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)

The receptors for interleukin 2 (IL-2) and interleukin 15 (IL-15) in T cells share the IL-2R beta subunit (CD122) and gamma(C) subunit but have private alpha subunits. Despite utilizing the same receptor chains known to be necessary and sufficient to transduce IL-2 signals the two cytokines manifest different cellular effects. It is commonly held that the alpha subunit of the IL-2R (CD25) is involved solely in the generation of a high affinity receptor complex. This is questioned by the development of autoimmune diseases in instances where the expression of CD25 is absent. The timely expression of CD25 in the thymus has been linked with clonal deletion. Evidence from peripheral T cells indicates that survival signals arising from the intermediate affinity IL-2R (lacking CD25) do not require the activation of Janus kinase 3 (Jak3) but do require the presence of the membrane proximal region of the gamma(C) chain. This particular signalling pathway is not observed in the high affinity receptor complex where Jak3 is activated. Recent data point to CD25 having a surface distribution consistent with it being localized within membrane microdomains. Here we suggest that in the absence of CD25 expression, IL-2R activation occurs within the soluble membrane fraction. This membrane environment and the absence of CD25 promotes Jak3 independent signal transduction and induction of antiapoptotic mechanisms. T cell antigen receptor (TCR) signalling leads to the induction of CD25 expression, which localizes to membrane microdomains. There is a dynamic pre-association of CD25 and CD122 leading to the loose association of the heterodimer with membrane microdomains. High affinity IL-2R signalling in the context of CD25 and the microdomain environment is characterized by Jak3 activation. The relative levels of high to intermediate affinity receptor signalling determines whether a cell proliferates or undergoes activation induced cell death dependent upon cell status.
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PMID:Possible mechanism for the alpha subunit of the interleukin-2 receptor (CD25) to influence interleukin-2 receptor signal transduction. 1212 Dec 24

A functional hybrid receptor associating the common gamma chain (gammac) with the granulocyte/macrophage colony-stimulating factor receptor beta (GM-CSFRbeta) chain is found in mobilized human peripheral blood (MPB) CD34+ hematopoietic progenitors, SCF/Flt3-L primed cord blood (CB) precursors (CBPr CD34+/CD56-), and CD34+ myeloid cell lines, but not in normal natural killer (NK) cells, the cytolytic NK-L cell line or nonhematopoietic cells. We demonstrated, using CD34+ TF1beta cells, which express an interleukin (IL)-15Ralpha/beta/gammac receptor, that within the hybrid receptor, the GM-CSFRbeta chain inhibits the IL-15-triggered gammac/JAK3-specific signaling controlling TF1beta cell proliferation. However, the gammac chain is part of a functional GM-CSFR, activating GM-CSF-dependent STAT5 nuclear translocation and the proliferation of TF1beta cells. The hybrid receptor is functional in normal hematopoietic progenitors in which both subunits control STAT5 activation. Finally, the parental TF1 cell line, which lacks the IL-15Rbeta chain, nevertheless expresses both a functional hybrid receptor that controls JAK3 phosphorylation and a novel IL-15alpha/gammac/TRAF2 complex that triggers nuclear factor kappaB activation. The lineage-dependent distribution and function of these receptors suggest that they are involved in hematopoiesis because they modify transduction pathways that play a major role in the differentiation of hematopoietic progenitors.
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PMID:Detection of a functional hybrid receptor gammac/GM-CSFRbeta in human hematopoietic CD34+ cells. 1264 4

Mast cells previously have been reported to be regulated by IL-15 and to express a distinct IL-15R, termed IL-15RX. To further examine IL-15 binding and signaling in mast cells, we have studied the nature of the IL-15R and some of its biological activities in these cells. In this study, we report the existence of three novel isoforms of the IL-15R alpha chain in murine bone marrow-derived mast cells as a result of an alternative exon-splicing mechanism within the IL-15R alpha gene. These correspond to new mRNA transcripts lacking exon 4; exons 3 and 4; or exons 3, 4, and 5 (IL-15R alpha Delta 4, IL-15R alpha Delta 3,4, IL-15R alpha Delta 3,4,5). After transient transfection in COS-7 cells, all IL-15R alpha isoforms associate with the Golgi apparatus, the endoplasmic reticulum, the perinuclear space, and the cell membrane. Analysis of glycosylation pattern demonstrates the usage of a single N-glycosylation site, while no O-glycosylation is observed. Importantly, IL-15 binds with high affinity to, and promotes the survival of, murine BA/F3 cells stably transfected with the IL-15R alpha isoforms. Furthermore, we report that signaling mediated by IL-15 binding to the newly identified IL-15R alpha isoforms involves the phosphorylation of STAT3, STAT5, STAT6, Janus kinase 2, and Syk kinase. Taken together, our data indicate that murine mast cells express novel, fully functional IL-15R alpha isoforms, which can explain the selective regulatory effects of IL-15 on these cells.
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PMID:Mast cells express novel functional IL-15 receptor alpha isoforms. 2128 16

