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

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GM-CSF signals through JAK2 and STAT5 and stimulates the expression of STAT5 target genes, such as pim-1 and CIS. Analyzed by EMSA, GM-CSF stimulation led to much stronger STAT5 DNA-binding to pim-1 or CIS GAS elements in primary human monocytes compared with mature macrophages. Similarly, GM-CSF-induced expression of pim-1 and CIS mRNAs was much stronger in monocytes. These differencies were not a result of downregulation of the GM-CSF receptor system or STAT5 expression, because monocytes and macrophages readily expressed GM-CSF receptor, JAK2, STAT5A, and STAT5B mRNAs and proteins. Monocytes expressed significant amounts of truncated STAT5 forms that took part in STAT5-DNA complex formation in GM-CSF-stimulated monocytes. This resulted in faster moving STAT5 complexes compared with macrophages in EMSA. Our results demonstrate that STAT5 isoform expression, GM-CSF-induced STAT5 activation, and STAT5 target-gene expression are altered significantly during monocyte/macrophage differentiation.
...
PMID:Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced STAT5 activation and target-gene expression during human monocyte/macrophage differentiation. 1186 89

Several reports have suggested an interaction between the erythropoietin receptor (EpoR) and the shared signaling subunit (hbeta(c)) of the human granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 receptors, although the functional consequences of this interaction are unclear. We previously showed that in vivo expression of constitutively active extracellular (EC) mutants of hbeta(c) induces erythrocytosis and Epo independence of erythroid colony-forming units (CFU-E). This occurs despite an apparent requirement of these mutants for the GM-CSF receptor alpha-subunit (GMRalpha), which is not expressed in CFU-E. Here, we show that coexpression of hbeta(c) EC mutants and EpoR in BaF-B03 cells, which lack GMRalpha, results in factor-independent proliferation and JAK2 activation. Mutant receptors that cannot activate JAK2 fail to produce a functional interaction. As there is no detectable phosphorylation of hbeta(c) on intracellular tyrosine residues, EpoR displays constitutive tyrosine phosphorylation. These observations suggest that JAK2 activation mediates cross-talk between EC mutants of hbeta(c) and EpoR. The implications of these data are discussed as are our findings that activated hbeta(c) mutants can functionally interact with certain other cytokine receptors.
...
PMID:Functional cross-talk between cytokine receptors revealed by activating mutations in the extracellular domain of the beta-subunit of the GM-CSF receptor. 1248 7

BCR-ABL expression led to a dramatic up-regulation of the IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor receptor beta common (IL-3Rbetac) and IL-3 receptor beta (IL-3Rbeta) chains in murine embryonic stem cell-derived hematopoietic cells coincident with an expansion of multipotent progenitors and myeloid elements. This up-regulation required BCR-ABL tyrosine kinase activity and led to IL-3Rbetac/beta chain tyrosine phosphorylation in the absence of detectable IL-3 production. These results suggested that cytokine-independent IL-3 receptor activation could be a dominant signaling component in BCR-ABL-induced leukemogenesis. To unambiguously define the significance of IL-3 receptor-dependent signaling in BCR-ABL-induced leukemogenesis, BCR-ABL-transduced bone marrow cells deficient in either IL-3Rbetac chain or both IL-3Rbetac/beta chain expression were examined for their ability in generating myeloproliferative disease (MPD). These BCR-ABL-expressing knockout cells were capable of generating MPD similar to control cells, demonstrating that IL-3 receptor activation is not essential for BCR-ABL-induced MPD. However, the IL-3Rbetac/beta chain could act as a cofactor in BCR-ABL-induced leukemogenesis by activation of its many known oncogenic signaling pathways.
...
PMID:IL-3 receptor signaling is dispensable for BCR-ABL-induced myeloproliferative disease. 1450 Aug 98

