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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemokines are a family of proinflammatory cytokines that attract and activate specific types of leukocytes. Chemokines mediate their effects via interaction with seven transmembrane G protein-coupled receptors (GPCR). Using CCR5-transfected HEK-293 cells, we show that both the CCR5 ligand, RANTES, as well as its derivative, aminooxypentane (AOP)- RANTES, trigger immediate responses such as Ca2+ influx, receptor dimerization, tyrosine phosphorylation, and Galphai as well as JAK/STAT association to the receptor. In contrast to RANTES, (AOP)-RANTES is unable to trigger late responses, as measured by the association of focal adhesion kinase (FAK) to the chemokine receptor complex, impaired cell polarization required for migration, or chemotaxis. The results are discussed in the context of the dissociation of the late signals, provoked by the chemokines required for cell migration, from early signals.
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PMID:Similarities and differences in RANTES- and (AOP)-RANTES-triggered signals: implications for chemotaxis. 1003 96

Binding of HIV-1 envelope glycoproteins to the surface of a CD4+ cell transduces intracellular signals through the primary envelope receptor, CD4, and/or the envelope coreceptor, a seven-transmembrane chemokine receptor. Macrophage-tropic strains of HIV-1 preferentially use CCR5 as an entry coreceptor, whereas T cell-tropic strains use CXC chemokine receptor-4 for entry. Intracellular signals transduced by HIV-1 envelope may have immunopathogenic consequences, including anergy, syncytium formation, apoptosis, and inappropriate cell trafficking. We demonstrate here that a recombinant envelope protein derived from an M-tropic isolate of HIV-1 can transduce CD4-dependent as well as CCR5-dependent intracellular signals in primary human CD4+ T cells. Novel HIV-induced intracellular signals that were identified include tyrosine phosphorylation of focal adhesion kinase (FAK) and CCR5, which are involved in cell adhesion and chemotaxis, respectively. HIV envelope-induced cellular association of FAK and CCR5 was also demonstrated, suggesting that ligation of CD4 and CCR5 leads to the formation of an activation complex composed of FAK and CCR5. Activation of this signaling pathway by HIV-1 envelope may be an important pathogenic mechanism of dysregulated cellular activation and trafficking during HIV infection.
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PMID:Induction of phosphorylation and intracellular association of CC chemokine receptor 5 and focal adhesion kinase in primary human CD4+ T cells by macrophage-tropic HIV envelope. 1038 44

To better understand a role of the delta32 allele of the CCR5 gene in HIV-1 transmission and disease progression, we determined the CCR5 genotypes within several groups of Koreans. Amplification of DNA from each subject was achieved with polymerase chain reaction, using the CCR5 specific primer pair, which flanks the 32 bp deletion. The 1.2 kb coding sequences of CCR5 were examined to see the possible effects of CCR5 polymorphism. All of the 339 healthy, HIV-uninfected individuals had no mutation in the CCR5 gene. All of the 115 HIV-1-infected patients including 11 long-term non-progressors (LTNPs) and 18 discordant spouses were also wild homozygotes. No variation in the 1.2kb CCR5 coding sequence was found in 5 LTNPs and 5 discordant spouses. In conclusion, the 32 bp deletion mutant is rarely present in Koreans. Our data suggest that factors other than the CCR5 coding sequences may also play a role in the resistance to HIV infection.
Int J STD AIDS 2000 Apr
PMID:The frequency of mutation in CCR5 gene among Koreans. 1077 93

