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)

To investigate the structural basis for human interferon gamma (huIFN gamma) binding to intracellular regions of the human IFN gamma receptor (huIFN gamma R), we have subcloned and expressed the huIFN gamma R free of fusion proteins in the yeast strain Pichia pastoris. HuIFN gamma bound to the cytoplasmic domain of the receptor via the IFN gamma C-terminus. Binding was inhibited by both human and mouse C-terminus peptides. N-terminus peptides failed to inhibit cytoplasmic binding. Thus, while extracellular receptor domain binding is species specific, binding to the cytoplasmic domain of the receptor is species non-specific. In solid-phase binding assays, IFN gamma had a Kd of 3.7 x 10(-8) M for the newly expressed cytoplasmic domain. Peptide competitions showed that IFN gamma bound to a receptor site corresponding to the membrane proximal residues 253-287, which is adjacent to the site of binding of the tyrosine kinase JAK2. The cytoplasmic binding affinity and binding site specificity suggest that the huIFN gamma R cytoplasmic domain can function independent of the extracellular domain to bind huIFN gamma and induce the biological activity previously associated with internalized huIFN gamma.
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PMID:Human IFN gamma receptor cytoplasmic domain: expression and interaction with HuIFN gamma. 947

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that is able to persist for decades in its host. HCMV has evolved protean countermeasures for anti-HCMV cellular immunity that facilitate establishment of persistence. Recently it has been shown that HCMV inhibits interferon gamma (IFN-gamma)-stimulated MHC class II expression, but the mechanism for this effect is unknown. IFN-gamma signal transduction (Jak/Stat pathway) and class II transactivator (CIITA) are required components for IFN-gamma-stimulated MHC class II expression. In this study, we demonstrate that both a clinical isolate and a laboratory strain of HCMV inhibit inducible MHC class II expression at the cell surface and at RNA level in human endothelial cells and fibroblasts. Moreover, reverse transcriptase polymerase chain reaction and Northern blot analyses demonstrate that neither CIITA nor interferon regulatory factor 1 are upregulated in infected cells. Electrophoretic mobility shift assays reveal a defect in IFN-gamma signal transduction, which was shown by immunoprecipitation to be associated with a striking decrease in Janus kinase 1 (Jak1) levels. Proteasome inhibitor studies with carboxybenzyl-leucyl-leucyl-leucine vinyl sulfone suggest an HCMV-associated enhancement of Jak1 protein degradation. This is the first report of a mechanism for the HCMV-mediated disruption of inducible MHC class II expression and a direct virus-associated alteration in Janus kinase levels. These findings are yet another example of the diverse mechanisms by which HCMV avoids immunosurveillance and establishes persistence.
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PMID:Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway. 948 Sep 77

We have reported JAK-signaling modulators, CIS1 (cytokine-inducible SH2 protein-1), CIS3 and JAB (JAK2 binding protein), which are structurally related. In M1 myeloid leukemia cells, CIS3 was induced by neither interleukin 6 (IL6) nor interferon gamma (IFNgamma), while JAB was induced strongly by IFNgamma and slightly by IL6 and leukemia inhibitory factor (ILF). Forced expression of CIS3 and JAB in M1 cells prevented IL6- or LIF-induced growth arrest and differentiation, even when their expression levels were comparable to endogenous ones in several cell lines such as HEL, UT-7, IFNgamma-treated M1, and CTLL2 cells. Pretreatment of parental M1 cells with IFNgamma but not IFNbeta resulted in suppression of LIF-induced STAT3 activation and differentiation, further supporting that physiological level of JAB is sufficient to inhibit LIF-signaling. However, unlike JAB, CIS3 did not inhibit IFNgamma-induced growth arrest, suggesting a difference in cytokine specificity between CIS3 and JAB. CIS3 inhibited STAT3 activation with slower kinetics than JAB and allowed rapid c-fos induction and partial FcgammaRI expression in response to IL6. In 293 cells, CIS3 as well as JAB bound to JAK2 tyrosine kinase domain (JH1), and inhibited its kinase activity, however, the effect of CIS3 on tyrosine kinase activity was weaker than that of JAB, indicating that CIS3 possesses lower affinity to JAK kinases than JAB. These findings suggest that CIS3 is a weaker inhibitor than JAB against JAK signaling, and JAB and CIS3 possess different regulatory roles in cytokine signaling.
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PMID:CIS3 and JAB have different regulatory roles in interleukin-6 mediated differentiation and STAT3 activation in M1 leukemia cells. 981 57

