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)

Arginine-derived nitric oxide (NO) has been identified in some tumor cell lines and solid human tumors. The effect of tumor cell NO on tumor biology is poorly understood. The purpose of this study was to investigate the effect of NO production by EMT-6 murine breast cancer cells on tumor cell growth in vitro and subcutaneous tumor growth and experimental pulmonary metastasis in vivo. EMT-6 cells were incubated with endotoxin (LPS, 10 microgram/ml) and interferon-gamma (IFN, 50 U/ml), in the presence or absence of the NO synthase inhibitor, omega-nitro-L-arginine methyl ester (L-NAME, 2 mM), and NO production and cell number were assessed 24 hr later. EMT-6 cells were also treated overnight with LPS/IFN, in the presence or absence of L-NAME, washed and injected either subcutaneously in the dorsal flank (n = 40) or via the tail vein (n = 40) of syngeneic BALB/c mice. Two weeks following tumor cell injection, tumor size and number of pulmonary metastases were assessed. LPS/IFN stimulated NO production in EMT-6 cells and inhibited cell growth in vitro by 50%. L-NAME blocked LPS/IFN stimulation of NO production and restored cell growth to near control levels. When injected into BALB/c mice, LPS/IFN-stimulated tumor cells demonstrated a two-fold increase in subcutaneous tumor growth and experimental pulmonary metastases over control cells. L-NAME reduced tumor size and number of lung metastases to control levels, suggesting that tumor cell NO production was responsible for this effect. In summary, LPS/IFN-stimulated NO production in EMT-6 tumor cells inhibits tumor cell growth in vitro, yet paradoxically augments tumor growth and metastasis in vivo.
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PMID:Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo. 866 Nov 71

Indoleamine 2,3-dioxygenase (INDO) is the rate-limiting enzyme in the catabolism of the essential amino acid L-tryptophan. It is induced strongly in many cell lines following interferon-gamma treatment. We report the cloning and characterization of the full-length human INDO promoter. This promoter is 1,245 base pairs long and includes two interferon-stimulated response elements (ISRE) separated by an approximately 1-kilobase sequence. The presence of these two ISREs is critical for maximum INDO promoter activity (50-fold induction). When the ISREs are present in two separate fragments cloned upstream of the chloramphenicol acetyltransferase (CAT) reporter vector, the INDO promoter activity drops significantly (7-fold induction). 5' end deletions of the wild type promoter sequence indicate that removal of the ISRE (ISRE1) at position -1126 reduces the induction level to approximately 25-fold. This activity does not change appreciably when the promoter is deleted down to position -241. Furthermore, site-directed mutagenesis of ISRE1 also decreases the promoter activity in a similar way. When ISRE1 is kept intact, deletion of the second ISRE (ISRE2) at position -111 leads to only 11-fold induction of the promoter. A similar result is obtained when substitution mutations are introduced in ISRE2. Deletion of a 748-base pair sequence between the two ISREs only shows a slight decrease in the INDO promoter activity. These data indicate that the two ISRE sequences are required for the full transcriptional induction of the interferon-gamma-inducible human INDO gene. INDO activity is not induced in the hepatic cell line HepG2. An analysis of INDO-CAT activity in this cell line indicated that the lack of INDO activity was at the transcriptional level and could reflect either the presence of a repressor or lack of a transcription factor. This lack of induction could be correlated with a truncated or unstable IRF-1. However, the levels of IRF-2, JAK2, and STAT 91 were similar in both ME180 and HepG2 cells.
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PMID:Importance of the two interferon-stimulated response element (ISRE) sequences in the regulation of the human indoleamine 2,3-dioxygenase gene. 870 90

JAK2, a member of the Janus kinase superfamily was found to interact functionally with Raf-1, a central component of the ras/mitogen-activated protein kinase signal transduction pathway. Interferon-gamma and several other cytokines that are known to activate JAK2 kinase were also found to stimulate Raf-1 kinase activity toward MEK-1 in mammalian cells. In the baculovirus coexpression system, Raf-1 was activated by JAK2 in the presence of p21ras. Under these conditions, a ternary complex of p21ras, JAK2, and Raf-1 was observed. In contrast, in the absence of p21ras, coexpression of JAK2 and Raf-1 resulted in an overall decrease in the Raf-1 kinase activity. In addition, JAK2 phosphorylated Raf-1 at sites different from those phosphorylated by pp60v-src. In mammalian cells treated with either erythropoietin or interferon-gamma, a small fraction of Raf-1 coimmunoprecipitated with JAK2 in lysates of cells in which JAK2 was activated as judged by its state of tyrosine phosphorylation. Taken together, these data suggest that JAK2 and p21ras cooperate to activate Raf-1.
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PMID:The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner. 887 96

