Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microenvironmental factors affect different aspects of tumor cell biology, including cell survival, invasion, and metastasis. Here, we report that hepatocyte growth factor and hypoxia may contribute to breast carcinoma cell invasiveness by inducing the chemokine receptor CXCR4. Hepatocyte growth factor enhanced CXCR4 mRNA and protein expression exclusively in MCF-7 (low invasive) carcinoma cells, while in response to hypoxia, CXCR4 induction was observed in both MCF-7 and MDA-MB 231 (highly invasive) carcinoma cells. The receptor induction had a functional role in cancer cells, as demonstrated by the fact that hepatocyte growth factor pretreatment promoted MCF-7 cell migration toward the CXCR4-specific ligand CXCL12. Extracellular signal-regulated protein kinase 1/2 (ERK1/2) and phosphoinositide-3-kinase (PI3K) transduction pathways seemed to be differently implicated in the early induction of CXCR4 by hepatocyte growth factor or hypoxia in the two breast carcinoma cells examined.
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PMID:Hepatocyte growth factor enhances CXCR4 expression favoring breast cancer cell invasiveness. 1611 11

Colorectal cancer (CRC) is characterized by a distinct metastatic pattern resembling chemokine-induced leukocyte trafficking. This prompted us to investigate expression, signal transduction and specific functions of the chemokine receptor CXCR4 in CRC cells and metastases. Using RT-PCR analysis and Western blotting, we demonstrated CXCR4 and CXCL12 expression in CRC and CRC metastases. Cell differentiation increases CXCL12 mRNA levels. Moreover, CXCR4 and its ligand are inversely expressed in CRC cell lines with high CXCR4 and low or not detectable CXCL12 expression. CXCL12 activates ERK-1/2, SAPK/JNK kinases, Akt and matrix metalloproteinase-9. These CXCL12-induced signals mediate reorganization of the actin cytoskeleton resulting in increased cancer cell migration and invasion. Moreover, CXCL12 increases vascular endothelial growth factor (VEGF) expression and cell proliferation but has no effect on CRC apoptosis. Therefore, the CXCL12/CXCR4 system is an important mediator of invasion and metastasis of CXCR4 expressing CRC cells.
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PMID:CXCR4 and CXCL12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and MMP-9 activation. 1612 70

Activation of the chemokine receptor CXCR4 by its agonist stromal cell-derived factor 1 (SDF-1) has been associated with cell migration and proliferation in many cell types, but the intracellular signaling cascades are incompletely defined. Here we show that CXCR4-dependent extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation was mediated through the Ras/Raf pathway, as demonstrated with a dominant-negative Ras mutant and pharmacological inhibitors. The Src inhibitor 4-amino-5-methylphenyl-7-(t-butyl)pyrazolo[3,4-d] pyrimidine (PP1) and the Rho-kinase (ROCK) inhibitor N-(4-pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamide dihydrochloride (Y27632) also attenuated SDF-1-induced ERK1/2 phosphorylation. Involvement of Src could furthermore be demonstrated by Src phosphorylation and by the shortened ERK1/2 phosphorylation in SYF cells, which are Src/Yes/Fyn-deficient compared with Src-reconstituted Src(++) cells. Membrane translocation of RhoA could be detected similarly. A large portion of the SDF-1-mediated ERK phosphorylation was detected in the nucleus, as shown by Western blotting and confocal microscopy, and resulted in the phosphorylation of the transcription factor Elk. It is interesting that the nuclear accumulation of ERK1/2 and Elk phosphorylation was completely blocked by dominant-negative Rho, Y27632, PP1, and latrunculin B, indicating that the Rho/ROCK pathway, Src kinase, and the actin cytoskeleton were required in this process. In accordance, neither nuclear ERK phosphorylation nor Elk phosphorylation were observed in SYF cells stimulated with SDF-1 but were reconstituted in Src(++) cells. In summary, these results demonstrate that Src, Rho/ROCK, and an intact cytoskeleton contribute to overall ERK1/2 activation in SDF-1-stimulated cells and are indispensable for nuclear translocation of ERK1/2 and activation of transcription factors.
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PMID:Regulation of CXCR4-mediated nuclear translocation of extracellular signal-related kinases 1 and 2. 1621 Apr 28

