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 involvement of focal adhesion kinase (FAK) in myeloid differentiation was investigated in primary murine bone marrow (BM) cells. In unstimulated BM, FAK mRNA was detected in myeloid and lymphoid cells, but not in erythroid precursors. When the BM cells were incubated with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), FAK expression showed a remarkable difference depending on the cytokine. Although FAK was upregulated in the cells stimulated by GM-CSF (GM-treated cells), the kinase was barely detectable in the cells cultured with IL-3 (IL-3-treated cells). Morphology and flow cytometry analysis showed GM-CSF promoted the growth and differentiation of monocyte/macrophage lineage stronger than IL-3. In addition, motility of the cytokine-differentiated cells showed an overt distinction between the cultures, which was closely correlated with FAK expression. After 7 days of stimulation, GM-treated cells showed active migration and chemoattractant-induced morphologic polarization. In contrast, IL-3-treated cells showed minimal migration and polarization. These results suggest an important role of GM-CSF in the terminal differentiation of monocytes/macrophages, and possible involvement of FAK in functional maturity of this lineage.
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PMID:Focal adhesion kinase upregulated by granulocyte-macrophage colony-stimulating factor but not by interleukin-3 in differentiating myeloid cells. 912 51

We have previously reported the development of in vivo functional assays for primitive human hematopoietic cells based on their ability to repopulate the bone marrow (BM) of severe combined immunodeficient (SCID) and nonobese diabetic/SCID (NOD/SCID) mice following intravenous transplantation. Accumulated data from gene marking and cell purification experiments indicate that the engrafting cells (defined as SCID-repopulating cells or SRC) are biologically distinct from and more primitive than most cells that can be assayed in vitro. Here we demonstrate through limiting dilution analysis that the NOD/SCID xenotransplant model provides a quantitative assay for SRC. Using this assay, the frequency of SRC in cord blood (CB) was found to be 1 in 9.3 x 10(5) cells. This was significantly higher than the frequency of 1 SRC in 3.0 x 10(6) adult BM cells or 1 in 6.0 x 10(6) mobilized peripheral blood (PB) cells from normal donors. Mice transplanted with limiting numbers of SRC were engrafted with both lymphoid and multilineage myeloid human cells. This functional assay is currently the only available method for quantitative analysis of human hematopoietic cells with repopulating capacity. Both CB and mobilized PB are increasingly being used as alternative sources of hematopoietic stem cells in allogeneic transplantation. Thus, the findings reported here will have important clinical as well as biologic implications.
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PMID:Primitive human hematopoietic cells are enriched in cord blood compared with adult bone marrow or mobilized peripheral blood as measured by the quantitative in vivo SCID-repopulating cell assay. 916 28

We cloned JAK3, the most recently described member of the JAK family of intracellular tyrosine kinases, from normal human CD34+ RNA. JAK3 is involved in the signal transduction pathways of the IL-2, IL-4, IL7, IL-9, and IL-15 receptors by association with their common gamma-chain (gamma[c]). JAK3 is critical to lymphoid development, as recently established by the linking of mutations in JAK3 to a subgroup of patients with SCID and the generation of JAK3-null mice with severe disruptions in normal lymphocytic development. However, JAK3 expression is not restricted to the lymphocytic compartment of bone marrow but is found in a wide range of tissues of both hematopoietic and non-hematopoietic origin. Northern blot analysis indicates that JAK3 is also expressed in adult placenta, lung, liver, kidney, pancreas, spleen, thymus, ovary, and small intestine. RNAse protection assays and RT-PCR indicate that JAK3 is expressed in a variety of leukemic-derived hematopoietic cell lines with myeloid and/or lymphoid phenotypes. In normal human bone marrow, JAK3 is expressed in the CD34+/lineage- fraction, which is highly enriched in hematopoietic stem/progenitor cells. In addition, we found a splice variant of JAK3 which is formed by the splicing of JAK3 with exon II of the leydig insulin-like (LEY I-L) hormone. RT-PCR and RNAse protection assay analyses indicate that this variant (termed I-JAK3) is normally expressed in almost all hematopoietic and non-hematopoietic tissues shown to express JAK3. Using fluorescence in situ hybridization we have localized JAK3 to 19p12-13.1, the same region of chromosome 19 to which the LEY I-L hormone maps (19p12-13.2).
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PMID:JAK3: expression and mapping to chromosome 19p12-13.1. 916 59

