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 tyrosine kinase inhibitor STI571 inhibits BCR/ABL and induces hematologic remission in most patients with chronic myeloid leukemia. In addition to BCR/ABL, STI571 also inhibits v-Abl, TEL/ABL, the native platelet-derived growth factor (PDGF)beta receptor, and c-KIT, but it does not inhibit SRC family kinases, c-FMS, FLT3, the epidermal growth factor receptor, or multiple other tyrosine kinases. ARG is a widely expressed tyrosine kinase that shares substantial sequence identity with c-ABL in the kinase domain and cooperates with ABL to regulate neurulation in the developing mouse embryo. As described here, ARG has recently been implicated in the pathogenesis of leukemia as a fusion partner of TEL. A TEL/ARG fusion was constructed to determine whether ARG can be inhibited by STI571. When expressed in the factor-dependent murine hematopoietic cell line Ba/F3, the TEL/ARG protein was heavily phosphorylated on tyrosine, increased tyrosine phosphorylation of multiple cellular proteins, and induced factor-independent proliferation. The effects of STI571 on Ba/F3 cells transformed with BCR/ABL, TEL/ABL, TEL/PDGFbetaR, or TEL/ARG were then compared. STI571 inhibited tyrosine phosphorylation and cell growth of Ba/F3 cells expressing BCR/ABL, TEL/ABL, TEL/PDGFbetaR, and TEL/ARG with an IC(50) of approximately 0.5 microM in each case, but it had no effect on untransformed Ba/F3 cells growing in IL-3 or on Ba/F3 cells transformed by TEL/JAK2. Culture of TEL/ARG-transfected Ba/F3 cells with IL-3 completely prevented STI571-induced apoptosis in these cells, similar to what has been observed with BCR/ABL- or TEL/ABL-transformed cells. These results indicate that ARG is a target of the small molecule, tyrosine kinase inhibitor STI571.
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PMID:ARG tyrosine kinase activity is inhibited by STI571. 1129 Jun 9

Various growth factor receptors contain intrinsic tyrosine kinase activity, indicating that protein tyrosine kinases (PTK) play an important role in signal transduction pathways for cell proliferation and differentiation. To identify oocyte-derived factors which control follicle cells as well as oocyte-controlling factors produced by follicle cells, we examined the expression of genes which contain the PTK domain in the porcine ovary, using a polymerase chain reaction-based amplification technique with degenerate oligonucleotide primers that are specific to the PTK domain. Clones for the porcine homologues of platelet-derived growth factor receptor alpha (PDGFRalpha) and of insulin-like growth factor-I receptor (IGF-IR) were found during follicle growth both in oocytes and follicle cells. Clones for the porcine homologues of focal adhesion kinase (FAK), of c-kit and of fms-like tyrosine kinase (FLT)-3 were found only in oocytes. Moreover, after 24 h of in-vitro maturation of the cumulus-oocyte complexes, clones for the porcine homologues of FLT-1, of FLT-4, of Tie2 and of RYK in oocytes were observed. Immunohistochemical studies revealed the existence of PDGFRalpha, platelet-derived growth factor A (PDGFA), FAK and FLT3 in oocytes at various stages of folliculogenesis. These results suggest that fluctuations in the expression of these PTK genes may be involved in follicle growth and maturation.
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PMID:Protein tyrosine kinase expression in the porcine ovary. 1147 Aug 59

Fusion gene products such as PML-RARalpha and BCR-ABL generated by leukemia-specific chromosomal translocations have been identified as target molecules for the treatment of leukemia. Here we describe one possibility for extending the frontier of mechanism-based medicine for acute myeloid leukemia (AML). FLT3, a receptor tyrosine kinase (RTK) preferentially expressed in hematopoietic progenitor cells, frequently has a gain-of-function mutation in AML. To search for FLT3-targeted compounds, we screened the growth-inhibitory effects of several tyrosine kinase inhibitors (TKIs) on mutant FLT3-transformed 32D cells. Herbimycin A at a concentration of 0.1 microM markedly inhibited the growth of the transfectants but at that concentration was ineffective in parental 32D cells. It suppressed the constitutive tyrosine phosphorylation of the mutant FLT3, but not the phosphorylation of the ligand-stimulated wild-type FLT3. In mice transplanted with transformed 32D cells, the administration of herbimycin A completely prevented leukemia progression. Recent studies have indicated that herbimycin A binds directly with HSP90, a molecular chaperone, and destabilizes HSP90-associated proteins. Another HSP90 inhibitor, radicicol, also induced apoptosis selectively in transformed 32D cells. HSP90 is a promising target for the treatment of AML with mutant FLT3.
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PMID:FLT3 tyrosine kinase as a target molecule for selective antileukemia therapy. 1158 62