Identification of cytokine-inducible genes is imperative for determining the mechanisms of cytokine action. A cytokine-inducible gene, mrg1 [melanocyte-specific gene (msg1) related gene], was identified through mRNA differential display of interleukin (IL) 9-stimulated and unstimulated mouse helper T cells. In addition to IL-9, mrg1 can be induced by other cytokines and biological stimuli, including IL-1alpha, -2, -4, -6, and -11, granulocyte/macrophage colony-stimulating factor, interferon gamma, platelet-derived growth factor, insulin, serum, and lipopolysaccharide in diverse cell types. The induction of mrg1 by these stimuli appears to be transient, with induction kinetics similar to other primary response genes, implicating its role in diverse biological processes. Deletion or point mutations of either the Box1 motif (binds Janus kinase 1) or the signal transducer and activator of transcription 3 binding site-containing region within the intracellular domain of the IL-9 receptor ligand binding subunit abolished or greatly reduced mrg1 induction by IL-9, suggesting that the Janus kinase/signal transducer and activator of transcription signaling pathway is required for mrg1 induction, at least in response to IL-9. Transfection of mrg1 cDNA into TS1, an IL-9-dependent mouse T cell line, converted these cells to IL-9-independent growth through a nonautocrine mechanism. Overexpression of mrg1 in Rat1 cells resulted in loss of cell contact inhibition, anchorage-independent growth in soft agar, and tumor formation in nude mice, demonstrating that mrg1 is a transforming gene. MRG1 is a transcriptional activator and may represent a founding member of an additional family of transcription factors.
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PMID:MRG1, the product of a melanocyte-specific gene related gene, is a cytokine-inducible transcription factor with transformation activity. 981 38

A novel T cell-specific adaptor protein, RIBP, was identified based on its ability to bind Rlk/Txk in a yeast two-hybrid screen of a mouse T cell lymphoma library. RIBP was also found to interact with a related member of the Tec family of tyrosine kinases, Itk. Expression of RIBP is restricted to T and natural killer cells and is upregulated substantially after T cell activation. RIBP-disrupted knockout mice displayed apparently normal T cell development. However, proliferation of RIBP-deficient T cells in response to T cell receptor (TCR)-mediated activation was significantly impaired. Furthermore, these activated T cells were defective in the production of interleukin (IL)-2 and interferon gamma, but not IL-4. These data suggest that RIBP plays an important role in TCR-mediated signal transduction pathways and that its binding to Itk and Rlk/Txk may regulate T cell differentiation.
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PMID:RIBP, a novel Rlk/Txk- and itk-binding adaptor protein that regulates T cell activation. 1058 56

Recently, constitutive activation of JAK kinases (JAKs) and/or signal transducers and activators of transcription (STATs) has been reported in growing numbers of human cancer cells as well as oncogene-transformed cells. JAB/SOCS-1 has been shown to be an intrinsic JAK tyrosine kinase inhibitor and to suppress the cytokine-dependent JAK-STAT pathway. In this report, we investigated the effect of ectopic expression of JAB on v-Src-induced JAK-STAT activation. Forced expression of JAB in v-Src-transformed NIH3T3 cells neither suppressed phosphorylation of STAT3 and JAK1/JAK2 nor blocked STAT3-reporter gene activation. Colony forming assay also showed that JAB did not suppress v-Src-induced transformation of NIH3T3 cells, while dominant negative STAT3 suppressed it. In contrast, JAB could downregulate phosphorylation of STAT1 and STAT3 induced by interferon gamma (IFNgamma) and interleukin-6 (IL-6) plus soluble IL6 receptor (sIL-6R), respectively. Furthermore, in vitro kinase assay indicated that JAB suppressed hyperactivation of JAK1/JAK2 and JAK1 induced by IFNgamma and IL-6 plus sIL-6R respectively, but not v-Src-induced basal JAK1/JAK2 activity. Nevertheless, both JAK1/JAK2 activated by v-Src and that activated by IL-6 plus sIL-6R could similarly bind JAB. These results clearly demonstrate that JAB distinguishes cytokine-induced JAK-STAT signaling from v-Src-induced one and can not suppress the transformation with v-Src.
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PMID:The JAK-inhibitor, JAB/SOCS-1 selectively inhibits cytokine-induced, but not v-Src induced JAK-STAT activation. 1103 30

Microglia rapidly respond to CNS injury, yet the mechanisms leading to their activation and inactivation remain poorly defined. In particular, few studies have established how interactions between inflammatory mediators affect the innate immune response of microglia. To begin to establish how microglia integrate signals from multiple inflammatory mediators, we examined the effects of interleukin 1beta (IL-1beta), interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), interferon gamma (IFN-gamma), and transforming growth factor beta1 (TGFbeta1) on both newborn and bulk-isolated adult microglia. To assess the functional state of the cells, we assayed the expression of cyclooxygenase 2 (Cox-2), interleukin 6, and tumor necrosis factor alpha, and two protein tyrosine kinases that have been implicated in microglial responses to activational stimuli, HCK and FAK. These studies demonstrated that IL-1beta, TNFalpha, IL-6, but not IFN-gamma increase the expression of Cox-2, whereas they all increase the expression of HCK and FAK. In these studies, TGFbeta1 either had no effect, or it decreased basal levels of these proteins. TGFbeta1 blocked activation by IL-1beta when given prior to, or simultaneously with, IL-1beta. TGFbeta1 blocked the induction of the tyrosine kinases, Cox-2, and the induction of IL-6 and TNFalpha mRNAs. However, TGFbeta1 was ineffective in antagonizing the induction of Cox-2 by either IL-6 or TNFalpha. We conclude that the TGFbeta receptor signaling cascades intersect with IL-1, but they may not interact with IL-6 or TNFalpha signaling pathways that lead to activation.
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PMID:Transforming growth factor beta1 prevents IL-1beta-induced microglial activation, whereas TNFalpha- and IL-6-stimulated activation are not antagonized. 1223 48