In this report, we demonstrate that insulin receptor substrate-2 (IRS-2) is tyrosyl-phosphorylated following stimulation of 3T3-F442A fibroblasts with growth hormone (GH), leukemia inhibitory factor and interferon-gamma. In response to GH and leukemia inhibitory factor, IRS-2 is immediately phosphorylated, with maximal phosphorylation detected at 15 min; the signal is substantially diminished by 60 min. In response to interferon-gamma, tyrosine phosphorylation of IRS-2 was prolonged, with substantial signal still detected at 60 min. Characterization of the mechanism of signaling utilized by GH indicated that tyrosine residues in GH receptor are not necessary for tyrosyl phosphorylation of IRS-2; however, the regions of GH receptor necessary for IRS-2 tyrosyl phosphorylation are the same as those required for JAK2 association and tyrosyl phosphorylation. The role of IRS-2 as a signaling molecule for GH is further demonstrated by the finding that GH stimulates association of IRS-2 with the 85-kDa regulatory subunit of phosphatidylinositol 3'-kinase and with the protein-tyrosine phosphatase SHP2. These results are consistent with the possibility that IRS-2 is a downstream signaling partner of multiple members of the cytokine family of receptors that activate JAK kinases.
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PMID:Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling. 891 Jun 7

There is evidence that the cellular responses to cytokines, such as granulocyte colony stimulating factor (G-CSF) and interferons, depend on prior activation of components of the JAK/STAT signalling pathway. We report here that the myeloid cell line NFS-60 shows aberrant JAK/STAT signalling yet elicits expected biological responses to G-CSF and interferons-alpha/beta and gamma. Instead of increased phosphorylation of JAK1 and JAK2 in response to G-CSF and interferon-gamma, and JAK1 and Tyk2 in response to interferon-alpha/beta, we observed only an increase of phosphorylation of Tyk2 in response to all of these cytokines in NFS-60 cells. The subset of STAT proteins being activated in response to these cytokines was unusual as well. G-CSF activated STAT3 and STAT5A, whereas interferons activated, in addition to STAT1 and STAT5 other, as yet unidentified, DNA binding proteins. However, NFS-60 cells show normal biological responses to these cytokines, such as proliferation in response to G-CSF, and reduction of proliferation, induction of an anti-viral response and induction of specific genes in response to interferons.
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PMID:Aberrant activation of JAK/STAT pathway components in response to G-CSF, interferon-alpha/beta and interferon-gamma in NFS-60 cells. 891 32

Selective induction of effector functions in a T cell clone, DB14, specific for pigeon cytochrome c 43-58 (p43-58) and restricted to I Ab was analyzed using professional antigen presenting cells (APC), B hybridoma (Th2.58), and various non professional APC, L cells transfected with I Ab (I-Ab L cells), a medullary thymic epithelial cell line (m-TEC) and a cortical thymic epithelial cell line (c-TEC). The m-TEC and c-TEC (m, c-TEC) expressed I-Ab after culturing with interferon-gamma (IFN-gamma). When stimulated with p43-58 in the presence of I-Ab L cells as well as Th2.58 cells, the DB14 cells showed marked proliferation and exhibited significant cytotoxicity against these APC after 18 hr of culture. By contrast, in the presence of m, c-TEC the DB14 cells showed neither proliferation nor cytotoxicity against these TEC but exhibited considerable detachment activity against them. Furthermore DB14 cells became expressed activation markers (CD69 and CD44) after antigen (p43-58) stimulation with m-TEC or c-TEC. Addition of rIL-2 to the culture of DB14 cells, p43-58 and m, c-TEC restored the proliferative responses. However, it was shown that anergy was not involved in the lack of proliferative response of DB14 cells after antigen stimulation with m, c-TEC. The present findings indicate that differences in APC function are present among non-professional APC and suggest that the selective induction of T cell functions can be achieved using appropriate non-professional APC. The characteristic activation of T cells by TEC may be related to their functional roles in situ.
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PMID:[Selective induction of effector functions in a T cell clone following antigen presentation in the presence of thymic epithelial cells]. 914 12

Interleukin-6 (IL-6) is an important B-cell growth and differentiation factor. IL-6 treatment of the human lymphoblastoid cell line, SKW6.4, leads to increased IgM production. We have previously shown that IL-6 induces activation of JAK1 and JAK2 in human B cell lines. A chimeric IL-6 receptor, comprised of the intracellular tail of the IL-6 receptor subunit gp130 fused to the extracellular domain of the epidermal growth factor (EGF) receptor, was stably transfected into SKW6.4 cells. EGF treatment induced IgM production in cells transfected with an intact gp130 cytoplasmic tail, but not in untransfected cells or cells transfected with a cytoplasmic tail lacking all four signal transducers and activators of transcription (Stat) binding sites. Moreover, EGF treatment induced Stat3 phosphorylation in cells transfected with the intact chimeric EGF-gp130 receptor along with induction of DNA-mobility shift of a classical interferon-gamma-activated site. To define further the relation between Stat3 activation and enhanced IgM production, we determined the effect of chimeric gp130 on the transcriptional activation of a genetic element linked to immunoglobulin production, namely the immunoglobulin heavy chain enhancer (IgH-enhancer). Parental as well as transfected SKW6.4 cells were transiently transfected with an IgH-enhancer-luciferase construct. The transcriptional activity of the IgH-luciferase construct was induced upon ligation of the full-length chimeric receptor but not by truncated gp130 receptors. Moreover, the gp130-induced activity of this reporter gene was abrogated by Stat3EE, a mutant Stat3 incapable of binding DNA. These results indicate that IL-6-induced B-cell differentiation, as measured by IgM production, may be controlled by Stat3 proteins.
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PMID:Involvement of Stat3 in interleukin-6-induced IgM production in a human B-cell line. 915 40

