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 BCR-ABL-negative chronic myeloproliferative disorders (CMPD) and myelodysplastic/myeloproliferative diseases (MDS/MPD) are a spectrum of related conditions for which the molecular pathogenesis is poorly understood. Translocations that disrupt and constitutively activate the platelet-derived growth factor receptor beta(PDGFRB) gene at chromosome band 5q33 have been described in some patients, the most common being the t(5;12)(q33;p13). An accurate molecular diagnosis of PDGFRB-rearranged patients has become increasingly important since recent data have indicated that they respond very well to imatinib mesylate therapy. In this study, we have tested nine patients with a CMPD or MDS/MPD and a translocation involving 5q31-33 for disruption of PDGFRB by two-colour fluorescence in situ hybridization (FISH) using differentially labelled, closely flanking probes. Normal control interphase cells gave a false positive rate of 3% (signals more than one signal width apart). Six patients showed a pattern of one fused signal (from the normal allele) and one pair of signals separated by more than one signal width in > 85% of interphase cells, indicating that PDGFRB was disrupted. These individuals had a t(1;5)(q21;q33), t(1;5)(q22;q31), t(1;3;5)(p36;p21;q33), t(2;12;5)(q37;q22;q33), t(3;5) (p21;q31) and t(5;14)(q33;q24) respectively. The remaining three patients with a t(1;5)(q21;q31), t(2;5)(p21;q33) and t(5;6)(q33;q24-25) showed a normal pattern of hybridization, with > or = 97% interphase cells with two fusion signals. We conclude that two-colour FISH is useful to determine the presence of a PDGFRB rearrangement, although, as we have shown previously, this technique may not detect subtle complex translocations at this locus. Our data indicate that several PDGFRB partner genes remain to be characterized.
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PMID:Novel translocations that disrupt the platelet-derived growth factor receptor beta (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders. 1254 82

Tyrosine phosphorylation of focal adhesion components is involved in the regulation of focal adhesion formation and turnover, yet the underlying molecular mechanisms are still poorly defined. In the present study, we have used quantitative fluorescence microscopy to investigate the dynamic relationships between the incorporation of new components into growing focal adhesions and tyrosine phosphorylation of these sites. For this purpose, a new approach for monitoring phosphotyrosine levels in live cells was developed, based on a 'phosphotyrosine reporter' consisting of yellow fluorescent protein fused to two consecutive phosphotyrosine-binding Src-homology 2 (SH2)-domains derived from pp60(c-Src). This YFP-dSH2 localized to cell-matrix adhesions and its intensity was linearly correlated with that of an anti-phosphotyrosine antibody labeling. The differential increase in vinculin and phosphotyrosine levels was examined in live cells by two-color time-lapse movies of CFP-vinculin and YFP-dSH2. In this study, focal adhesion growth was triggered by microtubule disruption, which was previously shown to stimulate focal adhesion development by inducing cellular contraction. We show here that, 2 minutes after addition of the microtubule-disrupting drug nocodazole, the local densities of the focal adhesion-associated proteins vinculin, paxillin and focal adhesion kinase (FAK) are significantly elevated and the focal adhesion area is increased, whereas elevation in tyrosine phosphorylation inside the growing adhesions occurs only a few minutes later. Phosphotyrosine and FAK density reach their maximum levels after 10 minutes of treatment, whereas vinculin and paxillin levels as well as focal adhesion size continue to grow, reaching a plateau at about 30 minutes. Our findings suggest that protein recruitment and growth of focal adhesions are an immediate and direct result of increased contractility induced by microtubule disruption, whereas tyrosine phosphorylation is activated later.
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PMID:Live-cell monitoring of tyrosine phosphorylation in focal adhesions following microtubule disruption. 1258 42