CD150 (signaling lymphocyte activation molecule [SLAM]) is a self-ligand cell surface glycoprotein expressed on T cells, B cells, macrophages, and dendritic cells. To further explore the role of CD150 signaling in costimulation and T(H)1 priming we have generated a panel of rat antimouse CD150 monoclonal antibodies. CD150 cell surface expression is up-regulated with rapid kinetics in activated T cells and lipopolysaccharide/interferon gamma (IFN-gamma)-activated macrophages. Anti-CD150 triggering induces strong costimulation of T cells triggered through CD3. DNA synthesis of murine T cells induced by anti-CD150 is not dependent on SLAM-associated protein (SAP, SH2D1A), because anti-CD150 induces similar levels of DNA synthesis in SAP(-/-) T cells. Antibodies to CD150 also enhance IFN-gamma production both in wild-type and SAP(-/-) T cells during primary stimulation. The level of IFN-gamma production is higher in SAP(-/-) T cells than in wild-type T cells. Anti-CD150 antibodies also synergize with interleukin 12 (IL-12) treatment in up-regulation of IL-12 receptor beta(2) mRNA during T(H)1 priming, and inhibit primary T(H)2 polarization in an IFN-gamma-dependent fashion. Cross-linking CD150 on CD4 T cells induces rapid serine phosphorylation of Akt/PKB. We speculate that this is an important pathway contributing to CD150-mediated T-cell proliferation.
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PMID:The role of SAP in murine CD150 (SLAM)-mediated T-cell proliferation and interferon gamma production. 1235 1

Natural killer (NK) cells decrease in function during chronic myelogenous leukemia (CML) progression from chronic phase to blast crisis, and they can become BCR/ABL(+) late in the disease course. To study this altered function, NK92 cells were transduced with the BCR/ABL oncogene. In contrast to the parental cells, which died when deprived of interleukin 2 (IL-2), p210(+) NK92 cells proliferated and survived indefinitely in the absence of IL-2. BCR/ABL also decreased the natural cytotoxicity of NK92 cells against K562 targets, without affecting IL-2, interferon gamma (IFN-gamma), or tumor necrosis factor alpha (TNF-alpha) production. Although the ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI-571) had no effect on parental NK92 cells, it markedly decreased the growth and survival of IL-2-independent p210(+) NK92 cells. In contrast to the parental cell line, serial analysis of p210(+) NK92 cells detected small populations that clonally expressed one or more killer immunoglobulin-like receptors (KIRs). Unlike the decreased natural cytotoxicity, the function of the activating CD158j receptor remained intact. Southern blotting and hybridization with an enhanced green fluorescence protein (eGFP) probe showed that KIR(-) and KIR(+) NK92 cells were all derived from the same clone, suggesting that KIR acquisition remains dynamic at the maturational stage represented by the NK92 cell line. When tested in primary CD56(+bright) NK cells, p210 induced partial IL-2-independent growth and increased KIR expression similar to findings in NK92 cells. This is the first study to show that BCR/ABL, well known for its effects on the myeloid lineage, can alter the function of lymphoid cells, which may be associated with the defect in innate immunity associated with CML progression.
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PMID:BCR/ABL alters the function of NK cells and the acquisition of killer immunoglobulin-like receptors (KIRs). 1251 22

The critical dependence of receptor-triggered signals on integrin-mediated cell-substrate interactions represents a fundamental biological paradigm in health and disease. However, the molecular connections of these permissive inputs, which operate through integrin-matrix interactions, has remained largely obscure. Here we show that the serine-threonine kinase protein kinase C epsilon (PKCepsilon) functions as a signal integrator between cytokine and integrin signalling pathways. Integrins are shown to control PKCepsilon phosphorylation acutely by determining complex formation with protein phosphatase 2A (PP2A) and the upstream kinase PDK1 (phosphoinositide-dependent kinase 1). The PP2A-induced loss of PKCepsilon function results in attenuated interferon gamma (INF-gamma)-induced phosphorylation of STAT1 (signal transducer and activator of transcription 1) downstream of Janus kinase 1/2 (JAK1/2). PKCepsilon function and the IFN-gamma response can be recovered by inhibition of PP2A if PDK1 is associated with PKCepsilon in this complex. More directly, a PP2A-resistant mutant of PKCepsilon is sufficient for restoration of the IFN-gamma response in suspension culture. Thus, PKCepsilon functions as a central point of integration through which integrin engagement exerts a permissive input on IFN-gamma signalling.
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PMID:PKCepsilon is a permissive link in integrin-dependent IFN-gamma signalling that facilitates JAK phosphorylation of STAT1. 1264 Apr 64


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