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 interleukin 4 (IL-4)/IL-4 receptor (IL-4R) system in promyelocytes is not well documented. Here, we used promyelocytic leukaemia PLB-985 cells differentiated with dimethylsulfoxide (PLB-985D) toward neutrophil-like phenotype to investigate the IL-4/IL-4R system. PLB-985 cells did not express CD132 (gammac) but expressed the complete IL-4 type II receptor (IL-4Ralpha and IL-13Ralpha1). Moreover, PLB-985 cells lost surface expression of IL-13Ralpha1 during differentiation, resulting in PLB-985D cells expressing only IL-4Ralpha fully responsive to IL-4, as judged by activation of mitogen-activated protein (MAP) kinases and Janus kinase 1. IL-4 also increased suppressor of cytokine signalling 3 (SOCS3) protein level in the presence of the proteasome inhibitor MG132 exclusively in PLB-985D cells. As the IL-4Ralpha chain has been associated with a component of the phagocyte NADPH oxidase, we used PLB-985-gp91(phox) deficient cells (mimicking chronic granulomatous disease, X-CGD), to investigate the IL-4/IL-4R system in X-CGD-D cells. IL-4 was found to activate MAP kinases in X-CGD-D cells but did not up-regulate SOCS3, in contrast to granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and IL-6. Utilization of catalase, cycloheximide and genistein inhibitors showed that IL-4 induced SOCS3 by a mechanism dependent on a complete NADPH oxidase complex, protein synthesis and tyrosine phosphorylation, but independent of production of reactive oxygen species. We conclude that IL-4 induces cell signalling in promyelocytes expressing only IL-4Ralpha.
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PMID:Investigation of the interleukin (IL)-4/IL-4 receptor system in promyelocytic leukaemia PLB-985 cells during differentiation toward neutrophil-like phenotype: mechanism involved in IL-4-induced SOCS3 protein expression. 1800 66

JAK2V617F is an acquired mutation associated with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We tested the hypothesis that the paradox of a single disease allele associated with 3 distinctive clinical phenotypes could be explained in part by host-modifying influences. We screened for genetic variation within 4 candidate genes involved in JAK-STAT signaling, including receptors for erythropoietin (EPOR), thrombopoietin (MPL), and granulocyte colony-stimulating factor (GCSFR), and JAK2. We genotyped 32 linkage disequilibrium tag single nucleotide polymorphism (SNP) loci in 179 white patients: 84 had PV, 58 had PMF, and 37 had ET. Genotype-phenotype analysis showed 3 JAK2 SNPs (rs7046736, rs10815148, and rs12342421) to be significantly but reciprocally associated with PV (P < .001 for all; odds ratio = 0.16, 2.72, and 2.46, respectively) and ET (P < .001 for all; odds ratio = 3.05, 0.29, and 0.30, respectively) but not with PMF. Three additional JAK2 SNPs (rs10758669, rs3808850, and rs10974947) and a single EPOR SNP (rs318699) were also significantly associated with PV but not with ET or PMF. Finally, intragene haplotypes in JAK2 were significantly associated with PV only. Thus, host genetic variation may contribute to phenotypic diversity among myeloproliferative disorders, including in the presence of a shared disease allele.
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PMID:Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders. 1800 99

Janus kinase 2 (JAK2)V617F-activating mutations (JAK2mu) occur in myeloproliferative disorders (MPDs) and myelodysplastic syndromes (MDSs). Cell lines MB-02, MUTZ-8, SET-2 and UKE-1 carry JAK2V617F and derive from patients with MPD/MDS histories. Challenging the consensus that expression of JAK2V617F is the sole precondition for cytokine independence in class I cytokine receptor-positive cells, two of four of the JAK2mu cell lines were growth factor-dependent. These cell lines resembled JAK2wt cells regarding JAK2/STAT5 activation: cytokine deprivation effected dephosphorylation, whereas erythropoetin or granulocyte colony-stimulating factor induced phosphorylation of JAK2 and STAT5. Cytokine independence correlated with low expression and cytokine dependence with high expression of the JAK/STAT pathway inhibitor suppressor of cytokine signaling 2 (SOCS2) suggesting a two-step mechanism for cytokine independence of MPD cells: (i) activation of the oncogene JAK2V617F and (ii) inactivation of the tumor suppressor gene SOCS2. Confirming that SOCS2 operates as a negative JAK2V617F regulator, SOCS2 knockdown induced constitutive STAT5 phosphorylation in JAK2mu cells. CpG island hypermethylation is reported to promote SOCS gene silencing in malignant diseases. Accordingly, in one of two cytokine-independent cell lines and in two of seven MPD patients, we found SOCS2 hypermethylation associated with reduced promoter access to transcription factors. Our results provide solid evidence that SOCS2 epigenetic downregulation might be an important second step in the genesis of cytokine-independent MPD clones.
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PMID:SOCS2: inhibitor of JAK2V617F-mediated signal transduction. 1876 47