To date, constitutively activating point mutations reported in hematopoietic growth factor receptors in patients with acute myeloid leukemia (AML) have been restricted to receptors with intrinsic tyrosine kinase activity such as c-kit and FLT3. We describe here a Thr617Asn mutation in the transmembrane domain of the non-tyrosine kinase receptor for granulocyte colony-stimulating factor (G-CSF) in the blast cells of two out of 555 AML patients examined. The mutant receptor conferred growth factor independence on factor-dependent Ba/F3 cells. In the absence of ligand, immunoblotting showed weak phosphorylation of JAK2, STAT3, ERKs 1 and 2 and the receptor itself, and there was approximately 70% of maximal growth in a proliferation assay. All signals were significantly enhanced in the presence of G-CSF. Retroviral transduction of mutant receptor into primary hematopoietic CD34+ cells induced G-CSF independent myeloid differentiation as assessed by the development of neutrophils and surface expression of CD11b and CD14. These results confirm the importance of the transmembrane domain for receptor function and suggest that introduction of an asparagine residue can cause sufficient stabilization of helix-helix interactions in the absence of ligand to activate downstream signaling pathways involved in directing proliferation and differentiation.
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PMID:An activating mutation in the transmembrane domain of the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia. 1220 10

Oncogenes involved in the development of hematological malignancies were first discovered through the study of experimental leukemias induced in animals by retroviruses. The discovery that some of these genes were located at the breakpoints of chromosome rearrangements in human malignancies, such as the MYC gene in Burkitt's lymphoma and the ABL gene in chronic myeloid leukemia (CML) has suggested that chromosome abnormalities were causally implicated in the pathogenesis of human diseases. Numerous nonrandom somatically acquired chromosomal translocations or inversions have been identified in human leukemias. The molecular cloning of the genes located at the breakpoints of these rearrangements allowed to identify more than 100 new oncogenes, the products of which affect normal programs of cell proliferation, differentiation and survival. Chromosome translocations can lead to the deregulated expression of a normal gene product, but in most cases of leukemia, chromosome rearrangements result in the expression of a chimeric fusion protein. Oncogene products associated with acute leukemias are often transcription factors while tyrosine kinases and antiapoptotic proteins are more commonly activated or overexpressed in chronic leukemias and in lymphomas. Recent data indicated that gene rearrangements were not the sole gene alterations occurring in human leukemia since point mutations could also affect the function of transcription factors playing a key role in hematopoiesis such as C/EBP alpha, GATA1 and AML1. But the most exciting finding was the discovery of activating point mutations in tyrosine kinase receptors such as FLT3 and c-KIT in acute leukemia. Treatment of leukemia could therefore benefit from new therapeutic approaches targeting the function of specific oncogene products as already demonstrated for CML and acute promyelocytic leukemia.
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PMID:[Oncogenes and leukemia: history and perspectives]. 1283 14

Tyrosine kinases are commonly mutated and activated in both acute and chronic myeloid leukemias. Here, we review the functions, signaling activities, mechanism of transformation, and therapeutic targeting of two prototypic tyrosine kinase oncogenes, BCR-ABL and FLT3, associated with chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), respectively. BCR-ABL is generated by the Philadelphia chromosome translocation between chromosomes 9 and 22, creating a chimeric oncogene in which the BCR and c-ABL genes are fused. The product of this oncogene, BCR-ABL, has elevated ABL tyrosine kinase activity and transforms hematopoietic cells by exerting a wide variety of biological effects, including reduction in growth factor dependence, enhanced viability, and altered adhesion of chronic myelocytic leukemia (CML) cells. Elevated tyrosine kinase activity of BCR-ABL is critical for activating downstream signalling cascades and for all aspects of transformation, explaining the remarkable clinical efficacy of the tyrosine kinase inhibitor, imatinib mesylate (STI571). By comparison, FLT3 is mutated in about one third of all cases of AML, most often through a mechanism that involves an internal tandem duplication (ITD) of a small number of amino acid residues in the juxtamembrane domain of the receptor. As is the case for BCR-ABL, these mutations activate the kinase activity constitutively, activate multiple signaling pathways, and result in an augmentation of proliferation and viability. Transformation by FLT3-ITD can readily be observed in murine models, and FLT3 cooperates with other types of oncogenes to create a fully transformed acute leukemia. FLT3 tyrosine kinase inhibitors are currently being evaluated in clinical trials and may be very useful therapeutic agents in AML.
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PMID:Mutated tyrosine kinases as therapeutic targets in myeloid leukemias. 1290 54

