF), can induce neuronal differentiation of PC12 cells but Mn-induced cell differentiation is dependent on its interaction with the cell surface integrin receptors and basement membrane proteins, vitronectin or fibronectin. Similar to NGF, Mn-induced neurite outgrowth is dependent on the phosphorylation and activation of the MAP kinases, ERK1 and 2 (p44/42). Unlike NGF, Mn is also cytotoxic having an IC50 value of approximately 600 microM. Although many apoptotic signals are turned on by Mn, cell death is caused ultimately by disruption of mitochondrial function leading to loss of ATP. RT-PCR and immunoblotting studies suggest that some uptake of Mn into PC12 cells depends on the divalent metal transporter 1 (DMT1). DMT1 exists in two isoforms resulting from alternate splicing of a single gene product with one of the two mRNA species containing an iron response element (IRE) motif downstream from the stop codon. The presence of the IRE provides a binding site for the iron response proteins (IRP1 and 2); binding of either of these proteins could stabilize DMT1 mRNA and would increase expression of the +IRE form of the transporter. Iron and Mn compete for transport into PC12 cells via DMT1, so removal of iron from the culture media enhances Mn toxicity. The two isoforms of DMT1 (+/-IRE) are distributed in different subcellular compartments with the -IRE species selectively present in the nucleus of neuronal and neuronal-like cells.
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PMID:Mechanisms of manganese-induced rat pheochromocytoma (PC12) cell death and cell differentiation. 1222 55

Proper stimulation of cell cycle progression and DNA synthesis requires cooperating signals from integrin and growth factor receptors. We previously found that the proinflammatory peptide, macrophage migration inhibitory factor (MIF), functions as an autocrine mediator of growth factor-dependent ERK MAP kinase activation and cell cycle progression. We now report that MIF secretion is induced by cell adhesion to fibronectin in quiescent mouse fibroblasts. Adhesion-mediated release of MIF subsequently promotes integrin-dependent activation of MAP kinase, cyclin D1 expression, and DNA synthesis. Secretion of MIF requires protein kinase C activity, and recombinant MIF reconstitutes the activation of MAP kinases in the presence of protein kinase C inhibition. Finally, we show that cells deficient in MIF have significantly higher retinoblastoma tumor suppressor and lower E2F transcriptional activities. These results suggest that MIF is an important autocrine mediator of adhesion-dependent signaling events and may provide mechanistic insight into how MIF regulates proliferative and oncogenic processes.
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PMID:Adhesion-dependent signaling by macrophage migration inhibitory factor (MIF). 1229 13

Angiotensin II (Ang II) is involved in hypertension-related arterial wall hypertrophy [1]. Regulation of AT II transduction pathway in vascular smooth muscle cells (VSMC) may involve cytoskeleton and extracellular matrix (ECM) [2]. We assessed the role of components of ECM on Cai2+ increase induced by Ang II in Wistar-Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR) aortic VSMC. The effect of Ang II (1 mumol) on Ca2+ mobilization was studied in cultured VSMC isolated from the aorta of 6-wk old WKY (MAP (m +/- SE) = 98 +/- 4 mmHg) and SHR (136 +/- 5 mmHg; p < 0.05), using fluorescent imaging microscopy (Fura-2 AM). Cai2+ release from internal stores and Ca2+ influx were assessed in the absence and upon reintroduction of external Ca2+ respectively. Cells were cultured on uncoated glass coverslips (control) or coated with either collagen I (10 micrograms/mL), collagen IV (7 micrograms/mL), vitronectin (0.1 microgram/mL), fibronectin (3 micrograms/mL) and extracellular matrix extract (matrigel, 1/10) and studied at confluence. Paxillin was located in cells by indirect immunofluorescence micrography. Results are expressed in % of Control. Statistical significance (p < 0.05) was assessed with Student's t-test for unpaired data. The effects on Ang II-induced Ca2+ mobilization of growing cells on ECM are in Table. Paxillin in Control cells appeared as dots at the cell boundaries. Density increased in cells grown on collagen I with a diffuse distribution in the WKY cells. On matrigel, paxillin was located in a belt-like fashion at the periphery of the cell. These effects were not linked to differences in cell cycle (flux cytometry).
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PMID:[Role of extracellular matrix in angiotensin II signalling in aortic smooth muscle cells: relationship with arterial hypertension]. 1236 72

A key event in neointima formation and atherogenesis is the migration of vascular smooth muscle cells (VSMCs) into the intima. This is controlled by cytokines and extracellular matix (ECM) components within the microenvironment of the diseased vessel wall. At present, these signals have only been partially identified. In this study, we demonstrate that Met, the receptor tyrosine kinase for hepatocyte growth factor (HGF), is expressed on VSMCs isolated from the intima of atherosclerotic plaques of carotid arteries. Stimulation with HGF led to activation of Met as well as to activation of PI3-K, PKB/Akt, MEK, and the MAP kinases Erk1 and -2. Moreover, HGF induced lamellipodia formation, a characteristic feature of motile cells, and promoted VSMC migration across fibronectin-coated filters. The HGF-induced cell migration was mediated by beta1 integrins and required PI3-K activation. Our results suggest a role for the HGF-Met signaling pathway in the pathogenesis of atherosclerosis and restenosis.
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PMID:Hepatocyte growth factor triggers signaling cascades mediating vascular smooth muscle cell migration. 1237 23

