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)

Interleukin-2 induces heterodimerization of the IL-2 receptor beta and gamma subunits. This study addresses a role of the Shb adapter protein in IL-2 receptor signaling in T and NK cells. The IL-2Rbeta and gamma chains were found to co-immunoprecipitate with Shb, when each alone was co-expressed with Shb in COS cells. Using fusion proteins, the Shb SH2 domain was found to associate in a phosphotyrosine-dependent manner with the IL-2 receptor beta and gamma subunits upon IL-2 stimulation in primary T cells and the NK cell line NK-92. The main binding site of the Shb SH2 domain was phosphorylated Tyr-510 in the IL-2Rbeta chain. Shb was also phosphorylated upon IL-2 stimulation when overexpressed together with IL-2Rbeta (in pre-B cells, which express the gamma chain constitutively). These cells were also less apoptotic in the presence of IL-2 than cells overexpressing a mutant Shb (with a defect SH2 domain) or cells expressing a mutant IL-2Rbeta, with the Shb binding sites mutated to phenylalanine (Y392F, Y510F). JAK1 and JAK3 were also found to associate with Shb, but in contrast to the Shb-IL-2 receptor association, JAK1 and 3 appear to associate with the proline-rich regions of Shb. In conclusion, Shb links the IL-2 receptor to other signaling proteins and mediates the regulation of apoptosis in the presence of IL-2.
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PMID:IL-2 receptor signaling through the Shb adapter protein in T and NK cells. 1220 Jan 37

A high-affinity IL-2 receptor requires two Janus protein tyrosine kinases (JAKs) for IL-2 signal transduction: JAK1 and JAK3. Since transphosphorylation of the two kinases is presumed to occur after receptor engagement we examined the phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD), which has two adjacent tyrosines. Mass spectral analysis of the enzymatically phosphorylated peptide showed that the second tyrosine was phosphorylated at a 30-fold greater rate than the first tyrosine. Moreover, no doubly phosphorylated peptide was detected by this analysis. Kinetic analysis of the reactions of singly phosphorylated JAK1 activation loop peptides showed that phosphorylating the first or second tyrosine decreased the k(cat)/K(m) for the phosphorylation of the other 115- and 26-fold, respectively. Singly changing each side chain of the KEYYTV portion of the peptide to a methyl group (alanine) yielded substrates comparable to the wild-type sequences in all cases except that of the first or second tyrosine, which showed a 153- or 70-fold drop in k(cat)/K(m), respectively. Using libraries of immobilized peptides with all 20 naturally occurring amino acids substituted for Y9 or T11 showed that the JAK3 tolerated substitution at T11 but prefers large hydrophobic amino acids at Y9. These results show that JAK3 does not act processively on the JAK1 activation loop in vitro and illustrate the role of Y9 in the recognition of the preferred site of phosphorylation which is Y10.
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PMID:Mechanism of Janus kinase 3-catalyzed phosphorylation of a Janus kinase 1 activation loop peptide. 1255 72

Janus kinase 3 (Jak3) is a nonreceptor tyrosine kinase essential for signaling via cytokine receptors that comprise the common gamma-chain (gammac), i.e., the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Jak3 is preferentially expressed in hemopoietic cells and is up-regulated upon cell differentiation and activation. Despite the importance of Jak3 in lymphoid development and immune function, the mechanisms that govern its expression have not been defined. To gain insight into this issue, we set out to characterize the Jak3 promoter. The 5'-untranslated region of the Jak3 gene is interrupted by a 3515-bp intron. Upstream of this intron and the transcription initiation site, we identified an approximately 1-kb segment that exhibited lymphoid-specific promoter activity and was responsive to TCR signals. Truncation of this fragment revealed that core promoter activity resided in a 267-bp fragment that contains putative Sp-1, AP-1, Ets, Stat, and other binding sites. Mutation of the AP-1 sites significantly diminished, whereas mutation of the Ets sites abolished, the inducibility of the promoter construct. Chromatin immunoprecipitation assays showed that histone acetylation correlates with mRNA expression and that Ets-1/2 binds this region. Thus, transcription factors that bind these sites, especially Ets family members, are likely to be important regulators of Jak3 expression.
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PMID:Characterization and analysis of the proximal Janus kinase 3 promoter. 1279 34