Much of our understanding of the molecular anomalies involved in the process of oncogenesis has resulted from research into malignant hematologic diseases, facilitated by the accessibility of hematopoietic cells. For example, in lymphoid tumors, rearrangement of the genomic DNA can lead to the juxtaposition of proto-oncogenes and the highly active sequences regulating synthesis of immunoglobulins or T-cell receptors. The subsequent malignancy results from an uncontrolled overexpression of a normal protein. This type of "quantitative" anomaly occurs in follicular lymphomas where B-cells overexpress the normal BCL2 protein which inhibits apoptosis, contributing to immortalization of the B done. The same type of rearrangement process can approach gene fragments which fusion and lead to production of a highly oncogenic chimerical or truncated abnormal protein. Such "qualitative" anomalies occur in myeloid hemopathies. Both types of anomalies involve genes controlling the cell cycle, cell differentiation or cell death (apoptosis), in particular transcription factors (for example, E2A, RARA, MYC) and molecules involved in signal transduction (for example RAS, ABL, LCK). A molecular anomaly can be detected in approximately 30% of all cases of acute leukemia and in up to 75% of the non-Hodgkin lymphomas. Analysis of the junction fragments of the different heavy chains of the immunoglobulins produced in these cases provides a specific marker for detecting the B or T-cell clone in digestive or skin biopsies. For example, detection of a BCR-ABL transcript in a patient with primary thrombocythemia or an atypical myeloproliferative syndrome can be diagnostic and detection of the donal immunoglobulin or T-cell receptor rearrangement can confirm the malignant nature of the lymphoid proliferation. Molecular markers also have prognostic value allowing patient stratification and more adapted therapy. Molecular anomalies detected in malignant hematologic diseases are thus examples of nearly perfect "tumor-specific" markers.
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PMID:[Molecular anomalies in malignant hemopathies]. 923 51

The molecular origin of the BCR-ABL chimeric gene is now reasonably well defined; a new breakpoint cluster region in the BCR gene, designated mu-bcr, has recently been identified. p210BCR-ABL binds with or phosphorylates a wide variety of intracellular proteins but the mechanism by which it exerts its oncogenic potential is not yet known. Treatment decisions for younger patients are often complex. Interferon alfa prolongs life in comparison with conventional cytotoxic drugs but the optimal starting dosage, the definition of response, and the management of interferon alfa responders remain controversial. Allografting is the treatment of choice for younger patients with HLA-identical siblings but its precise role for patients lacking such donors is still unclear. The transfusion of donor lymphoid cells is very effective in reinducing molecular remission in patients who relapse after allografting; the mechanism for this graft-versus-leukemia effect remains speculative. Autografting with Philadelphia-negative progenitor cells appears promising. A working algorithm for the management of patients not entered into prospective clinical studies is proposed; such an algorithm will need to be updated at frequent intervals.
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PMID:Chronic myeloid leukemia. 926 56

Contact with bone marrow stromal cells is crucial for the normal growth and development of B-cell precursors. We have previously shown that human bone marrow stromal cell tyrosine kinase activity can be activated by direct contact with B-lymphoid cells (J Immunol 155:2359, 1995). In the present study, we show that increased tyrosine phosphorylation of focal adhesion kinase, paxillin, and extracellular-related kinase 2 (or p42 MAP kinase) accounted for the major changes occurring in stromal cell tyrosine phosphorylation after 5 to 10 minutes of contact with the RAMOS B-lymphoma cell line. Although adhesion of B-cell precursors to stromal cells is primarily mediated by very late antigen-4 (VLA-4) and vascular cell adhesion molecule-1 (VCAM-1), VLA-4-deficient and adhesion-deficient RAMOS cells were equally capable of stimulating stromal cell tyrosine phosphorylation. Similar changes in the tyrosine phosphorylation pattern of stromal cells were induced by contact with normal human B-cell precursors and several other B-lineage cell lines. After 5 to 30 minutes of contact with stromal cells, no change in protein tyrosine phosphorylation was detected in RAMOS or normal human B-cell precursors removed from stromal cells. Pretreatment of stromal cells with cytochalasin D abrogated contact-mediated enhancement of stromal cell tyrosine phosphorylation, suggesting that an intact cytoskeleton was essential. These results suggest that B-cell contact activates stromal cell signaling cascades that regulate cytoskeletal organization and transcription, independent of the interaction mediated by VLA-4 and VCAM-1.
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PMID:Contact between human bone marrow stromal cells and B lymphocytes enhances very late antigen-4/vascular cell adhesion molecule-1-independent tyrosine phosphorylation of focal adhesion kinase, paxillin, and ERK2 in stromal cells. 926 82

