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

The evolutionarily conserved Ras/Raf/MEK/ERK pathway is thought to be essential for proliferation of eukaryotic cells. The human multiple myeloma (MM) cell line 8226 encodes an activated K-ras allele and proliferates without requirement for the main MM growth and survival factor IL-6. Surprisingly, the addition of the MEK1/2 inhibitors PD98059 or U0126 to 8226 cultures at doses that block virtually all ERK1/2 activity had minimal effects on the rapid proliferation of this cell line. In contrast, proliferation of the IL-6-dependent MM cell line, ANBL-6 was blocked by PD98059. Levels of activated forms of the other classical MAP kinases (JNK and p38) were very low during MM cell proliferation and, therefore, do not substitute for the mitogenic activities normally regulated by ERK kinases. These data demonstrate that proliferation of 8226 cells does not require ERK1/2 activity, and suggest that IL-6-independent growth of MM may correlate with independence from a requirement for ERK activity. Other signal transduction pathways that appear to regulate cell cycle progression in these cells were examined.
 ...
PMID:Proliferation of IL-6-independent multiple myeloma does not require the activity of extracellular signal-regulated kinases (ERK1/2). 1220 79

In the diaphragm muscle we tested the hypothesis that MAP kinase signaling pathways are activated by mechanical stress and such signaling pathways are dependent on the direction in which mechanical stress is applied. Although equal magnitudes of mechanical stress were applied axially and transversely a greater level of activation of ERK1/2, p38, Raf-1, p90 RSK, Elk-1, and the DNA binding activity of AP-1 transcription factor was produced when the muscle was stretched transversely than when stretched axially. A significant up-regulation in protein tyrosine phosphorylation was observed in axially or transversely loaded diaphragm muscles and the activation of ERK1/2 was completely inhibited by genistein (protein-tyrosine kinase inhibitor). Pretreatment of muscles with wortmannin (phosphoinositide 3-kinase inhibitor), TMB-8 (antagonist of intracellular calcium release), GF109203X (PKC inhibitor), or PD98059 (MEK1/2 inhibitor) blocked the activation of ERK1/2 kinases in response to axial but not to transverse loading. On the other hand, pretreatment of muscles with protein kinase A inhibitors H-7 and KT5720 completely suppressed the activation of ERK1/2 in response to transverse loading only. Taken together with the alterations of MAP kinases and the findings of elevations of downstream transcription targets, our data are consistent with two distinct MAP kinase signal transduction pathways in response to mechanical stress.
 ...
PMID:Distinct signaling pathways are activated in response to mechanical stress applied axially and transversely to skeletal muscle fibers. 1222 Oct 78

Within epithelial tissue, cells are held together by specialized lateral junctions. At particular stages of development and in pathological processes such as metastasis, cells break down the intercellular junctions, separate from the epithelial sheet and migrate individually. Despite the importance of these processes, little is understood about the regulatory mechanisms of active cell separation. In view of the effects of insulin-like growth factor I (IGF-I) on mammary gland development and cancer, we developed a model using MCF-7 human breast cancer cells in which the process of cell separation can be induced by IGF-I. The separation was enhanced in MCF-7 cells overexpressing the IGF-IR and blocked in the cells expressing a dead-kinase mutant of this receptor. Activation of the IGF-IR resulted in a rapid formation of motile actin microspikes at the regions of cell-cell contacts, disorganization of mature adherens junctions and the onset of cell migration. In cell separation, the signaling between the IGF-IR kinase and actin required phosphatidylinositol 3 (PI 3)-kinase-generated phospholipids but not MAP kinases and was mediated by alpha-actinin. The activity of MEK1/2 kinases was needed for consecutive cell migration. This work also defined a new function for alpha-actinin. Upon IGF-IR activation, green fluorescence protein (GFP)-labeled alpha-actinin concentrated at the base of actin microspikes. Deletion of the N-terminal actin-binding domain of alpha-actinin prevented this redistribution, indicating that this domain is necessary. Detection of the C-terminal tail of alpha-actinin reduced the number of microspikes, showing that alpha-actinin has a role in the development of microspikes and is not passively reorganized with filamentous actin. We suggest that the signaling pathway from the IGF-IR kinase through the PI-3 kinase to alpha-actinin participates in the rapid organization of actin into microspikes at the cell-cell junctions and leads to active cell separation, whereas signaling through ERK1/2 MAP kinases controls cell migration following cell separation.
 ...
PMID:Functional role of alpha-actinin, PI 3-kinase and MEK1/2 in insulin-like growth factor I receptor kinase regulated motility of human breast carcinoma cells. 1235 18

