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)

Alendronate is one of the nitrogen-containing bisphosphonates (NBPs) used as anti-bone resorptive drugs. However, NBPs have inflammatory side effects including osteomyelitis and osteonecrosis of the jaw. In the present study, we examined the effects of alendronate on chemokine production by the macrophage-like cell line, J774.1, when incubated with Pam(3)CSK(4) (a Toll-like receptor (TLR) 2 agonist) and Lipid A (a TLR4 agonist). Pretreatment of J774.1 cells with alendronate decreased the production of TLR ligand-induced monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) but did not influence nuclear factor-kappaB (NF-kappaB) activation. While this agent induced caspase-8 activation, a caspase-8 inhibitor did not affect the decrease in MCP-1 production by alendronate and TLR ligands. Thus, the alendronate-mediated decrease in chemokine production was independent of NF-kappaB and caspase-8 activation. Although transforming growth factor-beta1 (TGF-beta1) is known to inhibit chemokine production by various cell types via Smad3 activation, pretreatment with alendronate did not increase TGF-beta1 production by J774.1 cells incubated in the presence or absence of TLR ligands. However, alendronate directly activated Smad3. These results suggest that by down-regulating MCP-1 and MIP-1alpha production via Smad3, long-term use of alendronate might inhibit normal activation and migration of osteoclasts and cause osteonecrosis.
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PMID:Mouse macrophages primed with alendronate down-regulate monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) production in response to Toll-like receptor (TLR) 2 and TLR4 agonist via Smad3 activation. 1950 Nov 97

The metastatic spread of tumors is a well-coordinated process in which different types of cancers tend to form metastases in defined organs. The formation of site-specific metastases requires full compatibility between the intrinsic properties of the tumor cells and the tumor microenvironment. It was recently found that chemokines which are expressed in specific loci promote the adhesion, migration and invasion of tumor cells that express the corresponding receptor(s). Of the different members of the family, the CXCL12 chemokine and its cognate CXCR4 receptor are the prototypes of this process, although other members of the family (e.g. CCR7 and CCR10) also play a role in determination of the metastatic spread. This commentary addresses the fundamental roles of chemokines and their receptors in site-specific metastasis, with emphasis on CXCL12-CXCR4. The article also describes some of the efforts that were performed thus far in order to identify the intracellular components involved in this process. The focus is put on the roles played by proteins that regulate adhesion and migration of tumor cells in response to CXCL12, including mainly focal adhesion kinase (FAK), Pyk2/RAFTK and members of the Rho family of GTPases (RhoA, Rac, Cdc42). This is followed by discussion of open questions that need to be addressed in future research, and of the potential therapeutic implications of the findings that are available to date in this field.
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PMID:Site-specific metastasis formation: chemokines as regulators of tumor cell adhesion, motility and invasion. 1955 Jan 36

Traditionally, Crohn's disease has been associated with a Th1 cytokine profile, while Th2 cytokines are modulators of ulcerative colitis. This concept has been challenged by the description of tolerising regulatory T cells (Treg) and by proinflammatory Th17 cells, a novel T cell population characterised by the master transcription factor RORgammat, the surface markers IL23R and CCR6, and by production of the proinflammatory cytokines IL17A, IL17F, IL21, IL22 and IL26, and the chemokine CCL20. Th17 cells differentiate under the influence of IL1beta, IL6, IL21 and IL23. Recent studies indicate that TGFbeta is essential not only for the development of murine Th17 cells but also for differentiation of human Th17 cells. TGFbeta reciprocally regulates the differentiation of inflammatory Th17 cells and suppressive Treg subsets, with the concomitant presence of proinflammatory cytokines favouring Th17 cell differentiation. Several studies demonstrated an important role of Th17 cells in intestinal inflammation, particularly in Crohn's disease. Genome-wide association studies indicate that IL23R and five additional genes involved in Th17 differentiation (IL12B, JAK2, STAT3, CCR6 and TNFSF15) are associated with susceptibility to Crohn's disease and partly also to ulcerative colitis. Taken together, both Th1 and Th17 cells are important mediators of inflammation in Crohn's disease, although activities previously ascribed to IL12 may be mediated by IL23. Anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is effective in Crohn's disease. However, the complex relationship between Th1 and Th17 cells has not been completely analysed. This will be of great importance to delineate the specific contributions of these cells to Crohn's disease and other autoimmune diseases.
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PMID:Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. 1959 95