The chemokine receptor CXCR4 regulates neuronal survival and differentiation and is involved in a number of pathologies, including cancer and human immunodeficiency virus (HIV). Recent data suggest that chemokines act in concert with neurotransmitters and neuropeptides, such as opioids. This study aimed to determine whether mu-opioid agonists alter the effect of CXCL12 (the specific CXCR4 ligand) on central neurons. Neuronal expression of CXCR4 and micro-opioid receptors (MORs) was analyzed by Western blot, immunostaining, and flow cytometry. Single-cell studies showed that all CXCR4-positive neurons coexpress MORs. Treatment of neuronal cultures with the selective MOR agonist DAMGO or the endogenous peptide endomorphin-1 inhibited intracellular signaling pathways (ERK1/2 and Akt) activated by CXCL12. Furthermore, DAMGO abolished the neuroprotective effect of CXCL12 in N-methyl-d-aspartate (NMDA) neurotoxicity studies. The effects of DAMGO and endomorphin-1 were inhibited by a general or a micro-specific opioid receptor antagonist, and not caused by changes in neuronal CXCR4 levels. DAMGO did not affect CXCL12-induced internalization of CXCR4. The authors propose that interactions between MOR and CXCR4 signaling can modulate the action of CXCL12 on neuronal survival-which may have important implications to neuroAIDS as well as other neuroinflammatory disorders.
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PMID:Modulation of neuronal CXCR4 by the micro-opioid agonist DAMGO. 1716 64

The chemokine receptor CXCR4 mediates the migration of hematopoietic cells to the stroma-derived factor 1alpha (SDF-1alpha)-producing bone marrow microenvironment. Using peptide-based CXCR4 inhibitors derived from the chemokine viral macrophage inflammatory protein II, we tested the hypothesis that the inhibition of CXCR4 increases sensitivity to chemotherapy by interfering with stromal/leukemia cell interactions. First, leukemic cells expressing varying amounts of surface CXCR4 were examined for their chemotactic response to SDF-1alpha or stromal cells, alone or in the presence of different CXCR4 inhibitors. Results showed that the polypeptide RCP168 had the strongest antagonistic effect on the SDF-1alpha- or stromal cell-induced chemotaxis of leukemic cells. Furthermore, RCP168 blocked the binding of anti-CXCR4 monoclonal antibody 12G5 to surface CXCR4 in a concentration-dependent manner and inhibited SDF-1alpha-induced AKT and extracellular signal-regulated kinase phosphorylation. Finally, RCP168 significantly enhanced chemotherapy-induced apoptosis in stroma-cocultured Jurkat, primary chronic lymphocytic leukemia, and in a subset of acute myelogenous leukemia cells harboring Flt3 mutation. Equivalent results were obtained with the small-molecule CXCR4 inhibitor AMD3465. Our data therefore suggest that the SDF-1alpha/CXCR4 interaction contributes to the resistance of leukemia cells to chemotherapy-induced apoptosis. Disruption of these interactions by the peptide CXCR4 inhibitor RCP168 represents a novel strategy for targeting leukemic cells within the bone marrow microenvironment.
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PMID:Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias. 1717 14