In the pipeline, there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials. The major target of new agents are cell-surface molecules important in immune cell interactions (especially the costimulatory pathway), signaling pathways that activate T cells, T-cell proliferation and trafficking and recruitment of immune cells responsible for rejection. The most promising biologic agents include a humanized anti-CD11a (anti-LFA1), humanized anti-B7.1/B7.2, a second-generation CTLA4Ig (LEA29Y) and a humanized antibody to anti-CD45 RB. Inhibitors of T-cell activation and signaling are still in preclinical development. The most interesting inhibitors of T-cell proliferation include inhibitors of the Janus protein tyrosine kinase, JAK3, and FK778, a leflunomide analog. Chemokines play an important role in rejection by virtue of their critical role as regulator of trafficking and activation of lymphocytes. Early trials of FTY720, a synthetic small molecule with functional homology to sphingosine-1 phosphate leading to lymphocyte sequestration, appear very promising; however, enthusiasm for this drug is mitigated by its potential cardiac side-effects. Antagonists to several chemokine receptors, including CCR1, CXCR3 and CCR5, have been shown to be effective in experimental transplantation and are likely to be considered for clinical development.
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PMID:What's in the pipeline? New immunosuppressive drugs in transplantation. 1248 41

An effective inflammatory immune response first requires the recruitment of cells to the site of inflammation and then their appropriate activation and regulation. Chemokines are critical in this response since they are both chemotactic and immunoregulatory molecules. In this regard, the interaction between CCL5 and CCR5 may be critical in regulating T cell functions, by mediating their recruitment and polarization, activation, and differentiation. Various tyrosine phosphorylation signaling cascades can be engaged following chemokine receptor aggregation on T cells, including the Jak-Stat pathway, FAK activation, the MAP kinase pathway, PI3-kinase activation, and transactivation of the T cell receptor. This review will address specific aspects related to chemokine-T cell interactions and the molecular signaling mechanisms that influence T cell function in an inflammatory immune response.
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PMID:Chemokines: attractive mediators of the immune response. 1249 36

Human immunodeficiency virus (HIV) gp120 induces multiple cellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3-kinase) pathway. The role of the PI3-kinase pathway in HIV-1 replication is not understood. Here we examined whether HIV-1 gp120 upregulates the PI3-kinase pathway and whether PI3-kinase activity plays a role in virus replication in primary human CD4(+) T cells and macrophages. Soluble and virion-associated HIV-1 gp120 induced calcium mobilization and phosphorylation of the PI3-kinase downstream effectors PKB/Akt and p70 S6 kinase. gp120-induced PI3-kinase activity and calcium mobilization were inhibited by pertussis toxin and blocking antibodies directed against CCR5 and CXCR4, suggesting that the signaling is mediated through the chemokine receptor. The PI3-kinase inhibitor LY294002 inhibited infection of CD4(+) T cells and macrophages with X4 and R5 HIV-1-pseudotyped viruses at concentrations that did not induce cell toxicity or downregulate HIV-1 coreceptor expression. When gp120-induced signaling was bypassed with the vesicular stomatitis virus G envelope protein, infection was still sensitive to PI3-kinase inhibition, suggesting that basal PI3-kinase activity is required for infection. LY294002 inhibited HIV-1 infection when added after viral entry and did not affect formation of the HIV-1 reverse transcriptase products R/U5 and long terminal repeat/Gag in the presence of the inhibitor. However, when the inhibitor was added after viral integration had occurred, no inhibition of HIV infection was observed. Our studies show that inhibition of the PI3-kinase signaling pathway suppresses virus infection post-viral entry and post-reverse transcription but prior to HIV gene expression. This type of host-virus interaction has implications for anti-HIV therapeutics that target cellular signaling machinery.
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PMID:Phosphatidylinositol 3-kinase regulates human immunodeficiency virus type 1 replication following viral entry in primary CD4+ T lymphocytes and macrophages. 1255 92

Chemokines are implicated in tumor pathogenesis, although it is unclear whether they affect human cancer progression positively or negatively. We found that activation of the chemokine receptor CCR5 regulates p53 transcriptional activity in breast cancer cells through pertussis toxin-, JAK2-, and p38 mitogen-activated protein kinase-dependent mechanisms. CCR5 blockade significantly enhanced proliferation of xenografts from tumor cells bearing wild-type p53, but did not affect proliferation of tumor xenografts bearing a p53 mutation. In parallel, data obtained in a primary breast cancer clinical series showed that disease-free survival was shorter in individuals bearing the CCR5Delta32 allele than in CCR5 wild-type patients, but only for those whose tumors expressed wild-type p53. These findings suggest that CCR5 activity influences human breast cancer progression in a p53-dependent manner.
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PMID:CCR5 expression influences the progression of human breast cancer in a p53-dependent manner. 1459 37