Human immunodeficiency virus type 1 (HIV-1) infects cells of the monocyte/macrophage lineage. While infection of macrophages by HIV-1 is generally not cytopathic, it does impair macrophage function. In this study, we examined the effect of HIV-1 infection on intracellular signaling in human monocyte-derived macrophages (MDM) stimulated with the growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is an important growth factor for cells of both the macrophage and granulocyte lineages and enhances effector functions of these cells via the heterodimeric GM-CSF receptor (GM-CSFR). A major pathway which mediates the effects of GM-CSF on macrophages involves activation of the latent transcription factor STAT5A via a Janus kinase 2 (JAK2)-dependent pathway. We demonstrate that GM-CSF-induced activation of STAT5A is inhibited in MDM after infection in vitro with the laboratory-adapted R5 strain of HIV-1, HIV-1(Ba-L), but not after infection with adenovirus. HIV-1 infection of MDM did not decrease the STAT5A or JAK2 mRNA level or STAT5A protein level or result in increased constitutive activation of STAT5A. Surface expression of either the alpha-chain or common beta(c)-chain of GM-CSFR was also unaffected. We conclude that HIV-1 inhibits GM-CSF activation of STAT5A without affecting expression of the known components of the signaling pathway. These data provide further evidence of disruption of cellular signaling pathways after HIV-1 infection, which may contribute to immune dysfunction and HIV-1 pathogenesis.
...
PMID:Human immunodeficiency virus type 1 infection inhibits granulocyte-macrophage colony-stimulating factor-induced activation of STAT5A in human monocyte-derived macrophages. 1461 Jan 85

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has a dismal prognosis. We prospectively evaluated minimal residual disease (MRD) by measuring BCR/ ABL levels with a quantitative real-time PCR procedure after induction and after consolidation in 45 adults with Ph+ ALL who obtained complete hematological remission after a high-dose daunorubicin induction schedule. At diagnosis, the mean BCR-ABL/GUS ratio was 1.55 +/- 1.78. A total of 42 patients evaluable for outcome analysis were operationally divided into two MRD groups: good molecular responders (GMRs; n = 28) with > 2 log reduction of residual disease after induction and > 3 log reduction after consolidation therapy, and poor molecular responders (PMRs; n = 14) who, despite complete hematological remission, had a higher MRD at both time points. In GMR, the actuarial probability of relapse-free, disease-free and overall survival at two years was 38, 27 and 48%, respectively, as compared to 0, 0 and 0% in PMR (P = 0.0035, 0.0076 and 0.0026, respectively). Salvage therapy induced a second sustained complete hematological remission in three GMR patients, but in no PMR patient. Our data indicate that, as already shown in children, adult Ph+ ALL patients have a heterogeneous sensitivity to treatment, and that early quantification of residual disease is a prognostic parameter in this disease.
...
PMID:Significant reduction of the hybrid BCR/ABL transcripts after induction and consolidation therapy is a powerful predictor of treatment response in adult Philadelphia-positive acute lymphoblastic leukemia. 1574 51

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.
...
PMID:JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. 1659 6

A common point mutation in the JAK2 tyrosine kinase leads to constitutive hematopoietic growth factor receptor signaling and was recently described in many patients with myeloproliferative disorders (MPDs). However, this JAK2 mutation is present in only a subset (35-50%) of patients with essential thrombocythemia (ET). Thus, the proliferative signals responsible for MPDs in the absence of JAK2 mutations remain largely unknown. Despite intriguing pre-clinical data, where transgenic mice overexpressing FLT3-ITD developed a MPD resembling ET, none of the patient samples from ET patients who were JAK2(V617F)-negative demonstrated the presence of activating mutations in the FLT3 receptor.
...
PMID:Absence of FTL3 mutations in patients with JAK2V617F mutation negative essential thrombocythemia. 1701 13