The chemokine receptor CXCR4, which binds the chemokine stromal cell-derived factor 1, has been reported to be involved in the chemotaxis of inflammatory cells. In addition, AMD3100, an antagonist of CXCR4, has been reported to be an attractive drug candidate for therapeutic intervention in several disorders in which CXCR4 is critically involved. However, little is known about the therapeutic value of AMD3100 in the treatment of pulmonary fibrosis. In this study, we examined the effects of AMD3100 on a murine bleomycin-induced pulmonary fibrosis model. Concurrent administration of AMD3100 and bleomycin apparently attenuated bleomycin-induced pulmonary inflammation. In this process, an inhibition of neutrophil recruitment at early stage followed by the decrease of other inflammatory cell recruitment in the lung were observed. In addition, it also inhibited the expression of cytokines, including MCP-1, MIP-2, MIP-1alpha, and TGF-beta. In contrast, when AMD3100 was administered following bleomycin treatment, the bleomycin-induced lung inflammation progressed and resulted in severe pulmonary fibrosis. In this process, an increase of inflammatory cell recruitment, an up-regulation of lung MCP-1 and TGF-beta, and a remarkable activation of p44/42 MAPK in neutrophils were observed. U0126, an inhibitor of p44/42 MAPK, significantly abolished these effects. Thus, AMD3100 has dual effect on bleomycin-induced pulmonary fibrosis. Difference of inflammatory cell recruitment and activation might be associated with the dual effect of AMD3100 on bleomycin-induced pulmonary fibrosis.
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PMID:Dual effect of AMD3100, a CXCR4 antagonist, on bleomycin-induced lung inflammation. 1894 Dec 58

Mutations in the superoxide dismutase 1 (SOD1) gene are associated with familial amyotrophic lateral sclerosis (ALS), and the SOD1(G93A) transgenic mouse has been widely used as one animal model for studies of this neurodegenerative disorder. Recently, several reports have shown that abnormalities in neuronal development in other models of neurodegeneration occur much earlier than previously thought. To study the role of mutant SOD1 in glial progenitor biology, we immortalized glial restricted precursors (GRIPs) derived from mouse E11.5 neural tubes of wild-type and SOD1(G93A) mutant mice. Immunocytochemistry using cell lineage markers shows that these cell lines can be maintained as glial progenitors, because they continue to express A2B5, with very low levels of glial fibrillary acidic protein (astrocyte), betaIII-tubulin (neuron), and undetected GalC (oligodendrocyte) markers. RT-PCR and immunoblot analyses indicate that the chemokine receptor CXCR4 is reduced in SOD1(G93A) GRIPs. Subsequently, SOD1(G93A) GRIPs are unable to respond to SDF1alpha to activate ERK1/2 enzymes and the transcription factor CREB. This may be one pathway leading to a reduction in SOD1(G93A) cell migration. These data indicate that the abnormalities in SOD1(G93A) glial progenitor expression of CXCR4 and its mediated signaling and function occur during spinal cord development and highlight nonneuronal (glial) abnormalities in this ALS model.
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PMID:Impaired SDF1/CXCR4 signaling in glial progenitors derived from SOD1(G93A) mice. 1756 84

The mechanisms leading to renal cell carcinoma (RCC) metastasis are incompletely understood. Although evidence shows that the chemokine receptor CXCR4 and its ligand CXCL12 may regulate tumor dissemination, their role in RCC is not clearly defined. We examined CXCR4 expression and functionality on RCC cell lines, and explored CXCL12-triggered tumor adhesion to human endothelium (HUVEC) or extracellular matrix proteins. Functional CXCR4 was expressed on A498 tumor cells, enabling them to migrate towards a CXCL12 gradient. CXCR4 engagement by CXCL12 induced elevated cell adhesion to HUVEC, to immobilized fibronectin, laminin or collagen. Anti-CXCR4 antibodies or CXCR4 knock down by siRNA applied prior to CXCL12 stimulation impaired CXCL12-triggered tumor adhesion. However, blocking CXCR4 subsequent to CXCL12 stimulation did not. This pointed to an indirect control of tumor cell adhesion by CXCR4. In fact, CXCR4 engagement by CXCL12 also induced alterations of receptors of the integrin family, notably alpha3, alpha5, beta1 and beta3 subunits, and blocking beta1 integrins with a function-blocking antibody prevented CXCL12-induced A498 adhesion. Focal adhesion kinase (total and activated) and integrin-linked kinase significantly increased in CXCL12-treated A498 cells, accompanied by a distinct up-regulation of ERK1/2, JNK and p38 phosphorylation. Therefore, CXCR4 may be crucial in controlling adhesion of A498 cells via cross talking with integrin receptors. These data show that CXCR4 receptors contribute to RCC dissemination and may provide a novel link between CXCR4 chemokine receptor expression and integrin triggered RCC adhesion to the vascular wall and subendothelial matrix components.
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PMID:CXCR4 chemokine receptor engagement modifies integrin dependent adhesion of renal carcinoma cells. 1770 41