Adiponectin is believed to exert hepatoprotective effects and induces CXCL8, a chemokine that functions as a survival factor, in vascular cells. In the current study, it is demonstrated that adiponectin also induces CXCL8 expression in primary human hepatocytes but not in hepatocellular carcinoma cell lines. Knock down of the adiponectin receptor (AdipoR) 1 or AdipoR2 by small-interfering RNA indicates that AdipoR1 is involved in adiponectin-stimulated CXCL8 release. Adiponectin activates nuclear factor (NF)-kappaB in primary hepatocytes and pharmacological inhibition of NF-kappaB, the p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase (ERK) 1/ERK2 reduces adiponectin-mediated CXCL8 secretion. Furthermore, adiponectin also activates STAT3 involved in interleukin (IL)-6 and leptin-mediated CXCL8 induction in primary hepatocytes. Inhibition of JAK2 by AG-490 does not abolish adiponectin-stimulated CXCL8, indicating that this kinase is not involved. Pretreatment of primary cells with "STAT3 Inhibitor VI," however, elevates hepatocytic CXCL8 secretion, demonstrating that STAT3 is a negative regulator of CXCL8 in these cells. In accordance with this assumption, IL-6, a well-characterized activator of STAT3, reduces hepatocytic CXCL8. Therefore, adiponectin-stimulated induction of CXCL8 seems to be tightly controlled in primary human hepatocytes, whereas neither NF-kappaB, STAT3, nor CXCL8 are influenced in hepatocytic cell lines. CXCL8 is a survival factor, and its upregulation by adiponectin may contribute to the hepatoprotective effects of this adipokine.
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PMID:Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-kappaB, and STAT3 signaling pathways. 1960 29

Toxoplasma gondii provoked rapid and sustained nuclear translocation of signal transducer and activator of transcription (STAT) 6, a central mediator of interleukin (IL)-4, in macrophage-differentiated human acute monocytic leukemia cells without exogenous IL-4 in western blot and immunofluorescence assay. Phosphorylation of STAT6 occurred immediately after the entry of T. gondii and only by live tachyzoites, not by killed or soluble extract. It was impeded by Janus kinase (JAK) 3 inhibitor and small interfering RNA (siRNA) of STAT6. It induced expression of IL-4 responsive genes such as IL-4R, CD40, and CD23. It also mediated expression of two large clusters of C-C chemokine ligands (CCLs) and serine protease inhibitors (SERPINs) in microarray of T. gondii-infected macrophages. CCL1, 2, 8, 13, and 22 and SPINT2, SERPINB3, B4, and B13 were increased by the infection and inhibited by the treatment of JAK3 inhibitor and siRNA-mediated STAT6 silencing, which suggested the expression was governed by STAT6 activation. Secreting those CCLs, T. gondii-infected macrophages may attract more monocytes and Th2 cells of CCR3 and CCR4 to enrich the Th2 environment nearby the infected macrophages, and induced SERPINs may participate in protection from intracellular damages produced by activated lysosomal enzymes and in the inhibition of caspase activity to block the apoptosis. This suggests that T. gondii exploits cytokine cross-regulation through STAT6 activation to obviate various toxoplasmacidal reactions by interferon-gamma.
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PMID:STAT6 activation by Toxoplasma gondii infection induces the expression of Th2 C-C chemokine ligands and B clade serine protease inhibitors in macrophage. 1965 72

Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal and cancer cells, such as 5-bromo-2'-deoxyuridine (BrdU), distamycin A (DMA), aphidicolin and hydroxyurea, persistently activate Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and expression of interferon-stimulated genes (ISGs), such as MX1, OAS, ISG15, STAT1, PML, IRF1 and IRF7, in several human cancer cell lines. JAK1/STAT-activating ligands, interleukin 10 (IL10), IL20, IL24, interferon gamma (IFNgamma), IFNbeta and IL6, were also expressed by senescent cells, supporting autocrine/paracrine activation of JAK1/STAT. Furthermore, cytokine genes, including proinflammatory IL1, tumor necrosis factor and transforming growth factor families, were highly expressed. The strongest inducer of JAK/STAT signaling, cytokine production and senescence was BrdU combined with DMA. RNA interference-mediated knockdown of JAK1 abolished expression of ISGs, but not DNA damage signaling or senescence. Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNbeta-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence. These results highlight shared and unique features of drug-induced cellular senescence, and implicate induction of cancer secretory phenotype in chemotherapy.
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PMID:Cytokine expression and signaling in drug-induced cellular senescence. 1980 7

Deregulation of signal transducer and activator of transcription (STAT)-3 signaling plays crucial role in oncogenesis of various cancers. However, the molecular mechanism by which osteopontin (OPN), a chemokine-like extracellular matrix-associated protein, regulates STAT3 activation that leads to tumor progression and inhibits apoptosis in breast cancer cells is not well understood. In this study, we for the first time report that OPN upregulates alphavbeta3 integrin-mediated Janus kinase 2 (JAK2) phosphorylation and STAT3 activation in breast cancer (MDA-MB-468 and MCF-7) cells. Pretreatment of cells with JAK2 inhibitor (AG 490) suppresses OPN-induced STAT3 phosphorylation, its nuclear localization and DNA binding indicating that JAK2 is involved in this process. Transfection of cells with wild-type (wt) STAT3 enhanced whereas mutant STAT3 (STAT3 Y705F) suppressed OPN-induced breast tumor cell migration. Treatment of cells with OPN followed by staurosporine (STS) showed that OPN protects the cells from STS-induced apoptosis. Moreover, transfection of cells with wt STAT3 upregulates whereas STAT3 Y705F downregulates Bcl2 and cyclin D1 expressions in response to OPN. Interestingly, STAT3-overexpressing cells when injected to non-obese diabetic/severe combined immunodeficiency mice followed by OPN treatment, the mice developed enhanced tumor growth as compared with STAT3 Y705F-injected mice or mice injected with OPN alone. The levels of Bcl2 and cyclin D1 in wt STAT3 tumors were significantly higher than controls. Clinical specimen analysis revealed that increased OPN and pSTAT3 expressions correlate with enhanced breast tumor progression. Thus, targeting OPN and its regulated STAT3 signaling could be a potent therapeutic approach and understanding these mechanisms may form the basis of new therapeutic regimen for the management of breast cancer.
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PMID:Activation of JAK2/STAT3 signaling by osteopontin promotes tumor growth in human breast cancer cells. 1992 37

The aim of this study was to define the effects on antigen-presenting cells of the expression of HIV antigens from an attenuated poxvirus vector. We have analyzed the transcriptional changes in gene expression following infection of human immature monocyte-derived dendritic cells (DC) with recombinant modified vaccinia virus Ankara (MVA) expressing the genes encoding the gp120 and Gag-Pol-Nef antigens of HIV type 1 clade B (referred to as MVA-B) versus parental MVA infection. Using microarray technology and real-time reverse transcription-PCR, we demonstrated that the HIV proteins induced the expression of cytokines, cytokine receptors, chemokines, chemokine receptors, and molecules involved in antigen uptake and processing, including major histocompatibility complex (MHC) genes. Levels of mRNAs for interleukin-1, beta interferon, CCR8, and SCYA20 were higher after HIV antigen production. MVA-B infection also modulated the expression of antigen processing and presentation genes: the gene for MICA was upregulated, whereas those for HLA-DRA and HSPA5 were downregulated. Indeed, the increased expression of the gene for MICA, a glycoprotein related to major histocompatibility complex class I molecules, was shown to enhance the interaction between MVA-B-infected target cells and cytotoxic lymphocytes. The expression profiles of the genes for protein kinases such as JAK1 and IRAK2 were activated after HIV antigen expression. Several genes included in the JAK-STAT and mitogen-activated protein kinase signaling pathways were regulated after HIV antigen expression. Our findings provide the first gene signatures in DC of a candidate MVA-B vaccine expressing four HIV antigens and identified the biological roles of some of the regulatory genes, like that for MICA, which will help in the design of more effective MVA-derived vaccines.
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PMID:Selective induction of host genes by MVA-B, a candidate vaccine against HIV/AIDS. 2053 57