Interleukin-18 (IL-18) was identified as an inducer of interferon-gamma (IFN-gamma) production by stimulated T cells. In this study, we used an ovalbumin-responsive murine Th1 clone (OVA#4), in which DNA synthesis was reportedly enhanced after IL-18 treatment in the presence of a non-mitogenic TCR/CD3 stimulus, to examine signal transduction pathways. In the presence of the stimulus, IL-18 induced the appearance of tyrosine-phosphorylated proteins and herbimycin A inhibited DNA synthesis. It is suggested that protein tyrosine kinase (PTK) mediated signaling is induced by IL-18. Specifically, IL-18 induced phosphorylation of phosphorylates p56(lck) (LCK) and mitogen-activated protein kinase (MAPK). IL-18 alone induced the kinase activities of both LCK and MAPK, and the activities were increased by the TCR/CD3 stimulus. Simultaneously, IL-18 induced the association of LCK with MAPK and this was also increased by the TCR/CD3 stimulus. The activation of the LCK-MAPK pathway correlated with enhanced DNA synthesis in OVA#4 cells. These results suggest that the LCK-MAPK pathway is involved in IL-18 signaling and that IL-18 may play an important role in modification of TCR/CD3-mediated response.
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PMID:Interleukin-18 induces activation and association of p56(lck) and MAPK in a murine TH1 clone. 926 43

The urokinase-type plasminogen activator (uPA) binds to cells via a specific receptor attached to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor. Despite the lack of a transmembrane domain, the urokinase receptor (uPAR) is capable of transducing extracellular signals affecting growth, migration, and adhesion. Several Tyr kinases of the src family as well as beta1, beta2, and beta3 integrins were found to be associated with the uPAR. We found that in the human kidney epithelial line TCL-598, also components of the JAK1/STAT1 signal transduction pathway including gp130, are associated with uPAR as revealed by coimmunoprecipitation and are co-localized in caveolae. Upon clustering of uPA.uPAR complex by a monoclonal antibody, JAK1 associates with uPAR, which in turn leads to STAT1 phosphorylation, dimerization, specific binding to DNA, and gene activation. To prove the dependence of STAT1 activation on the uPAR, TCL-598 cells were treated with sense and antisense uPAR oligonucleotides. In antisense-treated cells in which uPAR expression was reduced to less then one third, activation of STAT1 by the clustering antibody was abolished while STAT1 activation by interferon-gamma was unaffected. Therefore, in this cell line, uPA.uPAR also utilizes the JAK1/STAT1 pathway for signaling, and gp130 might be the transmembrane adapter for this signal transduction pathway.
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PMID:Urokinase receptor is associated with the components of the JAK1/STAT1 signaling pathway and leads to activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598. 935 20

SIRPs (signal-regulatory proteins) are a family of transmembrane glycoproteins that were identified by their association with the Src homology 2 domain-containing protein-tyrosine phosphatase SHP-2 in response to insulin. Here we examine whether SIRPalpha and SHP-2 are signaling molecules for the receptors for growth hormone (GH), leukemia inhibitory factor (LIF), or interferon-gamma (IFNgamma), cytokine receptor superfamily members that bind to and activate Janus kinase 2 (JAK2). In 3T3-F442A fibroblasts, GH rapidly stimulates tyrosyl phosphorylation of both SIRPalpha and SHP-2 and enhances association of SHP-2 with SIRPalpha. Consistent with JAK2 binding and phosphorylating SIRPalpha in response to GH, co-expression of SIRPalpha and JAK2 in COS cells results in tyrosyl phosphorylation of SIRPalpha and JAK2 association with SIRPalpha. LIF does not stimulate tyrosyl phosphorylation of SIRPalpha but stimulates greater tyrosyl phosphorylation of SHP-2 than GH. Additionally, LIF enhances association of SHP-2 with the gp130 subunit of the LIF receptor signaling complex. IFNgamma, which stimulates JAK2 to a greater extent than LIF, is ineffective at stimulating tyrosyl phosphorylation of SIRPalpha or SHP-2. These results suggest that SIRPalpha is a signaling molecule for GH but not for LIF or IFNgamma. Differential phosphorylation of SIRPalpha and SHP-2 may contribute to the distinct physiological effects of these ligands.
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PMID:Growth hormone regulation of SIRP and SHP-2 tyrosyl phosphorylation and association. 950 23


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