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

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

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

Janus tyrosine kinases (JAKs) are cytoplasmic protein tyrosine kinases that play a crucial role in the initial steps of cytokine signaling. JAK3, a member of JAK kinase family of four (JAK1, JAK2, JAK3 and TYK2), is abundantly expressed in lymphoid cells. JAK3 has been found to initiate signaling of interleukin (IL)-2, IL-4, IL-7, IL-9, IL-13 and IL-15. Indispensable role of JAK3 in lymphocyte development and function has been revealed recently. Because of the involvement of JAK3 in T cell activation and proliferation, and the documented genetic evidence for the role of JAK3 in autoimmune or transplant -induced inflammatory disorders, the selective targeting of JAK3 in T cells may potentially be clinically beneficial in T cell-derived pathologic disorders. In this review we discuss inhibitors of JAK3 as a new class of immunomodulatory agents with immunosuppressive, anti-inflammatory, anti-allergic, and anti-leukemic properties. Preclinical data from multiple experimental model systems of autoimmune diabetes, allergy, solid organ transplantation, pancreatic islet transplantation and bone marrow transplantation are discussed in the context of the clinical need for new immunomodulatory agents with such properties.
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PMID:Targeting Janus kinase 3 in the treatment of leukemia and inflammatory diseases. 1517 21

The results from this study implicate membrane-anchored interleukin (IL)-15 constitutively expressed on the cell surface of PC-3 human prostate carcinoma cells and interferon-gamma-activated human monocytes in reverse signaling upon stimulation with soluble IL-15 receptor-alpha or anti-IL-15 antibodies, mediating the outside-to-inside signal transduction that involves the activation of members of the MAPK family (ERK and p38) and focal adhesion kinase. The presence of membrane-bound IL-15 was not dependent on the expression of the trimeric IL-15 receptor complex by these cells and resisted treatment with acidic buffer or trypsin. Reverse signaling through membrane-bound IL-15 considerably increased the production of several pro-inflammatory cytokines by monocytes, such as IL-6, IL-8, and tumor necrosis factor-alpha, thereby indicating the relevance of this process to the complex immunomodulatory function of these cells. Furthermore, stimulation of transmembrane IL-15 also enhanced the transcription of IL-6 and IL-8 in the PC-3 cell line and promoted migration of PC-3 cells as well as LNCaP human prostate carcinoma cells stably expressing IL-15 on the cell surface. Thus, IL-15 can exist as a biologically active transmembrane molecule that possesses dual ligand-receptor qualities with a potential to induce bidirectional signaling. This fact highlights a new level of complexity in the biology of IL-15 and offers novel important insights into our understanding of the cellular responses modulated by this pleiotropic cytokine.
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PMID:Reverse signaling through membrane-bound interleukin-15. 2149 71

Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase associated with the common gamma chain, an integral component of cytokine receptors of the interleukin (IL)-2 family, including IL-4, -7, -9, -15, and -21. CP-690550 is a JAK3 inhibitor with immunosuppressive properties under development for transplantation. We evaluated alterations in circulating lymphocyte subsets in cynomolgus monkey blood following chronic (3-week), oral CP-690550 administration. Natural killer (NK) and CD8+ T cell numbers were reduced in a dose- and time-dependent manner; the latter was a primary effect on memory subsets. CD4+ T and B cell numbers were unaffected or slightly increased, respectively. NK cell numbers were reduced approximately 80% (vs. 35% in vehicle-treated animals) and returned to baseline levels within 3 weeks following treatment cessation. CD8+ T cells declined by a maximum 43% (vs. 25% for vehicle-treated animals) but rebounded significantly (300%) within 2 weeks after the last dose. Although CP-690550 did not result in reduction of CD4+ T cell number, these cells also increased (225%) within 2 weeks of treatment cessation. IL-15 is important for maintaining homeostasis of these cell types, and CP-690550 inhibited IL-15-induced CD69 expression in NK cells [inhibitory concentration 50% (IC50)=48.0+/-8.4 nM] and CD8+ T cells (IC50=16.2+/-1.5 nM).
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PMID:The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing. 1537 89

The transcription factor T-bet promotes the differentiation of inflammatory Th1 T helper cells. T-bet expression in lymphoid cells is regulated by cytoplasmic signaling through Janus kinase phosphorylation, nuclear signaling using signal transducers and activators of transcription (Stat) family proteins, and autocrine/paracrine feedback involving interferon (IFN)-gamma. T-bet is here shown to be present in epithelial cells of the human female reproductive tract. Regulation of T-bet expression was modulated by cytokines and the female reproductive steroids, estrogen, and progesterone. The mechanisms of T-bet regulation in epithelia differ from those in conventional immune cells. During a 15-d exposure to progesterone, T-bet levels in endometrial epithelial cells (EECs) undulated. Prior exposure to estrogen enhanced these effects. More prolonged exposure of EECs to these hormones, singly or in combination, suppressed T-bet production. Stat1 and Stat5 bound to the EEC T-bet regulatory region (TRR) at the IFN-gamma-activated sequence site, but Stat3 and Stat4 did not. Binding of Stat1 and Stat5 to the TRR were modified by progesterone in distinct ways. Estrogen suppressed the binding of Stat1 and Stat5 to the TRR. Mutation of gamma-activated sequence element reduced T-bet promoter activity, binding of Stat proteins to the TRR and regulation of the promoter by cytokines and hormones. In EECs, cytokine exposure caused phosphorylation of Janus kinase 2 and TRR-bound Stat proteins; female steroid hormones altered only phosphorylation of TRR-bound Stat5. Although there is no autocrine IFN-gamma feedback loop in reproductive tract epithelial cells, an IL-15/T-bet positive feedback loop may exist. The implications of hormonally regulated T-bet expression are discussed.
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PMID:Female steroid hormones use signal transducers and activators of transcription protein-mediated pathways to modulate the expression of T-bet in epithelial cells: a mechanism for local immune regulation in the human reproductive tract. 1586 May 46


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