The BCR-ABL fusion in chronic myeloid leukaemia (CML) is generated by the Philadelphia (Ph) translocation t(9;22) or, in 10% of patients, variants thereof (vPh). Deletion encompassing the reciprocal product (ABL-BCR) from the derivative chromosome 9 [der(9)] occurs in 15% of all patients, but with greater frequency in vPh patients. Reports of physical separation of ABL-BCR in non-deleted patients, as well as evolution from classical to variant Ph, introduce further heterogeneity to the vPh subgroup and raise the possibility that such translocations may herald disease progression. Survival analyses, however, have thus far yielded contradictory results. We assessed the frequency of der(9) deletions, ABL-BCR abrogation, cytogenetic evolution and cryptic rearrangement in a large cohort of 54 patients with vPh CML. Deletions encompassing ABL-BCR were detected in 37% of patients, consistent with a model in which a greater number of chromosome breaks increases the risk of genomic loss. The components of ABL-BCR were physically separated in a further 52% of patients while fused in the remaining 11%. Evolution from classical to vPh was demonstrated in three patients. The difference in survival, as indicated by Kaplan-Meier analysis, was marked between classical and vPh patients (105 vs 60 months respectively; P = 0.0002). Importantly, this difference disappeared when patients with deletions were removed from the analysis. Our study showed that, despite the existence of several levels of genomic heterogeneity in variant Ph-positive CML, der(9) deletion status is the key prognostic factor.
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PMID:Survival implications of molecular heterogeneity in variant Philadelphia-positive chronic myeloid leukaemia. 1271 64

In the present study, we examined regulation of activated focal adhesion kinase localization in focal adhesions. By using focal adhesion kinase fused to an inert transmembrane anchor, we found that the focal contact targeting region within focal adhesion kinase was preserved in the membrane-targeted fusion protein. However, upon tyrosine phosphorylation, full-length focal adhesion kinase became excluded from focal adhesions. This negative regulation of localization could be abolished by mutating key amino acid residues of focal adhesion kinase shown previously to be involved in adhesion-mediated signal transduction. Hyper-phosphorylation of endogenous focal adhesion kinase induced by pervanadate resulted in a similar reduction of localization at focal adhesions. We also show here that Src family kinases are essential for the phosphorylation-dependent exclusion of focal adhesion kinase from focal adhesions. We propose here a molecular model for the tyrosine phosphorylation-dependent regulation of focal adhesion kinase organization involving Src kinases and an inhibitory phosphorylation of the C-terminal (Tyr-925) tyrosine residue.
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PMID:Targeting membrane-localized focal adhesion kinase to focal adhesions: roles of tyrosine phosphorylation and SRC family kinases. 1275 19

Prolactin (PRL) interacts with a single-chain prolactin-specific receptor of the cytokine receptor superfamily. PRL triggers the activation of JAK2 kinase, which phosphorylates the PRL receptor itself, and of STAT5, a member of the family of signal transducers and activators of transcription (STAT). We have shown that the STAT5-dependent immediate early gene, CIS1 (Cytokine-Inducible SH2 domain-containing protein-1), suppresses PRL-induced STAT5 activation in vitro as well as in transgenic mice. To facilitate the study of the interactions between CIS1 and the PRL receptor, we have developed the yeast tri-hybrid system, a modification of the yeast two-hybrid system. We expressed CIS1 fused to the DNA-binding domain and PRL receptor cytoplasmic domain fused to the transcription activation domain in the presence or absence of the tyrosine kinase domain of JAK2 in yeast. CIS1 bound to the PRL receptor cytoplasmic domain in a JAK2-dependent manner. Moreover, we determined that the phosphorylated Y532 of the murine PRL receptor is the binding site for CIS1. Interestingly, Y532 has been shown to be unnecessary for STAT5 activation, although CIS1 overexpression suppressed PRL-induced STAT5 activation. These data suggest that the suppression of STAT5 activation by CIS1 is not due to a simple competition with STAT5 but rather to a modification of the receptor by CIS1 binding.
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PMID:CIS1 interacts with the Y532 of the prolactin receptor and suppresses prolactin-dependent STAT5 activation. 1276 Dec 5

ARG is a tyrosine kinase closely related to ABL, which is oncogenic when fused to the transcriptional repressor ETV6 (ETS translocation variant 6). In this study, we investigated the growth-inhibitory effect of STI571 (signal transduction inhibitor number 571) on ETV6/ARG-expressing cells and its molecular mechanisms using HT93A, a cell line derived from a patient with AML-M3 carrying t(1;12). STI571 effectively suppressed overall tyrosyl phosphorylation of intracellular proteins including ETV6/ARG fusion protein, as well as the growth of HT93A cells with an IC(50) of 200 nM. The growth inhibition was primarily because of cell cycle arrest at G1 phase when cells were treated with 100 nM STI571 for 48 h, and apoptosis was induced after longer exposure (72 h) or by a higher dose (1000 nM). STI571 increased the amount of p18/INK4c after 2 h of culture, when the cell cycle pattern was not yet affected, but not that of other CDK inhibitors (CKI). p18/INK4c was more abundant in G1-enriched fractions than in S- and G2/M-enriched fractions of STI571-treated HT93A cells, suggesting that the upregulation of p18/INK4c expression correlates with the cell cycle arrest. Treatment of HT93A cells with antisense oligonucleotides against the Ink4c gene abrogated the growth inhibition by STI571. These results suggest that leukemogenesis by an aberrant ARG kinase involves the suppression of p18/INK4c, which is ubiquitously expressed and considered the major CKI in hematopoietic stem cells. STI571 can be an effective drug for the treatment of leukemias with deregulated ARG kinase activity.
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PMID:Suppression of ARG kinase activity by STI571 induces cell cycle arrest through up-regulation of CDK inhibitor p18/INK4c. 1282 41