MAP (mitogen-activated protein) kinase (also called Erk 1/2) plays a crucial role in cell proliferation and differentiation. Its impact on secretory events is less well established. The interplay of protein kinase C (PKC), PI3-kinase and cellular tyrosine kinase with MAP kinase activity using inhibitors and compounds such as glucose, phorbol 12-myristate 13-acetate (PMA) and agonists of G-protein coupled receptors like gastrin releasing peptide (GRP), oxytocin (OT) and glucose-dependent insulinotropic peptide (GIP) was investigated in INS-1 cells, an insulin secreting cell line. MAP kinase activity was determined by using a peptide derived from the EGF receptor as a MAP kinase substrate and [32P]ATP. Glucose as well as GRP, OT and GIP exhibited a time-dependent increase in MAP kinase activity with a maximum at time point 2.5 min. All further experiments were performed using 2.5 min incubations. The flavone PD 098059 is known to bind to the inactive forms of MEK1 (MAPK/ERK-Kinase) thus preventing activation by upstream activators. 20 microM PD 098059 (IC50 = 5 microM) inhibited MAP kinase stimulated by either glucose, GRP, OT, GIP or PMA. Inhibiton ("downregulation") of PKC by a long term (22 h) pretreatment with 1 microM PMA did not influence MAP kinase activity when augmented by either of the above mentioned compound. To investigate whether PI3-kinase and cellular tyrosine kinase are involved in G-protein mediated effects on MAP kinase, inhibitors were used: 100 nM wortmannin (PI3-kinase inhibitor) reduced the effects of GRP, OT and GIP but not that of PMA; 100 microM genistein (tyrosine kinase inhibitor) inhibited the stimulatory effect of either above mentioned compound on MAP kinase activation. Inhibition of MAP kinase by 20 microM PD 098059 did not influence insulin secretion modulated by either compound (glucose, GRP, OT or GIP). [3H]Thymidine incorporation, however, was severely inhibited by PD 098059. Thus MAP kinase is important for INS-1 cell proliferation but not for its insulin secretory response with respect to major initiators and modulators of insulin release. The data indicate that MAP kinase is active and under the control of MAP kinase. PKC is upstream of a genistein-sensitive tyrosine kinase and probably downstream of a PI3-kinase in INS-1 cells.
 ...
PMID:Role of protein kinase C, PI3-kinase and tyrosine kinase in activation of MAP kinase by glucose and agonists of G-protein coupled receptors in INS-1 cells. 1236 12

Increases in extracellular calcium concentration ([Ca(2+)](o)) stimulate from normal and malignant cells secretion of parathroid hormone-related protein (PTHrP), a major mediator of humoral hypercalcemia of malignancy. Because the calcium-sensing receptor (CaR) is a determinant of calcium-regulated hormone secretion, we examined whether HEK cells stably transfected with human CaR secreted PTHrP in response to CaR stimulation. Increases in [Ca(2+)](o) or neomycin and Gd(3+) all substantially increased PTHrP secretion in CaR-HEK cells but had no effect on nontransfected cells. CaR activation likewise increased PTHrP transcripts. PD-098059 and U-0126, inhibitors of the mitogen-activated protein kinase kinase MEK1/2, abolished CaR-stimulated secretion but had no effect on basal secretion. An inhibitor of p38 MAP kinase, SB-203580, also attenuated CaR-stimulated secretion. Western analysis revealed that CaR activation caused a robust increase in MEK1/2 and p38 MAP kinase phosphorylation. A Src family kinase inhibitor, PP2, blocked both basal and CaR-stimulated secretion. We conclude that CaR specifically mediates the effect of increasing [Ca(2+)](o) on PTHrP synthesis and secretion and that activated MEK1/2 and p38 MAP kinases are determinants of the CaR's stimulation of PTHrP secretion.
 ...
PMID:PTHrP stimulated by the calcium-sensing receptor requires MAP kinase activation. 1238 58

