Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for IL-4, IL-7, IL-9, and IL-15 as well as IL-2. Here we show that the gamma(c) is also shared with the IL-21R complex. Although IL-21 binds to the IL-21R expressed on gamma(c)-deficient ED40515(-) cells, IL-21 is unable to transduce any intracytoplasmic signals. However, in EDgamma-16 cells, a gamma(c)-transfected ED40515(-) cell line, IL-21 binds to the IL-21R and can activate Janus kinase (JAK)1, JAK3, STAT1, and STAT3. The chemical cross-linking study reveals the direct binding of IL-21 to the gamma(c). These data clearly demonstrate that the gamma(c) is an indispensable subunit of the functional IL-21R complex.
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PMID:Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex. 1141 23

The common cytokine receptor gamma chain (gamma c), an essential component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, is critical for the development and function of lymphocytes. Recently, a novel lymphokine (IL-21) and its receptor (IL-21R alpha) were described which profoundly affect the growth and activation state of B, T, and NK cells in concert with other lymphokines or stimuli [Parrish-Novak, J., et al. (2000) Nature 408, 57-63]. In this report, we show that gamma c is also a required signaling component of the IL-21 receptor (IL-21R) using the gamma c-deficient X-linked severe combined immunodeficiency (XSCID) lymphoblastoid cell line JT, and JT cells reconstituted with gamma c (JT/gamma c). Moreover, we demonstrate a functional requirement for both gamma c and the gamma c-associated Janus family tyrosine kinase 3 (JAK3) in IL-21-induced proliferation of pro-B-lymphoid cells engineered to express human IL-21R alpha (BaF3/IL-21R alpha). Retroviral-mediated transduction of wild-type gamma c into XSCID JT cells restored function to the IL-21R, as shown by IL-21-induced tyrosine phosphorylation of JAK1 and JAK3, and downstream activation of STAT5, in JT/gamma c cells as well as BaF3/IL-21R alpha and primary splenic B cells. In contrast, IL-21 failed to activate the JAK-STAT pathway in nonreconstituted JT cells. Monoclonal antibodies specific for the gamma c chain effectively inhibited IL-21-induced growth of BaF3/IL-21R alpha cells, supporting a functional role for this molecule in the IL-21R complex. In addition, the specific JAK3 tyrosine kinase inhibitor WHI-P131 significantly reduced IL-21-induced proliferation of BaF3/IL-21R alpha cells. Taken together, these results definitively demonstrate that IL-21-mediated signaling requires the gamma c chain, and indicate that JAK3 is an essential transducer of gamma c-dependent survival and/or mitogenic signals induced by this cytokine.
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PMID:The common gamma chain (gamma c) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3. 1209 91

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

Cytokines are critical in regulating the development and function of diverse cells. Janus kinase 3 (Jak3) is a tyrosine kinase expressed in hematopoietic cells that associates with the common gamma chain (gammac) and is required for signaling for a family of cytokines including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21; deficiency of either Jak3 or gammac results in severe combined immunodeficiency (SCID). While Jak3 is essential for lymphoid-cell development, the potential roles for Jak3 in regulating dendritic cells (DCs) were unclear. Herein, we show that although CD8+CD11c+ splenic DCs are absent in Jak3-/- mice, bone marrow-derived DCs developed normally in vitro from Jak3-/- precursor cells. In fact, the survival of Jak3-/- DCs was enhanced, and they expressed lower levels of proapoptotic proteins. Jak3-/- DCs exhibited normal antigen uptake and up-regulation of costimulatory molecules. However, Jak3-/- DCs produced more IL-12 and IL-10 in response to Toll-like receptor ligands, which correlated with enhanced T helper 1 (Th1) differentiation in vivo. In summary, Jak3 is not essential for DC development but unexpectedly appears to be an important negative regulator. These results may be relevant clinically for patients with SCID who have undergone hematopoietic stem cell transplantation and for patients who might be treated with a Jak3 inhibitor.
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PMID:Jak3 negatively regulates dendritic-cell cytokine production and survival. 1602 May 5