GM-CSF is recently being suggested to play important role(s) in the nervous system. Present study was intended to understand signal transduction pathways of GM-CSF in human neuroblastoma (SK-N-(BE)2) and glioblastoma (A172) cell lines. The expression of GM-CSF receptors on the surface of these cells was confirmed by immunocytochemistry, Western blot analysis and RT-PCR. When treated for 10min, GM-CSF activated the signal transducer and activator of transcription 5 (STAT5) and extracellular signal regulated kinase (ERK) in both cell lines. However, Janus kinase 2 (JAK2) was activated only in A172 cells but not in SK-N-(BE)2 cells by GM-CSF. The GM-CSF-activated cellular signal pathways were specifically inhibited by the pretreatment of GM-CSF receptor alpha antibody, suggesting the specificity of the signal activation. The experiment using specific inhibitors (AG490) to the JAK/STAT pathway showed that JAK2/STAT5 cascade was well preserved and activated by GM-CSF in A172 cells, while STAT5 was activated by GM-CSF without JAK2 activation in SK-N-(EB)2 cells. The ERK pathway was activated by GM-CSF independently of JAK2 in both cell lines. Finally, GM-CSF showed cytoprotective effect on these cell lines by inhibiting cytotoxicity of saturosporine. The results revealed the signal transduction pathways activated by GM-CSF in neural cells and suggested that GM-CSF might affect the neural functions via these signal pathways.
...
PMID:Signal transduction pathways of GM-CSF in neural cell lines. 1755 97

Granulocyte/macrophage colony-stimulating factor promotes growth, survival, differentiation, and activation of normal myeloid cells and plays an important role in myeloid leukemias. The GM-CSF receptor (GMR) shares a signaling subunit, beta(c), with interleukin-3 and interleukin-5 receptors and has recently been shown to induce activation of Janus kinase 2 (JAK2) and downstream signaling via formation of a unique dodecameric receptor complex. In this study we use 2 activated beta(c) mutants that display distinct signaling capacity and have differential requirements for the GMR alpha-subunit (GMR-alpha) to dissect the signaling pathways associated with the GM-CSF response. The V449E transmembrane mutant selectively activates JAK2/signal transducer and activator of transcription 5 and extracellular signal-regulated kinase (ERK) pathways, resulting in a high level of sensitivity to JAK and ERK inhibitors, whereas the extracellular mutant (FIDelta) selectively activates the phosphoinositide 3-kinase/Akt and IkappaKbeta/nuclear factorkappaB pathways. We also demonstrate a novel and direct interaction between the SH3 domains of Lyn and Src with a conserved proline-rich motif in GMR-alpha and show a selective requirement for Src family kinases by the FIDelta mutant. We relate the nonoverlapping nature of signaling by the activated mutants to the structure of the unique GMR complex and propose alternative modes of receptor activation acting synergistically in the mature liganded receptor complex.
...
PMID:Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common beta-subunit. 2017 16

Cytokines are secreted soluble peptides that precisely regulate multiple cellular functions. Amongst these the GM-CSF/IL-3/IL-5 family of cytokines controls whether hematopoietic cells will survive or apoptose, proliferate, differentiate, migrate, or perform effector functions such as phagocytosis or reactive oxygen species release. Their potent and pleiotropic activities are mediated through binding to high affinity membrane receptors at surprisingly low numbers per cell. Receptor binding triggers a cascade of intracellular signaling events, including reversible phosphorylation of receptor subunits and associated signaling molecules, leading to multiple biological responses, with the prevention of apoptosis or "cell survival" being a key cellular function that underpins all others. Many chronic inflammatory diseases and a number of haematological malignancies are driven by deregulated GM-CSF, IL-3, or IL-5 cytokine receptor signaling, highlighting their importance in disease. A major step in understanding how these cytokine receptors function is to elucidate their three dimensional structure and to relate this to the many signaling pathways emanating from their receptors. We have recently solved the structure of the human GM-CSF receptor complexed to GM-CSF which revealed distinct forms of receptor assembly: a hexamer that comprises two molecules each of GM-CSF, GM-CSF receptor alpha chain and GM-CSF receptor beta chain; and an unexpected dodecamer in which two hexameric complexes associate through a novel site 4. This latter form is necessary to bring JAK2 molecules sufficiently close together to enable full receptor activation. In this review we focus on the most recent insights in cytokine receptor signaling, and in receptor assembly. The stage is now set to link distinct forms of cytokine receptor assembled structures to specific forms of cytokine receptor signaling and function. Armed with this knowledge it may be possible to map distinct cytokine receptor signaling pathways from the cell surface to the cell nucleus which may themselves become new therapeutic targets.
...
PMID:Molecular basis of cytokine receptor activation. 2054 Jan 54


<< Previous 1 2 3 4 5 Next >>

---