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)

Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) encodes a structural and functional homologue of human IL-6 called viral IL-6 (vIL-6). Expression of vIL-6 in KSHV-related lymphoproliferative disorders has been implicated in their pathogenesis. vIL-6 has been shown to mimic a number of IL-6 activities including stimulating the growth of IL-6 dependent cell lines and activating the JAK1 and STAT1/3 pathway in HepG2 cells. However, IL-6 and vIL-6 display differences in receptor usage that may give rise to underlying qualitative and quantitative differences in the signaling pathways utilized. While IL-6 has an absolute requirement for both the IL-6 Ralpha and the gp130 subunits, vIL-6 appears to require only gp130. In addition to JAK1 and STAT1/3 pathways, IL-6 activates multiple other pathways including the direct activation of STAT 5 by JAK1, the Ras-MAP kinase cascade and a novel H7-sensitive pathway. In this study we examined whether vIL-6 is capable of signaling via distinct IL-6 response elements (IL-6 RE) under the control of these different pathways. We show that vIL-6 activates both STAT1/3- and STAT5-dependent Type II IL-6 REs. In addition, vIL-6 induces transcriptional activation via a Type I IL-6 RE that binds C/EBP, indicative of Ras-MAP kinase pathway induction. Furthermore, vIL-6 is capable of activating the IL-6 response element in the c-jun promoter (RE-IL-6). vIL-6 induced activation of JRE-IL-6 requires both the Ets- and Cre-like sites, suggesting that vIL-6 is capable of stimulating the same novel serine/threonine kinase mediated pathway as IL-6. These results demonstrate that vIL-6 can stimulate all of the known IL-6-induced signaling pathways. Therefore, vIL-6 could potentially contribute to KSHV-related disease progression by continued activation of IL-6-stimulated growth and anti-apoptotic pathways even when cells attempt to protect themselves from IL-6 over-stimulation by downmodulating their IL-6Ralpha subunits.
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PMID:KSHV-encoded viral IL-6 activates multiple human IL-6 signaling pathways. 1056 91

Interferon (IFN)-alpha has proven useful for treating several clinical conditions, including chronic viral hepatitis and chronic myeloproliferative and lymphoproliferative disorders. In addition to its well-known antiviral effects, the cytokine exerts antiproliferative effects on many cell types, helping to explain its therapeutic usefulness in these latter conditions. However, this same property accounts for several undesirable effects, including thrombocytopenia, which can interfere with the successful clinical application of IFN-alpha. Unfortunately, the mechanisms responsible for the myelosuppressive effects of the cytokine are incompletely understood. The effects of IFN-alpha on megakaryocyte (MK) development were studied. Using several marrow cell purification techniques and quantitative culture methods, it was found that IFN-alpha directly inhibits thrombopoietin (TPO)-induced MK growth. Previous studies indicated that Janus kinase (JAK) and its substrates mediate the effects of TPO on cellular proliferation and survival. It was found that IFN-alpha directly suppresses TPO-induced phosphorylation of the JAK2 substrates c-Mpl and STAT 5 in a TPO-dependent hematopoietic cell line and of Mpl and STAT3 in primary murine MK. Moreover, IFN-alpha induces SOCS-1 production in these cells, which has been shown to inhibit TPO-induced cell growth. Because SOCS protein expression is induced by many cytokines and has been reported to extinguish signaling from several hematopoietic cytokine receptors, these results identify a molecular mechanism responsible for cytokine receptor cross-talk.
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PMID:Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1. 1097 53

In this review, we focus on new data from basic, translational and clinical research relating to the Epstein-Barr virus (EBV). Beside its well-known tropism for B lymphocytes and epithelial cells, EBV also infects T lymphocytes, monocytes and granulocytes. After primary infection, EBV persists throughout the life span in resting memory B cells, from where it is reactivated upon breakdown of cellular immunity. In the process of neoplastic transformation, the EBV-encoded latent membrane protein 1 (LMP1) oncogene represents the major driving force. LMP1 acts like a constitutively activated receptor of the tumor necrosis factor receptor family and allows the amplification or bypassing of physiological regulatory signals through direct and indirect interactions with proteins of the tumor necrosis factor receptor-associated factor (TRAF) family. TRAF2-mediated NF-kappaB activation, AP-1 induction and JAK3/STAT activation may result in sustained proliferation leading to lymphoma. The ability of LMP1 to suppress germinal center formation and its capacity to mediate its own transcriptional activation shed new light on the pathogenesis of EBV-associated latency type II lymphoproliferations like Hodgkin's disease and angioimmunoblastic lymphadenopathy. The carboxy terminus of LMP1 is also a reliable marker for individual EBV strain identification and thus offers new possibilities in tracing the molecular events leading to posttransplant lymphoproliferative disorders (PTLDs). Cytotoxic T lymphocytes directed against well-characterized epitopes of EBV latency genes represent an already successful and promising therapeutic approach to EBV-associated lymphomas, in particular PTLDs.
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PMID:The role of Epstein-Barr virus in neoplastic transformation. 1140 95