The interaction of the chemokine receptor, CCR5, expressed in recombinant cells, with different G proteins was investigated and CCR5 was found to interact with Gi, Go and Gq species. Interaction with Gi leads to G protein activation, whereas Gq does not seem to be activated. Additionally, CCR5 activation also leads to phosphorylation of Janus kinase 2 (JAK2). Activation of JAK2 is independent of Gi or Gq activation. Gi protein activation was not prevented by inhibition of JAK, showing that heterotrimeric G protein activation and activation of the JAK/signal transducer and activator of transcription (STAT) pathway are independent of each other.
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PMID:CCL3, acting via the chemokine receptor CCR5, leads to independent activation of Janus kinase 2 (JAK2) and Gi proteins. 1525 52

Microglia, the resident macrophages of the CNS, are responsible for the innate immune response in the brain and participate in the pathogenesis of certain neurodegenerative disorders. Chemokines initiate activation and migration of microglia. The beta-chemokine CCL5 induces an elevation in intracellular calcium concentration ([Ca(2+)](i)) in human microglia. Here, we examined the signal transduction pathway linking activation of chemokine receptor CCR5 to an elevation in [Ca(2+)](i) in cultured microglia by using pharmacological approaches in combination with Fura-2-based digital imaging. The CCL5-induced response required Janus kinase (Jak) activity and the stimulation of an inhibitory G protein. Multiple downstream signaling pathways were involved, including phosphatidylinositol 3-kinase (PI3K), Bruton's tyrosine kinase (Btk), and phospholipase C (PLC)-mediated release of Ca(2+) from inositol 1,4,5-trisphosphate (IP(3))-sensitive stores. Activation of both the kinase and the lipase pathways was required for eliciting the Ca(2+) response. However, the majority of the [Ca(2+)](i) increase was derived from sources activated by NAD metabolites. Cyclic ADP-ribose (cADPR) evoked Ca(2+) release from intracellular stores, and ADPR evoked Ca(2+) influx via a nimodipine-sensitive channel. Thus, a multistep cascade couples CCR5 activation to Ca(2+) increases in human microglia. Because changes in [Ca(2+)](i) affect chemotaxis, secretion, and gene expression, pharmacologic modulation of this pathway may alter inflammatory and degenerative processes in the CNS.
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PMID:CCL5 evokes calcium signals in microglia through a kinase-, phosphoinositide-, and nucleotide-dependent mechanism. 1654 71

The chemokine receptors CCR5 and CXCR4 serve, in addition to CD4, as coreceptors for human immunodeficiency virus-1 (HIV-1), and infection with HIV-1 can cause dementia. In brain-derived cells, HIV-1 envelope glycoprotein gp120 initiates a signaling cascade that involves p38 mitogen-activated protein kinase and leads to neuronal cell death. Using mixed neuronal/glial cultures from rats and mice genetically deficient in one or both HIV coreceptors, we show here that CCR5, CXCR4 or both can mediate HIV/gp120 neurotoxicity depending on the viral strain. Paradoxically, we also found evidence for a CCR5-mediated neuroprotective pathway. We identify protein kinase Akt/PKB as an essential component of this pathway, which can be triggered by the CCR5 agonists macrophage inflammatory protein-1beta and regulated-and-normal-T-cell-expressed-and-secreted. Moreover, these CCR5 ligands prevent neuronal cell death induced by stromal cell-derived factor-1, a CXCR4 agonist. Both neurons and glia coexpress CXCR4 and CCR5. Ca2+ imaging experiments demonstrate that engagement of CCR5 prevents CXCR4-triggered increases in intracellular free Ca2+. This finding suggests that CCR5 ligands can protect neurons at least, in part, by modulating CXCR4-mediated toxicity through heterologous desensitization.
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PMID:HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection. 1684 Oct 89


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