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal (GI) tract. The c-kit receptor tyrosine kinase (KIT) is expressed by practically all GISTs, and gain-of-function mutations of KIT are present in most GISTs. Interstitial cells of Cajal (ICC) are the pacemaker of the peristaltic movement of the GI tract. Since signals through KIT are essential for development of ICC and since multiple GISTs develop from the hyperplastic lesion of ICCs in familial GIST patients with germline mutations of KIT, GISTs are considered to originate from ICC. Imatinib mesylate, which was developed for treatment of chronic myeloid leukemia (CML), was found to be useful for treatment of GISTs. Imatinib mesylate inhibits BCR-ABL fused tyrosine kinase that causes CML. Imatinib mesylate also inhibits the mutated KIT observed in most GISTs, and this explains the effectiveness of Imatinib mesylate on GISTs. GISTs appear to serve as a model for molecule-based diagnosis and treatment of solid tumors.
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PMID:Gastrointestinal stromal tumors (GIST): a model for molecule-based diagnosis and treatment of solid tumors. 1282 97

p/CIP/SRC-3 is a member of a family of steroid receptor coactivators/nuclear receptor coactivators (SRC/NCoA) proteins that mediate the transcriptional effects of nuclear hormone receptors (NRs). Using deletion analysis we have mapped the location of two distinct activation domains in p/CIP (AD1 and AD2) capable of activating transcription in mammalian cells when fused to the Gal4-DNA binding domain. In addition to AD1 being coincident with the interaction domain for CBP, we demonstrate a novel in vivo interaction between the AD1 and GCN5. Overexpression of a Gal4-AD1 fusion protein in yeast leads to growth arrest that is relieved by mutation of genes encoding components of the SAGA complex including GCN5, ADA3, and SPT7. In addition, the AD1 of p/CIP and the ADA3 gene are shown to be essential for retinoic acid receptor alpha-dependent transcription in yeast. Transient transfection assays in mammalian cells indicate that GCN5 cooperates with p/CIP as a coactivator of RAR alpha-dependent transcription. Down-regulation of GCN5 using small interfering RNA in mammalian cells indicates that the AD1 domain and the RAR beta promoter activity are dependent, in part, on GCN5. Mutational analysis of AD1 has identified two helical motifs that are required for interactions with GCN5 and CBP. Taken together, these results support a model by which p/CIP functions as a ligand-dependent adapter, through specific protein-protein interactions with AD1, to recruit members from at least two distinct families of acetyltransferase proteins to NRs.
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PMID:The coactivator p/CIP/SRC-3 facilitates retinoic acid receptor signaling via recruitment of GCN5. 1288 66

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

The Philadelphia (Ph) chromosome is found in more than 90% of chronic myelocytic leukemia (CML) patients. In most cases, it results from the reciprocal t(9;22)(q34;q11), with the ABL proto-oncogene from 9q34 fused to the breakpoint cluster region (BCR) locus on 22q11. In 5%-10% of patients with CML, the Ph chromosome originates from variant translocations, involving various breakpoints in addition to 9q34 and 22q11. In our investigation, three CML cases with complex Ph translocations have been analyzed by G-banding and fluorescence in situ hybridization (FISH). FISH with breakpoint-spanning probes for the BCR and ABL genes revealed information about the genesis of complex Ph translocations. The occurrence of one fusion signal indicates a one-step mechanism (case 1). Two fusion signals indicate a two-step mechanism (case 2). Lack of signals indicates deletions of parts of the BCR and ABL genes or of adjacent regions (case 3).
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PMID:Genesis of variant Philadelphia chromosome translocations in chronic myelocytic leukemia. 1458 Jul 66


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