The association of myeloproliferative and lymphoproliferative disorders is well known after cytotoxic drug or radiation exposure, while it is remarkably rare prior to therapy. We report on a patient simultaneously diagnosed as having polycythemia vera and II3A follicle center cell non-Hodgkin lymphoma (grade 1). At this timepoint, he is on 12-year follow-up, characterized by post-polycythemia myeloid metaplasia with myelofibrosis and persistent complete remission of lymphoma. The conventional marrow cytogenetic analysis performed during the course of the disease demonstrated an abnormal karyotype with deletion of the long arm of chromosome 20 and trisomy 8, while molecular analysis failed to detect BCR-ABL rearrangement in peripheral blood cells. To the best of our knowledge based on a computer-aided review of the literature (MED-LINE 1966-2002), this is the sixth case of concomitant primary polycythemia vera and lymphoma of non-Hodgkin type. Besides, there is a single literature report on polycythemia vera coexisting with the Hodgkin's lymphoma. In our case as well as in the recorded ones, two independent malignant clones of myeloid and lymphoid origin, respectively, seem to have arisen. Further reports, supported by chromosomal and molecular studies, could improve our knowledge on this extremely infrequent disease association.
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PMID:Concomitant primary polycythemia vera and follicle center cell non-Hodgkin lymphoma: a case report and review of the literature. 1253 50

This study analysed the T-cell receptor (TCR)-CD3 zeta complex and the signal transduction apparatus of T-acute lymphoblastic leukaemia (T-ALL) blasts, and investigated the function of the ubiquitin-proteasome system. In all nine T-ALL samples studied, the leukaemic cells showed a marked reduction in the expression of the zeta chain, while a variety of tyrosine kinases (p56lck, ZAP70 and SYK) were normally present. There was no expression of the FcepsilonRIgamma chain. To confirm that this aberration was specific to immature T-ALL blasts, we investigated two patients with lymphoproliferative disorders of granular lymphocytes (LDGL), characterized by the expansion of mature T lymphocytes and found normal zeta chain expression. The reduction of the zeta chain protein was not reversible after 72 h stimulation with the anti-CD3 monoclonal antibody and interleukin 2, either alone or in combination. Northern blot analysis indicated that the reduced protein expression did not correspond to a defect at the mRNA level, nor were mutations in the coding region of the zeta chain found. We, therefore, hypothesized that the observed reduction of protein expression in T-ALL blasts could be secondary to an increased degradation at the proteasome level. Following selective inhibition of the proteasome, a marked increase of the zeta chain expression was observed. Moreover, an increase in the surface expression of CD3 was also documented. Taken together, these results indicate that the expression of the zeta subunit of the TCR-CD3 complex is consistently reduced in T-ALL blasts and that degradation of the protein is mediated by the proteasome system.
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PMID:Defective expression of the T-cell receptor-CD3 zeta chain in T-cell acute lymphoblastic leukaemia. 1254 76

B-lymphocytes are exposed to a reduction/oxidation environment during activation or inflammatory process, and the antioxidant systems are functional to protect themselves against harmful reactive oxygen species (ROS). The crucial roles of thioredoxin-2 (Trx-2) and a DNA repair enzyme APE/Ref-1 in mitochondria are reported in B-lymphocytes. Furthermore, ROS stimulate different signaling pathways in many cellular responses. Their effects often cause some diseases or are utilized for the treatment of other diseases. For example, the cells derived from Fanconi anemia (FA) patients are intolerant of oxidative stress and the therapeutic effect of anti-CD20 monoclonal antibody rituximab on B cell lymphoproliferative disorders is due to the generation of ROS. To clarify the oxidative stress-induced signaling pathways, we stimulated a B cell line with various concentrations of H(2)O(2). As a result, a protein tyrosine kinase, Syk was involved in the induction of G2/M arrest and protection of cells from apoptosis. Syk might inhibit the activation of caspase-9 through Akt thereby protecting cells from oxidative stress-induced apoptosis. On the other hand, Syk-dependent PLC-gamma2 activation was required for acceleration towards apoptosis following oxidative stress. These findings suggest that oxidative stress-induced Syk activation triggers the activation of different pathways, such as pro-apoptotic or survival pathways, and that the balance of these pathways is a key factor in determining the fate of the cells exposed to oxidative stress. In contrast, the stimulation with the millimolar concentrations of H(2)O(2) rapidly led to necrosis in which tyrosine phosphorylation of FAK was involved at the downstream of Lyn and Syk.
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PMID:B cell responses to oxidative stress. 1503 88