The clonal expansion of chronic lymphocytic leukemia (CLL) cells requires the interaction with the microenvironment and is under the control of several cytokines. Here, we investigated the effect of IL-15 and IL-21, which are closely related to IL-2 and share the usage of the common gamma chain and of its JAK3-associated pathway. We found remarkable differences in the signal transduction pathways activated by these cytokines, which determined different responses in CLL cells. IL-15 caused cell proliferation and prevented apoptosis induced by surface IgM cross-linking. These effects were more evident in cells stimulated via surface CD40, which exhibited increased cell expression of IL-15Ralpha chain and, in some of the cases, also of IL-2Rbeta. IL-21 failed to induce CLL cell proliferation and instead promoted apoptosis. Following cell exposure to IL-15, phosphorylation of STAT5 was predominantly observed, whereas, following stimulation with IL-21, there was predominant STAT1 and STAT3 activation. Moreover, IL-15 but not IL-21 caused an increased phosphorylation of Shc and ERK1/2. Pharmacological inhibition of JAK3 or of MEK, which phosphorylates ERK1/2, efficiently blocked IL-15-induced CLL cell proliferation and the antiapoptotic effect of this cytokine. The knowledge of the signaling pathways regulating CLL cell survival and proliferation may provide new molecular targets for therapeutic intervention.
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PMID:The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways. 1793 55

Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.
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PMID:Cellular and molecular mechanisms of fibrosis. 1816 45

The gammac-family cytokine IL-2 activates signaling events that contribute to cell survival and proliferation, the best-studied of which are the STAT-5 and phosphatidylinositol 3-kinase (PI3K) pathways. The starting point of this study was to define genes regulated by the IL-2R-mediated PI3K pathway in T cells. Accordingly, we used an erythropoietin (EPO) receptor chimeric receptor system in which IL-2-dependent HT-2 T cells expressed a mutant EPO-IL-2Rbeta construct where Tyr-338 is mutated to Phe. Cells expressing this mutant IL-2Rbeta chain fail to induce phosphorylation of PI3K-p85alpha/beta or activate Akt, but mediate normal IL-2-dependent proliferation and activation of JAK1 and STAT-5A/B. Microarray analyses revealed differential regulation of numerous genes compared with cells expressing a wild-type IL-2Rbeta, including up-regulation of the IL-17 receptor subunit IL-17RA. Blockade of the PI3K pathway but not p70S6K led to up-regulation of IL-17RA, and constitutive Akt activation was associated with suppressed IL-17RA expression. Moreover, similar to the mutant EPO-IL-2Rbeta chimera, IL-15 and IL-21 induced IL-17RA preferentially compared with IL-2, and IL-2 but not IL-15 or IL-21 mediated prolonged activation of the PI3K p85 regulatory subunit. Thus, there are intrinsic signaling differences between IL-2 and IL-15 that can be attributed to differences in activation of the PI3K pathway.
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PMID:Differential regulation of the IL-17 receptor by gammac cytokines: inhibitory signaling by the phosphatidylinositol 3-kinase pathway. 1834 82

Interleukin (IL)-17 is a pro-inflammatory cytokine produced by recently described T helper type 17 (Th17) cells, which have critical role in immunity to extracellular bacteria and the pathogenesis of several autoimmune disorders. IL-6 and transforming growth factor (TGF)-beta are crucial for the generation of Th17 cells in mice, while the production of IL-17 is supported by various cytokines, including IL-23, IL-1beta, IL-21, IL-15 and tumour necrosis factor (TNF)-alpha. In this study, the influence of a multifunctional cytokine, macrophage migration inhibitory factor (MIF), on IL-17 production in mice was investigated. Treatment of lymph node cells (LNCs) with recombinant MIF up-regulated mitogen-stimulated IL-17 expression and secretion. Additionally, LNCs from MIF knockout mice (mif(-/-)) had severely impaired production of IL-17, as well as of IL-1beta, IL-6, IL-23 and TGF-beta. When stimulated with recombinant IL-1beta, IL-23 or TNF-alpha, mitogen-triggered mif(-/-) LNCs were fully able to achieve the IL-17 production seen in wild-type (WT) LNCs, while the addition of IL-6 and TGF-beta had no effect. Finally, after injection of mice with complete Freund's adjuvant, secretion of IL-17 as well as the number of IL-17-positive cells was significantly lower in the draining lymph nodes of mif(-/-) mice in comparison with WT mice. The effect of MIF on IL-17 production was dependent on p38, extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and Janus kinase 2/signal transducer and activator of transcription 3 (Jak2/STAT3), and not on nuclear factor (NF)-kappaB and nuclear factor of activated T cells (NFAT) signalling. Bearing in mind the contribution of MIF and IL-17 to the pathology of inflammatory and autoimmune disorders, from the results presented here it seems plausible that targeting MIF biological activity could be a valid therapeutic approach for the treatment of such diseases.
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PMID:Macrophage migration inhibitory factor stimulates interleukin-17 expression and production in lymph node cells. 1862 29

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


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