CSF3R [G-CSF (granulocyte colony-stimulating factor) receptor] controls survival, proliferation and differentiation of myeloid progenitor cells via activation of multiple JAKs (Janus kinases). In addition to their role in phosphorylation of receptor tyrosine residues and downstream signalling substrates, JAKs have recently been implicated in controlling expression of cytokine receptors, predominantly by masking critical motifs involved in endocytosis and lysosomal targeting. In the present study, we show that increasing the levels of JAK1, JAK2 and TYK2 (tyrosine kinase 2) elevated steady-state CSF3R cell-surface expression and enhanced CSF3R protein stability in haematopoietic cells. This effect was not due to inhibition of endocytotic routing, since JAKs did not functionally interfere with the dileucine-based internalization motif or lysine-mediated lysosomal degradation of CSF3R. Rather, JAKs appeared to act on CSF3R in the biosynthetic pathway at the level of the ER (endoplasmic reticulum). Strikingly, increased JAK levels synergized with internalization- or lysosomal-routing-defective CSF3R mutants to confer growth-factor independent STAT3 (signal transducer and activator of transcription 3) activation and cell survival, providing a model for how increased JAK expression and disturbed intracellular routing of CSF3R synergize in the transformation of haematopoietic cells.
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PMID:Janus kinases promote cell-surface expression and provoke autonomous signalling from routing-defective G-CSF receptors. 1892 33

Granulocyte colony-stimulating factor (G-CSF) is a common inducer of the release of hematopoietic progenitor cells (HPC) from the bone marrow into the peripheral blood. However, the molecular mechanisms underlying this action of G-CSF have not been fully elucidated. Herein, we demonstrate that G-CSF is a powerful chemotactic agent for human HPC other than modulating the adhesion molecules expressed on HPC or bone marrow stromal cells. G-CSF directly chemoattracted HPC in transwell assay and this chemotaxis is time dependent and is specifically neutralized with antibodies that target its receptor. The number of cells transmigrated through the transwell toward G-CSF stimuli was more than that of stromal cell-derived factor-1 at every concentration. G-CSF induced a rapid, transient increase in F-actin polymerization and the formation of focal contact rings in HPC, which are prerequisites for cell migration. The mechanism of G-CSF-induced chemotaxis appears to involve the phosphorylation of JAK1/STAT3 pathway. Collectively, these results provide evidence that G-CSF promotes chemotactic functionality and suggests new avenues of investigation relevant to the mobilization of HPC.
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PMID:A novel function of granulocyte colony-stimulating factor in mobilization of human hematopoietic progenitor cells. 1925 88

The abnormal trafficking of CD34+ cells is a unique characteristic of primary myelofibrosis (PMF). We have further studied the behavior of PMF CD34+ cells by examining their homing to the marrow and the spleens of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Following the infusion of PMF and normal granulocyte colony-stimulating factor-mobilized peripheral blood (mPB) CD34+ cells into NOD/SCID mice, reduced numbers of PMF CD34+ cells and granulocyte-macrophage colony-forming unit (CFU-GM) compared with mPB were detected in the marrow of these mice, whereas similar numbers of PMF and mPB CD34+ cells and CFU-GM homed to their spleens. The abnormal homing of PMF CD34+ cells was associated with reduced expression of CXCR4, but was not related to the presence of JAK2V617F. The sequential treatment of PMF CD34+ cells with the chromatin-modifying agents 5-aza-2'-deoxycytidine (5azaD) and trichostatin A (TSA), but not treatment with small molecule inhibitors of JAK2, resulted in the generation of increased numbers of CD34+CXCR4+ cells, which was accompanied by enhanced homing of PMF CD34+ cells to the marrow but not the spleens of NOD/SCID mice. Following 5azaD/TSA treatment, JAK2V617F-negative PMF hematopoietic progenitor cells preferentially homed to the marrow but not the spleens of recipient mice. Our data suggest that PMF CD34+ cells are characterized by a reduced ability to home to the marrow but not the spleens of NOD/SCID mice and that this homing defect can be corrected by sequential treatment with chromatin-modifying agents.
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PMID:Correction of the abnormal trafficking of primary myelofibrosis CD34+ cells by treatment with chromatin-modifying agents. 1975 87