Csk phosphorylates Src family tyrosine kinases and down-regulates their activities in vitro and in vivo. To gain insight into the integrin-mediated cellular functions of this negative regulator of the Src family, we examined integrin-mediated signals in Csk-deficient fibroblasts (Csk(-) cells) and their stable transfectants expressing re-introduced Csk (Csk(-)/Csk cells). Integrin-mediated activation of extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase in Csk(-)/Csk cells upon adhesion to fibronectin or laminin-10/11 was down-regulated, whereas Akt activation increased. Interestingly, the suppression of ERK-MAP kinase activation in Csk(-)/Csk cells was restored by overexpression of a dominant-negative Akt. In agreement with these results, Csk(-)/Csk cells were more resistant to apoptosis induced by serum depletion, but were less proliferative, compared with Csk(-) cells. These results, taken together, demonstrate that Csk is an important regulator of integrin-mediated signaling and cellular behavior.
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PMID:Csk regulates integrin-mediated signals: involvement of differential activation of ERK and Akt. 1267 May 7

A PMMA-based polymer previously shown to inhibit cell proliferation was compared to untreated PMMA. Conformation of adsorbed proteins, cell adhesion, cytoskeleton formation, and integrin activation were examined. Fibronectin adsorbed in a different conformation on the PMMA-based polymer exposing a different balance of the heparin-binding domains. Fibroblasts attached in equal numbers to both surfaces over a 4-h period, but the integrins involved in the adhesion process elicited different intracellular signaling pathways. Cells attached to PMMA showed activation of FAK and MAP as they spread using an assembled actin cytoskeleton. Cells attached to the polymer showed early and strong MAP activity that resulted in nonassembly of the actin cytoskeleton and sub-optimal cell spreading. We conclude that the chemistry of the polymer surface dictated a different conformation of the adsorbed proteins that resulted in alternative cell signaling and diminished cell spreading. This accounted for the biological inhibition previously reported on the PMMA-based polymer.
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PMID:Alternative intracellular signaling mechanism involved in the inhibitory biological response of functionalized PMMA-based polymers. 1274 96

The neoplastic production of the insulin-like growth factor binding protein (IGFBP)-2 often correlates with tumor malignancy and aggressiveness. Since IGFBP-2 contains an RGD motif in its C-terminus, it was hypothesized that this protein may act independently of IGF on tumor cells through integrins. To investigate this, integrin binding, intracellular signaling and the impact of IGFBP-2 on cell adhesion and proliferation were examined in two tumor cell lines. In tracer displacement studies, up to 30% of the added (125)I-hIGFBP-2 specifically bound to the cells. Bound (125)I-hIGFBP-2 was reversibly displaced by IGFBP-2, IGFBP-1 and RGD-(Gly-Arg-Asp)-containing peptides, but not by IGFBP-3, -4, -5, -6 and RGE-(Gly-Arg-Glu)-containing peptides. Blocking with antibodies directed against different integrins and with fibronectin demonstrated that IGFBP-2 cell surface binding is specific for alpha5beta1-integrin. Incubation of IGFBP-2 with equimolar quantities of IGF-I and IGF-II annihilated RGD-specific binding. IGFBP-2 binding at the cell surface led to dephosphorylation of the focal adhesion-kinase (FAK) of up to 37% (P<0.01), and of the p42/44 MAP-kinases of up to 40% (P<0.01). In addition, IGFBP-2 promoted de-adhesion of the cells dose-dependently by up to 30% (P<0.05), and reduced proliferation by 24% (P<0.01). Since one of the cell lines used does not express a functional IGF-I receptor, these data demonstrate that IGFBP-2 can act in an IGF-independent manner, at least in part by an interaction with alpha5beta1-integrin.
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PMID:Integrin-mediated action of insulin-like growth factor binding protein-2 in tumor cells. 1517 17

Neisseria meningitidis traversal across the blood-cerebrospinal fluid barrier is an essential step in the pathogenesis of bacterial meningitis. We have previously shown that invasion of human brain microvascular endothelial cells (HBMEC) by meningococci is mediated by bacterial outer membrane protein Opc that binds fibronectin, thereby anchoring the bacterium to the integrin alpha 5 beta 1-receptor on the endothelial cell surface. However, subsequent signal transduction mechanisms essential for or regulated by N. meningitidis adhesion and invasion, or HBMEC responses to N. meningitidis are unknown. In this report we investigated the role of c-Jun N-terminal kinases 1 and 2 (JNK1 and JNK2), p38 mitogen-activated (MAP) kinase and protein tyrosine kinases in endothelial-N. meningitidis interaction. Binding of meningococci to HBMEC phosphorylated and activated JNK1 and JNK2 and p38 MAPK as well as their direct substrates c-Jun and MAP kinase activated kinase-2 (MAPKAPK-2), respectively. Non-invasive meningococcal strains lacking opc gene (opc mutants and sequence type 11 complex meningococci) still activated p38 MAPK, however, failed to activate JNK. Inhibition of JNK1 and JNK2 significantly reduced internalization of N. meningitidis by HBMEC without affecting its adherence. Blocking the endothelial integrin alpha 5 beta 1 also decreased N. meningitidis-induced JNK activation in HBMEC. These findings indicate the crucial role of JNK signalling pathway in N. meningitidis invasion in HBMEC. In contrast, p38 MAPK pathway was important for the control of interleukin-6 (IL-6) and IL-8 release by HBMEC. Genistein, a protein tyrosine kinase inhibitor, decreased both invasion of N. meningitidis into HBMEC and IL-6 and IL-8 release, indicating that protein tyrosine kinases, which link signals from integrins to intracellular signalling pathways are essential for both bacterial internalization and cytokine secretion by HBMEC.
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PMID:Interaction of Neisseria meningitidis with human brain microvascular endothelial cells: role of MAP- and tyrosine kinases in invasion and inflammatory cytokine release. 1552 95


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