The chemokine receptor CXCR4 plays a central role in organ-specific homing and tumor spreading and is induced by hypoxia. B lymphocytes are exposed to low oxygen tensions during their development, but the influence of hypoxia on their physiology is poorly understood. Here, we show that hypoxia is associated with up-regulation of CXCR4 expression in human normal and malignant B cells, through both transcriptional and posttranslational mechanisms. However, a dichotomic functional response to CXCR4 triggering was observed: both peripheral B cells and lymphomas arising from mature B cells displayed increased responses to CXCR4 triggering under hypoxia, whereas germinal center (GC) B cells as well as GC-derived lymphomas showed CXCR4 receptor desensitization. This phenomenon was associated with differential modulation of key signal-transducing molecules, including mitogen-activated protein kinase phosphatase-1 and regulator of G protein signaling molecule-1. The unresponsiveness of GC-derived lymphomatous B cells to CXCR4 triggering under hypoxia may have implications for the development and pathogenesis of GC-derived lymphoid tumors.
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PMID:Differential regulation of hypoxia-induced CXCR4 triggering during B-cell development and lymphomagenesis. 1787

The chemokine receptor CXCR4-mediated signaling cascades play an important role in cell proliferation and migration, but the underlying mechanisms by which the receptor signaling is regulated remain incompletely understood. Here, we demonstrate that CXCR4 was co-immunoprecipitated with cyclophilin A (CyPA) from the lysate of HEK293 cells stably expressing CXCR4. Although both the glutathione S-transferase-CXCR4 N- and C-terminal fusion proteins were associated with the purified CyPA, truncation of the C-terminal domain of CXCR4 robustly inhibited the receptor co-immunoprecipitation with CyPA in intact cells, thereby suggesting a critical role of the receptor C terminus in this interaction. Ligand stimulation of CXCR4 induced CyPA phosphorylation and nuclear translocation, both of which were inhibited by truncation of the C-terminal domain of CXCR4. CyPA was associated with transportin 1, and knockdown of transportin 1 by RNA interference (RNAi) blocked CXCL12-induced nuclear translocation of CyPA, thereby suggesting a transportin 1-mediated nuclear import of CyPA. CyPA formed a complex with heterogeneous nuclear ribonucleoprotein (hnRNP) A2, which underwent nuclear export in response to activation of CXCR4. Interestingly, the CXCR4-mediated nuclear export of hnRNP A2 was blocked by RNAi of CyPA. Moreover, CXCR4-evoked activation of extracellular signal-regulated kinase 1/2 (ERK1/2) was attenuated by CyPA RNAi, by overexpression of a PPIase-deficient mutant of CyPA (CyPA-R55A), and by pretreatment of the immunosuppressive drugs, cyclosporine A and sanglifehrin A. Finally, CXCL12-induced chemotaxis of HEK293 cells stably expressing CXCR4 or Jurkat T cells was inhibited by CyPA RNAi or CsA treatment.
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PMID:Cyclophilin A is required for CXCR4-mediated nuclear export of heterogeneous nuclear ribonucleoprotein A2, activation and nuclear translocation of ERK1/2, and chemotactic cell migration. 1799 43


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