IL-6-mediated B-cell growth promotion is involved in the pathogenesis of EBV+ lymphoproliferative disorders of immunosuppressed patients. Since retinoic acid (RA) inhibits the proliferation of EBV-immortalized lymphoblastoid B-cell lines (LCLs), we have investigated the effects of RA on IL-6 signaling in these cells. RA down-regulated IL-6-receptor components with IL-6 agonist activity (membrane and soluble gp80) and increased the levels of soluble gp130, an IL-6 antagonist. These changes, however, were not related to the enhanced production of endogenous IL-6 induced by RA in LCLs. RA-induced modulation of IL-6 receptor components did not abolish IL-6-mediated phosphorylation of gp130, whereas JAK1 and STAT3 phosphorylation and activation induced by IL-6 were markedly inhibited. Overall, the effects of RA resulted in the induction of a complete resistance of LCLs to IL-6-mediated growth promotion. Conversely, RA did not inhibit the constitutive activation of JAK1, TYK2, STAT3 and ERK1/2, ruling out that the JAK/STAT and MAPK pathways may mediate the antiproliferative activity of RA. The finding that RA severely impairs IL-6-dependent signalings in LCLs and inhibits their growth despite the presence of constitutively active JAK/STAT and MAPK cascades provide additional support for a role of RA in the prevention and treatment of EBV-related lymphoproliferative disorders of immunosuppressed patients.
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PMID:Retinoic acid inhibits IL-6-dependent but not constitutive STAT3 activation in Epstein-Barr virus-immortalized B lymphocytes. 1525 31

Signal transducer and activator of transcription (STAT) proteins are phosphorylated and activated by Janus kinases (JAKs). Recently, several groups identified a recurrent somatic point mutation constitutively activating the hematopoietic growth factor receptor-associated JAK2 tyrosine kinase in diverse chronic myeloid disorders - most commonly classic myeloproliferative disorders (MPD), especially polycythemia vera. We hypothesized that the JAK2 V617F mutation might also be present in samples from patients with acute myeloid leukemia (AML), especially erythroleukemia (AML-M6) or megakaryoblastic leukemia (AML-M7), where it might mimic erythropoietin or thrombopoietin signaling. First, we documented STAT3 activation by immunoblotting in AML-M6 and other AML subtypes. Immunoperoxidase staining confirmed phosphorylated STAT3 in malignant myeloblasts (21% of cases, including all AML-M3 samples tested). We then analyzed genomic DNA from 162 AML, 30 B-cell lymphoma, and 10 chronic lymphocytic leukemia (CLL) samples for JAK2 mutations, and assayed a subset for SOCS1 and FLT3 mutations. Janus kinase2 V617F was present in 13/162 AML samples (8%): 10/13 transformed MPD, and three apparent de novo AML (one of 12 AML-M6, one of 24 AML-M7, and one AML-M2 - all mixed clonality). FLT3 mutations were present in 5/32 (16%), while SOCS1 mutations were totally absent. Lymphoproliferative disorder samples were both JAK2 and SOCS1 wild type. Thus, while JAK2 V617F is uncommon in de novo AML and probably does not occur in lymphoid malignancy, unexplained STAT3 activation is common in AML. Janus kinase2 extrinsic regulators and other proteins in the JAK-STAT pathway should be interrogated to explain frequent STAT activation in AML.
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PMID:JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. 1659 6

Bruton's tyrosine kinase (Btk) is required for B-cell development. Btk deficiency causes X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Btk lacks a negative regulatory domain and may rely on cytoplasmic proteins to regulate its activity. Consistently, we identified an inhibitor of Btk, IBtk, which binds to the PH domain of Btk and down-regulates the Btk kinase activity. IBtk is an evolutionary conserved protein encoded by a single genomic sequence at 6q14.1 cytogenetic location, a region of recurrent chromosomal aberrations in lymphoproliferative disorders; however, the physical and functional organization of IBTK is unknown. Here, we report that the human IBTK locus includes three distinct mRNAs arising from complete intron splicing, an additional polyadenylation signal and a second transcription start site that utilizes a specific ATG for protein translation. By northern blot, 5'RACE and 3'RACE we identified three IBTKalpha, IBTKbeta and IBTKgamma mRNAs, whose transcription is driven by two distinct promoter regions; the corresponding IBtk proteins were detected in human cells and mouse tissues by specific antibodies. These results provide the first characterization of the human IBTK locus and may assist in understanding the in vivo function of IBtk.
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PMID:Physical and functional characterization of the genetic locus of IBtk, an inhibitor of Bruton's tyrosine kinase: evidence for three protein isoforms of IBtk. 1859 81

While the outcome for pediatric patients with lymphoproliferative disorders (LPD) or lymphoid malignancies, such as acute lymphoblastic leukemia (ALL), has improved dramatically, patients often suffer from therapeutic sequelae. Additionally, despite intensified treatment, the prognosis remains dismal for patients with refractory or relapsed disease. Thus, novel biologically targeted treatment approaches are needed. These targets can be identified by understanding how a loss of lymphocyte homeostasis can result in LPD or ALL. Herein, we review potential molecular and cellular therapeutic strategies that (i) target key signaling networks (e.g., PI3K/AKT/mTOR, JAK/STAT, Notch1, and SRC kinase family-containing pathways) which regulate lymphocyte growth, survival, and function; (ii) block the interaction of ALL cells with stromal cells or lymphoid growth factors secreted by the bone marrow microenvironment; or (iii) stimulate innate and adaptive immune responses.
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PMID:Novel molecular and cellular therapeutic targets in acute lymphoblastic leukemia and lymphoproliferative disease. 1871 18


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