It has been previously demonstrated that human carcinomas express interleukin-2 receptor (IL-2R) alpha, beta, and gamma chains. The beta and gamma chains of IL-2R have intermediate binding affinity for IL-2 and are responsible for the intracellular signaling cascades after IL-2 stimulation. IL-2Ralpha lacks the cytoplasmic domain, but is essential for increasing the IL-2-binding affinity of other receptors. Overexpression of IL-2Ralpha in tumor cells is associated with tumor progression and a poor patient prognosis. To define molecular mechanisms responsible for the effects associated with IL-2Ralpha expression, ex vivo experiments were performed with the squamous cell carcinoma head-and-neck cancer line, PCI-13, which was genetically engineered to overexpress the IL-2Ralpha chain. While IL-2Ralpha-overexpressing PCI-13 cells were capable of forming colonies in soft agar, PCI-13 cells transfected with the control vector or those expressing IL-2Rgamma did not. Consistently, IL-2Ralpha-expressing tumor cells proliferated more rapidly than the control or IL-2Rgamma+ cells, associated with increased levels of cyclins A and D1 and cyclin-dependent kinase (cdk(s)) 2 and 4 proteins. In addition, IL-2Ralpha-expressing cells were significantly more resistant to apoptosis induction by a tripeptidyl proteasome inhibitor (ALLN) and two chemotherapeutic drugs (VP-16 and taxol) than the control or IL-2Rgamma+ cells. Accompanying the drug resistance, high levels of anti-apoptotic Bcl-X(L) and Bcl-2 proteins were found in the mitochondria-containing fraction of IL-2Ralpha-expressing tumor cells. Treatment of IL-2Ralpha-expressing cells with a specific Janus kinase 3 (Jak3) inhibitor decreased expression of cyclin A, cyclin D1, Bcl-X(L), and Bcl-2 proteins. Finally, high levels of ubiquitinated proteins were detected in the proliferating IL-2Ralpha-expressing cells. Our data suggest that increased proliferation rates and decreased drug sensitivity of IL-2Ralpha-expressing tumor cells are responsible for the enhanced tumor aggressiveness and poor clinical prognosis of patients whose tumors express IL-2Ralpha.
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PMID:Overexpression of interleukin-2 receptor alpha in a human squamous cell carcinoma of the head and neck cell line is associated with increased proliferation, drug resistance, and transforming ability. 1285 47

The WD repeat-containing protein receptor for activated protein kinase C (RACK)-1 has been linked to a variety of signaling systems including protein kinase C, growth factors, and IFNs. In the IFN system, RACK-1 functions as an adaptor recruiting the transcription factor STAT1 to the receptor complex. However, RACK-1 should play a broader role in type I IFN signaling because mutation of the RACK-1 binding site in the IFN-alpha receptor 2/beta subunit of the type I IFN receptor abrogates not only STAT1, but also STAT2, activation. In this study, we demonstrate that RACK-1 serves as a scaffold protein for a multiprotein complex that includes the IFN-alpha receptor 2/beta-chain of the receptor, STAT1, Janus kinase 1, and tyrosine kinase 2. In vitro data further suggest that within this complex tyrosine kinase 2 is the tyrosine kinase responsible for the phosphorylation of STAT1. Finally, we provide evidence that RACK-1 may also serve as a scaffold protein in other cytokine systems such as IL-2, IL-4, and erythropoietin.
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PMID:The WD motif-containing protein RACK-1 functions as a scaffold protein within the type I IFN receptor-signaling complex. 1296 Mar 23

Pharmacological targeting of Janus kinase 3 (JAK3) has been employed successfully to control allograft rejection and graft-vs.-host disease (GVHD). Recent evidence suggests that in addition to its involvement in common-gamma chain (cgamma) signaling of cytokine receptors, JAK3 is also engaged in the CD40 signaling pathway of peripheral blood monocytes. In this study, we assessed the consequences of JAK3 inhibition during CD40-induced maturation of myeloid dendritic cells (DCs), and tested the impact thereof on the induction of T-cell alloreactivity. Dendritic cells triggering through CD40 induced JAK3 activity, the expression of costimulatory molecules, production of IL-12, and potent allogeneic stimulatory capacity. In contrast, JAK3 inhibition with the rationally designed JAK3 inhibitor WHI-P-154 prevented these effects arresting the DCs at an immature level. Interestingly, DCs exposed to the JAK3-inhibitor during CD40-ligation induced a state of hyporeactivity in alloreactive T cells that was reversible upon exogenous IL-2 supplementation to secondary cultures. These results suggest that immunosuppressive therapies targeting the tyrosine kinase JAK3 may also affect the function of myeloid cells. This property of JAK3 inhibitors therefore represents a further level of interference, which together with the well-established suppression of cgamma signaling could be responsible for their clinical efficacy.
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PMID:Prevention of CD40-triggered dendritic cell maturation and induction of T-cell hyporeactivity by targeting of Janus kinase 3. 1452 93

