Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The receptor protein tyrosine phosphatase density-enhanced phosphatase-1 (DEP-1) has been implicated in aberrant cancer cell growth and immune cell function, however, its function within cells has yet to be properly elucidated. To investigate the cellular function of DEP-1, stable cell lines inducibly expressing DEP-1 were generated. Induction of DEP-1 expression was found to decrease PDGF-stimulated tyrosine phosphorylation of a number of cellular proteins including the PDGF receptor, and to inhibit growth factor-stimulated phosphorylation of components of the MAPK pathway, indicating that DEP-1 antagonised PDGF receptor signalling. This was supported by data showing that DEP-1 expression resulted in a reduction in cell proliferation. DEP-1-expressing cells had fewer actin-containing microfilament bundles, reduced vinculin and paxillin-containing adhesion plaques, and were defective in interactions with fibronectin. Defective cell-substratum adhesion correlated with lack of activation of FAK in DEP-1-expressing cells. Time-lapse interference reflection microscopy of live cells revealed that although small focal contacts at the leading edge were generated in DEP-1-expressing cells, they failed to mature into stable focal adhesions, as found in control cells. Further motility analysis revealed that DEP-1-expressing cells retained limited random motility, but showed no chemotaxis towards a gradient of PDGF. In addition, cell-cell contacts were disrupted, with a change in the localisation of cadherin from discrete areas of cell-cell contact to large areas of membrane interaction, and there was a parallel redistribution of beta-catenin. These results demonstrate that DEP-1 is a negative regulator of cell proliferation, cell-substratum contacts, motility and chemotaxis in fibroblasts.
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PMID:The tyrosine phosphatase DEP-1 induces cytoskeletal rearrangements, aberrant cell-substratum interactions and a reduction in cell proliferation. 1470 17

Gastrointestinal stromal tumours (GISTs), the most common mesenchymal tumours of the digestive tract, are largely resistant to chemo- and radiotherapy. They are currently defined by their overexpression of the KIT receptor tyrosine kinase (CD117), a member of the family of receptor tyrosine kinases (RTKs), and exhibit KIT mutations in more than 85% of cases. Additionally, in more than one-third of KIT wild-type GISTs, mutations of platelet-derived growth factor receptor alpha (PDGF-R alpha), which also belongs to the family of RTKs, were recently found. Since these data indicate that uncontrolled RTK signalling may be implicated in the pathogenesis of GISTs, RTKs and the activated downstream signalling cascades are attractive targets in the therapy of these tumours. Imatinib is a small-molecule inhibitor that selectively blocks the activity of the PDGF-R, ABL and KIT receptor tyrosine kinases by competitive binding to the adenosine triphosphate binding site of their catalytic domains. We herein review the molecular pathological, preclinical and clinical data that identify imatinib as a valuable new agent in the treatment of GISTs.
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PMID:Gastrointestinal stromal tumours and their response to treatment with the tyrosine kinase inhibitor imatinib. 1473 60

The new knowledge in molecular biology and pathophysiology of chronic myeloid leukemia enabled the development of imatinib mesylate (Glivec, formerly STI571). Imatinib potently inhibits several protein tyrosine kinases, including BCR-ABL, c-Kit, and PDGF receptor. Imatinib blocks the phosphorylation of downstream target proteins and interrupts the malignant transformation leading to the development of CML. Phase I and II studies demonstrated that imatinib is highly effective and well tolerated in all phase of CML. We got our experience with imatinib on more than two-year monitoring 34 patients within the Expanded Access Study CST1571 0113. Imatinib 400 mg/d was administered orally to 10 women and 24 men in median age of 53 years (22-70) who were hematologically (n = 9) or cytogenetically (n = 13) resistant, cytogenetically refractory (n = 3) or intolerant (n = 9) to interferon alpha. The median follow-up time was 97.5 weeks (23-115), the median time from CML diagnosis to the start of the study was 32.3 months (6-140.5). Complete hematologic response was achieved in 33 of 34 (97%) pts, total major cytogenetic response (complete plus major) in 21 of 33 (63%) pts. Cytogenetic relapse was observed in 2 of 33 pts (6%), cytogenetic progression in 4 (12%) pts. Non-hematologic toxicity was mild (grade 1 or 2) and no patient was excluded from the study due to it. Hematological toxicity grade 3 limited dose of imatinib in 26% of patients and probably caused lower rate of cytogenetic responses in heavy pretreated patients. Both quantitative RT-PCR methods (competitive RT-PCR and real-time RT-PCR Light-Cycler) were found useful to monitor patients with CML on imatinib therapy. Our results confirmed high efficacy and safety of imatinib in late-chronic phase CML patients failing prior interferon therapy. The lower incidence of hematological toxicity and higher rate of cytogenetic responses in patients treated with imatinib in early-chronic phase CML justify according to our opinion the recommendation to administer imatinib early after the diagnosis of CML in patients who are not indicated for allogeneic transplantation.
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PMID:[Imatinib mesylate (Glivec) in treatment of chronic phase chronic myeloid leukemia]. 1501 23