Point mutations of D835/I836 of the FLT3 gene have been reported in adult acute myeloid leukemia (AML), but not in pediatric AML or acute lymphoblastic leukemia (ALL). FLT3-D835/I836 mutations were found in 6 (5.4%) of 112 children with ALL older than 1 year and in 8 (16.0%) of 50 infants with ALL. Missense mutations were found in 11 patients, 3-base pair deletions in 2 patients, and a deletion/insertion in 1 patient. Remarkably, FLT3-D835/I836 mutations were found in 8 (18.2%) of 44 infants with ALL with MLL rearrangements and in 4 (21.5%) of 19 patients with hyperdiploid ALL, but they were not found in any patients older than 1 year who had TEL-AML1 (n = 11), E2APBX1 (n = 4), or BCR-ABL (n = 6) fusion genes. Although infant ALL patients with mutations had poorer prognoses than did those without mutations, pediatric ALL patients with mutations who were older than 1 year had good prognoses. We also found FLT3-D835 mutations in 2 of 11 leukemic cell lines with MLL rearrangements. FLT3 was highly phosphorylated in these cell lines with FLT3-D835 mutations, leading to constitutive activation of downstream targets such as signal transducer and activator of transcription 5 (STAT5) without FLT3 ligand stimulation. These results suggested that FLT3-D835/I836 mutations are one of the second genetic events in infant ALL with MLL rearrangements or pediatric ALL with hyperdiploidy.
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PMID:FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. 1450 97

Molecular targeting therapies for hematological malignant diseases such as monoclonal antibodies and small molecules have been reviewed. Imatinib mesylate (STI571) targets the tyrosine kinase activity of the BCR-ABL fusion protein in CML, and was superior to IFN-alpha plus low-dose cytarabine in newly diagnosed chronic-phase CML in a phase III randomized study. Imatinib induced apoptosis in BCR-ABL-positive cells in vitro, and activates several signaling pathways such as PI3K/Akt, STAT5 and Ras/MAPK. Combination therapies with imatinib and new strategies for downregulation of intracellular BCR-ABL protein levels have also been investigated from the phenomenon of resistance to imatinib. Anti-CD20 (rituximab) became the first monoclonal antibody approved for the treatment of a relapsed/refractory follicular/low-grade NHL and promising results were obtained from a phase III randomized study. Although antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity are likely to be the major effectors of B-cell depletion in vivo, direct cytotoxicity by CD20 monoclonal antibody on B-cell lines in vitro has been reported. Anti-CD33 (Mylotarg) and FLT3 inhibitors for AML have also been used in clinical trials and signaling pathways induced by these agents are under intensive investigation. Arsenic trioxide, like all-TRANS-retinoic acid (ATRA), downregulates promyelocytic leukemia protein/retinoic acid receptor-alpha (PML/RARalpha) fusion protein and induced apoptosis in APL cells, and promising results were obtained from ATRA-resistant APL patients. Finally we show our promising in vitro and in vivo data of R-etodolac (a non-steroidal anti-inflammatory drug lacking cyclooxygenase inhibitor activity) against chronic lymphocytic leukemia (CLL) cells.
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PMID:Apoptosis induced by molecular targeting therapy in hematological malignancies. 1464 49

Targeted therapies for hematological malignancies have come of age since the advent of all trans retinoic acid (ATRA) for treating APL and STI571/Imatinib Mesylate/Gleevec for CML. There are good molecular targets for other malignancies and several new drugs are in clinical trials. In this review, we will concentrate on individual abnormalities that exist in the myelodysplastic syndromes (MDS) and myeloid leukemias that are targets for small molecule therapies (summarised in Fig. 1). We will cover fusion proteins that are produced as a result of translocations, including BCR-ABL, the FLT3 tyrosine kinase receptor and RAS. Progression of diseases such as MDS to secondary AML occur as a result of changes in the balance between cell proliferation and apoptosis and we will review targets in both these areas, including reversal of epigenetic silencing of genes such as p15(INK4B).
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PMID:Targeted therapies in myeloid leukemia. 1475 35

Abnormal protein tyrosine kinases (PTKs) cause many human leukemias. For example, BCR/ABL causes chronic myelogenous leukemia (CML), whereas FLT3 mutations contribute to the pathogenesis of acute myelogenous leukemia. The ABL inhibitor Imatinib (Gleevec, STI571) has remarkable efficacy for treating chronic phase CML, and FLT3 inhibitors (e.g., PKC412) show similar promise in preclinical studies. However, resistance to PTK inhibitors is a major emerging problem that may limit long-term therapeutic efficacy. Development of rational combination therapies will probably be required to effect cures of these and other neoplastic disorders. Here, we report that the mTOR inhibitor rapamycin synergizes with Imatinib against BCR/ABL-transformed myeloid and lymphoid cells and increases survival in a murine CML model. Rapamycin/Imatinib combinations also inhibit Imatinib-resistant mutants of BCR/ABL, and rapamycin plus PKC412 synergistically inhibits cells expressing PKC412-sensitive or -resistant leukemogenic FLT3 mutants. Biochemical analyses raise the possibility that inhibition of 4E-BP1 phosphorylation may be particularly important for the synergistic effects of PTK inhibitor/rapamycin combinations. Addition of a mitogen-activated protein kinase kinase inhibitor to rapamycin or rapamycin plus PTK inhibitor further increases efficacy. Our results suggest that simultaneous targeting of more than one signaling pathway required by leukemogenic PTKs may improve the treatment of primary and relapsed CML and/or acute myelogenous leukemia caused by FLT3 mutations. Similar strategies may be useful for treating solid tumors associated with mutant and/or overexpressed PTKs.
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PMID:Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. 1497 43


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