IL-21 is a recently described type I cytokine produced by activated CD4(+) T cells that profoundly affects the growth, survival, and functional activation of B, T, and natural killer lymphocytes in concert with other cytokines or activating stimuli. Structurally, IL-21 is predicted to display a 4-helix-bundle-type fold with significant homology to IL-2, IL-4, and IL-15 and mediates its biologic effects through a novel type I cytokine receptor, IL-21R, in conjunction with the common cytokine receptor gamma chain (gammac) of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors. As a new member of the gammac-dependent cytokine family, there is significant interest in IL-21, in part because of its potential to provide new insights into the immunologic phenotype caused by gammac deficiency. IL-21R knockout mice have been generated that have normal lymphoid cell development yet exhibit impaired production of the immunoglobulin IgG(1) and increased IgE responses after immunization. As expected for cytokines that use gammac, recent studies indicate that IL-21 induces Janus kinase 1 (JAK1) and JAK3 activation to initiate signal transduction, but unlike these other gammac-dependent cytokines, which predominantly activate signal transducer and activator of transcription 5 (STAT5), IL-21 preferentially activates STAT1 and STAT3. IL-21 potently enhances primary antigen responses and the effector functions of T and natural killer cells and stimulates IFN-gamma production alone or in concert with other cytokines. Thus, on the basis of primary structure, receptor composition, and biologic activities, IL-21 is a new IL-2-family cytokine that participates in both innate and adaptive immunity and might be important for the development of a T(H)1 immune response.
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PMID:IL-21: a novel IL-2-family lymphokine that modulates B, T, and natural killer cell responses. 1465 53

The effect of IL-2 on the expression of the mouse zinc-fingers and homeoboxes 1 (ZHX1) gene was investigated in a mouse cytotoxic T cell line, CTLL-2 cells. IL-2 specifically induced the expression of ZHX1 mRNA. The level of ZHX1 mRNA was decreased in the absence of IL-2. These alterations were in parallel with the status of cell proliferation. The signaling pathways involved in the induction were examined. AG-490, wortmannin, and LY294002 blocked the induction by IL-2. Nuclear run-on assays and a mRNA stability analysis revealed that the half-life of ZHX1 mRNA but not the transcription rate of the gene was increased by IL-2. Thus, we conclude that IL-2 induces the expression of the mouse ZHX1 gene in CTLL-2 cells, that both Janus kinase 3/signal transducer and activator of transcription 5 and phosphoinositide 3-kinase pathways are involved in the induction, and that the increased mRNA stability results in the induction.
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PMID:A mechanism of induction of the mouse zinc-fingers and homeoboxes 1 (ZHX1) gene expression by interleukin-2. 1474 19

Deficient T cell immune function and intracellular signaling in cancer patients may result from effects of tumors or their products on lymphocytes. Recently, it was demonstrated that several ovarian carcinoma cell lines could produce soluble factors that inhibited T cell proliferation. The aim of this study is to assess the effect of supernatants from 3 ovarian carcinoma cell lines (OVCAR3, CAOV3, SKOV3) on signal transduction elements that are linked to the IL-2R and its JAK-STAT pathway. A profound inhibition of proliferation, lower level of IFN-gamma and higher level of IL-10 gene expression were observed when CD8+ T cells were co-cultured with supernatants from 3 ovarian carcinoma cell lines. Cell cycle studies on inhibited CD8+ T cells showed most of them were growth arrested in G0/G1 phase. Western blot analysis showed that tumor supernatants suppressed expression of JAK3 and tyrosine phosphorylation of STAT5. JAK1 was not altered and the inhibition of STAT3 only appeared in OVCAR3 cells. Tumor supernatants also partially blocked induction of IL-2R beta and gamma chains expression. These findings suggest that ovarian carcinoma cells may suppress T cell proliferation through inhibition IL-2 dependent signaling pathways, which may be a mechanism of ovarian carcinoma induced immunosuppression.
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PMID:Ovarian carcinoma cells inhibit T cell proliferation: suppression of IL-2 receptor beta and gamma expression and their JAK-STAT signaling pathway. 1474 32

HTLV-I is the causative agent of adult T-cell leukemia (ATL). However, the precise mechanism underlying the neoplastic cell growth of ATL remains unclear. In this study, we established a leukemic cell line, termed SYK-11L(+), from tumor cells (S-YU) in an in vivo cell proliferation model of ATL using severe combined immunodeficiency (SCID) mice. Unexpectedly, SYK-11L(+) was found to have no tumorigenicity in SCID mice. Flow cytometric analysis showed that S-YU expressed cell adhesion molecules including CD44, ICAM-1 and OX40, whereas SYK-11L(+) had lost the expression of these molecules. The administration of anti-OX40 monoclonal antibody inhibited the engraftment of S-YU cells into SCID mice, suggesting that OX40 is a potential target for immunotherapy. Significant differences in responsiveness to IL-2 and IL-15 were observed between the two cell types. To better understand the molecular basis of tumorigenicity, cDNA microarray analysis was performed using tumorigenic S-YU and non-tumorigenic SYK-11L(+) cells. We obtained several candidate genes differentially overexpressed in S-YU compared with SYK-11L(+). Interestingly, one such gene, regulator of G protein signaling 1 (RGS1), was shown to be overexpressed in most ATL patients. Further characterization of the differentially expressed molecules, such as OX40 and RGS1, would provide useful information not only to elucidate the mechanism of ATL cell growth in vivo, but also to develop novel molecularly targeted therapies.
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PMID:Identification of differentially expressed molecules in adult T-cell leukemia cells proliferating in vivo. 1513 68


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