The involvement of Rho GTPases in signal transduction pathways leading to transcription activation is one of the major roles of this family of GTPases. Thus, the identification of transcription factors regulated by Rho GTPases and the understanding of the mechanisms of their activation and its biological outcome are of great interest. Here, we provide evidence that Rho GTPases modulate Stat5a, a transcription factor of the family of signal transducers and activators of transcription. RhoA triggers tyrosine phosphorylation (Y696) of Stat5a via a JAK2-dependent mechanism and promotes DNA-binding activity of Stat5a. Tyrosine phosphorylation of Stat5a is also stimulated physiologically by lysophosphatidic acid (LPA) in a Rho-dependent manner. Simultaneously, RhoA reduces serine phosphorylation of Stat5a at both serine residues S726 and S780, resulting in a further increase of activity as defined by mutagenesis experiments. Furthermore, serine dephosphorylation of Stat5a by RhoA does not take place by down-modulation of either JNK1, MEK1, or p38 MAP kinases, as determined by transfection experiments or chemical inhibition of both MEK1, p38, and JNK serine kinases. Thus, RhoA regulates Stat5a via tyrosine phosphorylation and via a yet to be determined novel down-modulating pathway that involves serine dephosphorylation. Finally, we provide evidence for a role of Stat5a in RhoA-induced epithelial-to-mesenchymal transition with concomitant increase in vimentin expression, E-cadherin down-regulation, and cell motility.
 ...
PMID:STAT5a activation mediates the epithelial to mesenchymal transition induced by oncogenic RhoA. 1252 25

Gap junction channels are essential for intercellular communication. Among the most abundant gap junction channel proteins is connexin 43 (Cx43). The goal of our study was to find out, whether Cx43 content may be regulated via adenylyl cyclase (AC)/cAMP/protein kinase A (PKA), protein kinase C (PKC) pathways or by a tyrosine kinase coupled pathway, i.e. TNF alpha-receptor dependent pathway. Therefore, we used HeLa cells transfected with Cx43 and exposed these cells for 24 h to either db-cAMP (10(-4)M), forskolin (10(-5)M), the phorbolester phorbol-12,13-didecanoate PDD (10(-7)M) (or its inactive form 4 alpha-PDD), TNF alpha (10 U/ml) with or without additional treatment with the MAP kinase inhibitors SB203580 (10(-5) M, p38 MAP-kinase inhibitor) or the MEK1-inhibitor PD98059 (10(-5)M). Cx43 content was analysed using Western blot analysis. All results were confirmed by a second series of identical experiments using Cx43 immunohistochemistry. We found significantly enhanced Cx43 content in cells treated with db-cAMP, forskolin, PDD or TNF alpha (p<0.05), while 4 alpha-PDD or the solvent DMSO exerted no effect. These increases in Cx43 content could be completely suppressed by SB203580 (p<0.05) but not by PD98059. In absence of a stimulating drug, these inhibitors (SB203580 or PD98059) did not affect Cx43 content. Additional PCR experiments revealed increases in Cx43-mRNA under the influence of db-cAMP, forskolin, PDD or TNFalpha (p<0.05), which all could be completely suppressed by SB203580. From these results we conclude that 1.Cx43 content can be regulated via AC/cAMP/PKA, PKC and TNF alpha-receptor-dependent pathways 2. Activation of p38 MAP kinase is a common pathway for regulation of Cx43 content in HeLa cells
 ...
PMID:Chronic regulation of the expression of the gap junction protein connexin 43 in transfected HeLa cells. 1282 13

Elastase degradation of elastin within alveolar walls is an important event in the development of pulmonary emphysema. In addition to elastolytic activities, elastases release growth factors from extracellular matrices and interstitial cell surfaces that can regulate elastogenesis and other cellular responses. In the present study, we demonstrate that brief treatment of matrix-laden rat pulmonary fibroblast cultures with pancreatic elastase results in the release of soluble heparin-binding epidermal growth factor-like growth factor (HB-EGF) concomitant with a decrease in HB-EGF binding to both heparan sulfate proteoglycan and receptor sites on the cells. In undigested, matrix-laden fibroblasts, HB-EGF significantly downregulates elastin mRNA via activation of epidermal growth factor receptor. Results from nuclear run-on analyses show that HB-EGF downregulates elastin mRNA via transcriptional suppression. HBEGF treatment stimulates MAP or ERK kinase (MEK)-dependent ERK1/2 phosphorylation and leads to nuclear accumulation of Fra-1. Blocking ERK1/2 activation by MEK1/2 inhibitors (PD-98059 or U-0126) diminishes HB-EGF-induced Fra-1 accumulation and subsequent downregulation of elastin mRNA. Coaddition of two elastase-released growth factors, HB-EGF and FGF-2, results in an additive inhibitory effect on elastin mRNA levels. Furthermore, HB-EGF addition to pulmonary fibroblasts increases FGF-2 mRNA and protein levels. These data suggest that HB-EGF and FGF-2 act in concert to regulate the synthesis of elastin in injury/repair situations.
 ...
PMID:Heparin-binding EGF-like growth factor regulates elastin and FGF-2 expression in pulmonary fibroblasts. 1288 62