Plasmin is recognized as a potent signaling molecule in particular human monocytes, inducing a pro-inflammatory response. Recently, the annexin A2 heterotetramer, a plasmin receptor, was described at the surface of the human monocytes. Plasmin is initiating a signaling in monocytes by cleavage of the annexin A2 subunit of the receptor and the apparent dissociation of the heterotetramer at the surface of cell. However, the exact mechanism linking this dissociation and the activation of the intracellular pathway remains undefined. Here we report that the molecular mechanism of monocyte activation may rely on a new molecule containing the amino-terminal end of annexin A2 (A2NP) generated by plasmin cleavage of its receptor - the annexin A2 heterotetramer - as in vitro A2NP is able to mimic plasmin activation of the tyrosine kinase JAK1 and STAT3 and the subsequent increase in expression and release of monocyte/macrophage chemoattractant protein (MCP)-1, which is a major chemokine released by monocytes/macrophages. Additionally, we show that plasmin-induced the phosphorylation of STAT3 is similar to that of IL-6 and IL-31, and protease-activated receptor 1 does not affect plasmin-induced cytokine MCP-1 release in human monocytes. Finally, our data demonstrate that plasmin triggers the production of MCP-1 in macrophages in vivo. Thus, A2NP generated by plasmin cleavage of the annexin A2 heterotetramer could serve as a new proteolytically generated signaling molecule activating an associated transmembrane co-receptor, such as type I cytokine receptors.
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PMID:A role for the annexin A2 amino-terminal peptide in the plasmin-induced activation of human peripheral monocytes. 2222 Mar 4

c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) family and controls essential processes such as inflammation, cell differentiation, and apoptosis. JNK signalling is triggered by extracellular signals such as cytokines and environmental stresses. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine with chemokine-like functions in leukocyte recruitment and atherosclerosis. MIF promotes MAPK signalling through ERK1/2, while it can either activate or inhibit JNK phosphorylation, depending on the cell type and underlying stimulation context. MIF activities are mediated by non-cognate interactions with the CXC chemokine receptors CXCR2 and CXCR4 or by ligation of CD74, which is the cell surface expressed form of the class II invariant chain. ERK1/2 signalling stimulated by MIF is dependent on CD74, but the receptor pathway involved in MIF activation of the JNK pathway is unknown. Here we comprehensively characterize the stimulatory effect of MIF on the canonical JNK/c-Jun/AP-1 pathway in fibroblasts and T cell lines and identify the upstream signalling components. Physiological concentrations of recombinant MIF triggered the phosphorylation of JNK and c-Jun and rapidly activated AP-1. In T cells, MIF-mediated activation of the JNK pathway led to upregulated gene expression of the inflammatory chemokine CXCL8. Activation of JNK signalling by MIF involved the upstream kinases PI3K and SRC and was found to be dependent on CXCR4 and CD74. Together, these data show that the CXCR4/CD74/SRC/PI3K axis mediates a rapid and transient activation of the JNK pathway as triggered by the inflammatory cytokine MIF in T cells and fibroblasts.
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PMID:Activation of the JNK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on CXCR4 and CD74. 2080 68


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