Interleukin (IL)-13 is a pleiotropic immunoregulatory cytokine that shares many, although not all, of the biological activities of IL-4. The overlapping biological properties of IL-4 and IL-13 appear to be due to the existence of shared components of the receptors, and we and others showed that the IL-4 receptor-alpha is involved in signal transduction paths activated by both. We show here that expression of the IL-13 receptor-alpha in two factor-dependent cell lines, the premyeloid FD5 and the T lymphoid CT4.S, conferred the ability to grow continuously in response to IL-13; to respond to IL-13 with tyrosine phosphorylation of JAK1, Tyk2, IL-4Ralpha, IRS-2, and STAT6; and to respond to IL-4 with tyrosine phosphorylation of Tyk2 in addition to those induced in parental cell lines. Expression of a truncated IL-13 receptor-alpha that lacked the cytoplasmic domain demonstrated that this domain was essential for IL-13-dependent growth and phosphorylation of the above substrates. Expression of this truncated IL-13 receptor also resulted in an inhibition of biochemical and biological responses to IL-4 that was exacerbated by the presence of IL-13. These dominant inhibitory effects indicate that the extracellular domain of the truncated IL-13 receptor competes with gammac for complexes of IL-4 and the IL-4 receptor-alpha, or, when itself bound to IL-13, competes with IL-4 for the IL-4 receptor-alpha.
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PMID:An interleukin (IL)-13 receptor lacking the cytoplasmic domain fails to transduce IL-13-induced signals and inhibits responses to IL-4. 927 58

Translocations in hematologic disease of myeloid or lymphoid origin with breakpoints at chromosome band 12p13 frequently result in rearrangements of the Ets variant gene 6 (ETV6). As a consequence either the ETS DNA-binding domain or the Helix-Loop-Helix (HLH) oligomerization domain of ETV6 is fused to different partner genes. We show here that a t(9;12)(p24;p13) in a case of early pre-B acute lymphoid leukemia and a t(9;15;12)(p24;q15;p13) in atypical chronic myelogenous leukemia in transformation involve the ETV6 gene at 12p13 and the JAK2 gene at 9p24. In each case different fusion mRNAs were found, with only one resulting in an open reading frame for a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the protein tyrosine kinase (PTK) domain of JAK2. The cloning of the complete human JAK2 coding and genomic sequences and of the genomic junction fragments of the translocations allowed a characterization of the different splice events leading to the various mRNAs. JAK2 plays a central role in non-protein tyrosine kinase receptor signaling pathways, which could explain its involvement in malignancies of different hematologic lineages. Besides hop in Drosophila no member of the JAK family has yet been implicated in tumorigenesis.
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PMID:Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. 932 18

The Tec family of tyrosine kinases are involved in signals emanating from cytokine receptors, antigen receptors, and other lymphoid cell surface receptors. One family member, ITK (inducible T cell kinase), is involved in T cell activation and can be activated by the T cell receptor and the CD28 cell surface receptor. This stimulation of tyrosine phosphorylation and activation of ITK can be mimicked by the Src family kinase Lck. We have explored the mechanism of this requirement for Src family kinases in the activation of ITK. We found that coexpression of ITK and Src results in increased membrane association, tyrosine phosphorylation and activation of ITK, which could be blocked by inhibitors of the lipid kinase phosphatidylinositol 3-kinase (PI 3-kinase) as well as overexpression of the p85 subunit of PI 3-kinase. Removal of the Pleckstrin homology domain (PH) of ITK resulted in a kinase that could no longer be induced to localize to the membrane or be activated by Src. The PH of ITK was also able to bind inositol phosphates phosphorylated at the D3 position. Membrane targeting of ITK without the PH recovered its ability to be activated by Src. These results suggest that ITK can be activated by a combination of Src and PI 3-kinase.
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PMID:Src-induced activation of inducible T cell kinase (ITK) requires phosphatidylinositol 3-kinase activity and the Pleckstrin homology domain of inducible T cell kinase. 932 91

Chronic myelogenous leukemia (CML) is a clonal disorder starting with a chronic phase and progressing to an acute blastic phase. Philadelphia (Ph) chromosome formation results in the relocation of the ABL oncogene from the chromosome 9q34 to BCR region on 22q11, forming the BCR/ABL fusion gene. The Ph chromosome once detected rarely disappears, except as a result of therapy. We present an unusual Ph-positive CML case, which developed lymphoid blast crisis in complete cytogenetic remission following interferon-alpha and hydroxyurea therapy. Sequential cytogenetic investigations were carried out on bone marrow. After a standard Ph translocation seen at diagnosis, from the 8th month of therapy all metaphases showed a normal diploid karyotype. Fluorescence in situ hybridization detected residual BCR/ABL-positive interphase cells during the 12th month of therapy. In the 14th month, the patient showed 27% blasts in marrow though normal cytogenetics was maintained. Present findings suggest blastic transformation occurred in a Ph-negative lymphoid clone. This supports the hypothesis that an actual leukemogenic event occurs in a multipotent stem cell prior to the acquisition of Ph translocation.
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PMID:Lymphoid blast crisis during complete cytogenetic remission following interferon-alpha and hydroxyurea therapy. 935 47


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