The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus.
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PMID:Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation. 2019 36

We report a case of a successful mobilization and harvest of the peripheral blood stem cells (PBSCs) in imatinib-pretreated and nilotinib treated 52-year-old woman diagnosed with Philadelphia chromosome-positive and BCR-ABL (b2a2) positive chronic phase CML in 2/2002. She failed interferon-alfa and imatinib treatment. She achieved her first complete molecular remission after 16 months of nilotinib treatment and later on was mobilized with filgrastim at a dose of 10 ug/kg/day applied subcutaneously once daily. The total number of 2.98 x 10(6) CD34+ cells/kg was harvested on the fourth day of the mobilization. The autologous graft of the stem cells was cryopreserved and tested for the residual disease: the FISH revealed negative results and the RT-PCR was positive (BCR-ABL/ABL ratio 0,0017 in RQ-PCR). To our knowledge, this is the first report of successful PBSC harvest in a patient significantly pretreated with imatinib and nilotinib.
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PMID:Successful peripheral blood stem cells collection in imatinib pretreated and nilotinib-treated chronic myeloid leukemia patient. 2022 40

The introduction of BCR-ABL tyrosine kinase inhibitors such as imatinib has changed the treatment of chronic myelogenous leukemia (CML). More than 75% of patients achieve complete cytogenetic remission (CCR) after treatment with imatinib, which provides an opportunity to collect minimally involved hematopoietic progenitor stem cell (HPC) products. In order to assess the feasibility of HPC collection in patients with CML, we prospectively enrolled 24 patients who achieved CCR on therapy with imatinib. Two patients could not undergo HPC collection because of coagulopathy. A CD34+ cell yield of > or =2.0 x 10(6)/kg body weight was obtained in 16/22 (73%) patients. Patients who stopped imatinib for at least 3 weeks prior to HPC collection had significantly higher CD34+ cell yields (median: 6.52 x 10(6)/kg body weight) when compared with patients who continued imatinib through the collection (median: 3.74 x 10(6)/kg body weight). Mobilization with granulocyte colony-stimulating factor (G-CSF) did not increase the levels of BCR-ABL transcript. With a mean follow-up of 46 months, all patients but one were in CCR. In conclusion, a significant number of CD34+ cells can be safely collected in patients with CML who are on imatinib therapy, but CD34+ cell yields improve when imatinib is temporarily withheld.
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PMID:Hematopoietic progenitor cell collection in patients with chronic myelogenous leukemia in complete cytogenetic remission after imatinib mesylate therapy. 2065 54

Granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSCs) are more frequently used as the cellular source in allogeneic hematopoietic stem cell transplantation (HSCT) than bone marrow stem cells (BMSCs) because they promote more rapid engraftment and immune reconstitution. However, the underlying mechanism for this is not fully understood. Here, we investigated the role of Toll-like receptor 2 (TLR2) on PBSCs in promoting rapid engraftment after allogeneic HSCT. We found that PBSCs highly expressed TLR2 in comparison to BMSCs, and TLR2 was directly induced by G-CSF signaling. Treatment with the TLR2 ligand, Pam(3)CSK(4) (PAM), more efficiently induced myeloid differentiation of PBSCs than BMSCs. Similarly, endogenous TLR2 ligands from the serum of recipients of allogeneic transplantation more rapidly stimulated myeloid differentiation of PBSCs compared with BMSCs. PAM treatment of TLR2(-/-) syngeneic recipient mice transplanted with PBSCs resulted in significantly elevated numbers of PBSC-derived myeloid cells and spleen colony formation compared with controls. Our results demonstrate that TLR2 signaling in PBSCs correlates with their ability to rapidly differentiate into myeloid cells, resulting in improved engraftment. Thus, TLR2 may be a novel target for increasing the efficiency of allogeneic HSCT by overcoming engraftment failure or delayed engraftment.
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PMID:Upregulation of TLR2 expression on G-CSF-mobilized peripheral blood stem cells is responsible for their rapid engraftment after allogeneic hematopoietic stem cell transplantation. 2123 80


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