A key task for the multifunctional von Hippel-Lindau protein (pVHL) is regulation of the activity of hypoxia-inducible factor-1alpha (HIF-1alpha) by targeting it to the proteasome for degradation under normoxia. pVHL binding to HIF-1alpha is lost under low O2 tension, leading to transcription of several genes involved in the hypoxia response. However, regulation of pVHL by hypoxia remains to be investigated. We evaluated the effects of hypoxia on pVHL expression in carcinoma and endothelial cells. We showed that hypoxia stimulates pVHL levels (2.5-fold) in renal Caki-1 cells expressing wild-type VHL (VHL+/+). This upregulation was independent of VHL status, because hypoxia also increased pVHL expression in renal 786-O cells carrying mutated VHL (VHL-/-). Hypoxia did not affect pVHL expression in endothelial cells. Hypoxia-induced pVHL in Caki-1 cells was RhoA dependent, because inhibition by exotoxin C3 prevented pVHL stimulation. Furthermore, inhibition of Rho kinase by Y-27632 blocked pVHL induction by hypoxia. During normoxia, pVHL expression was also induced in cells transfected with dominant-active RhoA. Furthermore, disruption of actin organization by chemical agents or by hypoxia stimulated pVHL expression in kidney cells. On the other hand, inhibition of MAP kinases p38 and JNK, but not MAP kinase kinase (MEK1/2), reduced pVHL upregulation by 30 and 72%, respectively, during hypoxia, supporting a significant role for these signaling pathways. Expression and phosphorylation of c-Jun were stimulated in cells transfected with dominant-active RhoA. Together, these findings demonstrate that hypoxia induces pVHL expression in renal cancer cells, and this induction is mediated by RhoA-dependent pathways.
 ...
PMID:Hypoxia upregulates von Hippel-Lindau tumor-suppressor protein through RhoA-dependent activity in renal cell carcinoma. 1458 36

In vivo and in vitro studies indicate that 4-hydroxy-2-nonenal (4-HNE), generated by cellular lipid peroxidation or after oxidative stress, affects endothelial permeability and vascular tone. However, the mechanism(s) of 4-HNE-induced endothelial barrier function is not well defined. Here we provide evidence for the first time on the involvement of mitogen-activated protein kinases (MAPKs) in 4-HNE-mediated actin stress fiber formation and barrier function in lung endothelial cells. Treatment of bovine lung microvascular endothelial cells with hydrogen peroxide (H(2)O(2)), as a model oxidant, resulted in accumulation of 4-HNE as evidenced by the formation of 4-HNE-Michael protein adducts. Exposure of cells to 4-HNE, in a dose- and time-dependent manner, decreased endothelial cell permeability measured as transendothelial electrical resistance. The 4-HNE-induced permeability changes were not because of cytotoxicity or endothelial cell apoptosis, which occurred after prolonged treatment and at higher concentrations of 4-HNE. 4-HNE-induced changes in transendothelial electrical resistance were calcium independent, as 4-HNE did not alter intracellular free calcium levels as compared with H(2)O(2) or diperoxovanadate. Stimulation of quiescent cells with 4-HNE (1-100 microm) resulted in phosphorylation of ERK1/2, JNK, and p38 MAPKs, and actin cytoskeleton remodeling. Furthermore, pretreatment of bovine lung microvascular endothelial cells with PD 98059 (25 microm), an inhibitor of MEK1/2, or SP 600125 (25 microm), an inhibitor of JNK, or SB 202190 (25 microm), an inhibitor of p38 MAPK, partially attenuated 4-HNE-mediated barrier function and cytoskeletal remodeling. These results suggest that the activation of ERK, JNK, and p38 MAP kinases is involved in 4-HNE-mediated actin remodeling and endothelial barrier function.
 ...
PMID:Role of mitogen-activated protein kinases in 4-hydroxy-2-nonenal-induced actin remodeling and barrier function in endothelial cells. 1469 26


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>