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract characterized by the expression of a receptor that activates tyrosine kinase called c-kit. Since malignant GISTs are resistant to conventional radiation therapy and chemotherapy, recurrent or malignant GIST has an extremely poor prognosis even after surgical resection. The development of a tyrosine kinase inhibitor, STI571 (imatinib mesylate, Glivec, Gleevec), which inhibits the BCR-ABL, PDGF-R alpha and c-kit receptors, has changed the management of unresectable malignant GIST and has improved the survival of patients with metastatic disease. We report a patient with GIST and diffused peritoneal metastases, whose tumor initially responded to STI571 and eventually became resistant. A 45-year-old woman underwent partial jejunostomy on September 3, 1998, under a diagnosis of submucosal tumor of the jejunum. Pathological examination of the primary tumor revealed a strong c-kit expression and GIST was diagnosed. The patient underwent an excision of peritoneal recurrences on October 31, 2000; April 17, 2001; and August 28, 2001. A treatment with STI571 (400 mg/day) was initiated on October 15, 2001, and she was free from peritoneal masses for 8 months after the fourth operation. However, the patient herself suspended the STI571 therapy for one month and multiple peritoneal metastases developed. Although the treatment with STI571 was restarted at 400 mg/day, the peritoneal masses did not respond this time. She died of liver, lung, and peritoneal metastases after the seventh cytoreductive operation on February 11, 2004. Several mechanisms of the resistance to STI571 have been identified. Amplification or an overexpression of KIT has been proposed to be involved in the resistance development. Several mutations of KIT were also correlated with the clinical outcome. Her tumors showed mutations in exons 9 or 11 of KIT, which had longer event-free and overall survival times than those tumors that had mutations of exons 13 or 17. In this case, an exon 11 mutation of KIT was initially noted. After the interruption of the treatment, an additional point mutation arose in exon 13 that caused a resistance to STI571. Currently STI571 is the first-line therapy for non-resectable GISTs, but a single-agent therapy often leads to tumor resistance. It is our hope that we will be able to design an alternative treatment to overcome such resistance.
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PMID:[A case of metastatic gastrointestinal stromal tumor developing a resistance to STI571 (imatinib mesylate)]. 1555 17

Imatinib mesylate is a potent and specific tyrosine kinase inhibitor against c-ABL, BCR-ABL, and c-KIT, and has been demonstrated to be highly active in chronic myeloid leukemia and gastrointestinal stromal tumors. We examined the antifibrotic effects of imatinib using a bleomycin-induced lung fibrosis model in mice because imatinib also inhibits tyrosine kinase of platelet-derived growth factor receptors (PDGFRs). Imatinib inhibited the growth of primary murine lung fibroblasts and the autophosphorylation of PDGFR-beta induced by PDGF. Administration of imatinib significantly prevented bleomycin-induced pulmonary fibrosis in mice, partly by reducing the number of mesenchymal cells incorporating bromodeoxyuridine. Analysis of bronchoalveolar lavage cells demonstrated that imatinib did not suppress early inflammation on Days 7 and 14 caused by bleomycin. These results suggest that imatinib has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that imatinib might be useful for the treatment of pulmonary fibrosis in humans.
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PMID:Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. 1573 62

We showed previously [K. Moissoglu, I.H. Gelman, J. Biol. Chem. 278 (2003) 47946-47959] that oncogenic v-Src could induce 7- to 10-fold greater anchorage-independent growth (AIG) in FAK-null mouse embryo fibroblasts (MEF) compared to those expressing FAK. Here, we demonstrate that the enhanced AIG (eAIG) correlates with increased activation levels of phosphatidylinositol 3-kinase (PI3K) and not with changes in the protein levels of the p85 regulatory subunit of PI3K, PDK1 or PTEN- modulators, and/or mediators of PI3K activity. eAIG could be blunted selectively by treatment with the PI3K inhibitor, LY294002, or by overexpression of either the PI3K antagonist, PTEN, dominant-interfering alleles of PI3K or a downstream PI3K mediator, AKT, but not by the MEK inhibitor, PD98059, dominant-interfering alleles of MEK or the signal transducer and activator of transcription (STAT)-3. In contrast, RNAi-mediated knockdown of FAK resulted in increased v-Src-induced AIG. Expression of a constitutively active PI3K allele was sufficient to induce higher levels of AIG, whereas overexpression of v-Src produced only larger-sized colonies in soft agar. Interestingly, FAK was required for full activation of PI3K by PDGF whereas the activation of PI3K by insulin was significantly increased in FAK-/- cells. Thus, although FAK is dispensable for v-Src-induced oncogenic transformation in vitro, it may exert either positive or negative effects on signaling or motility depending on which pathways are activated in cancer cells.
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PMID:Enhanced v-Src-induced oncogenic transformation in the absence of focal adhesion kinase is mediated by phosphatidylinositol 3-kinase. 1580 50

Aberrant migration of smooth muscle cells (SMCs) is a key feature of restenosis. Since extracellular matrix proteins and their receptors of the integrin family play a critical role in this process, it is instrumental to understand their contribution to cell migration and invasive motility of SMC on the molecular level. Therefore, we investigated the role of alpha(v)-containing integrins expressed by primary human coronary artery smooth muscle cells (hCASMCs) in vitronectin (VN)-initiated signaling events and cell migration. In hCASMC plated on VN, alpha(v)-containing integrins were localized at focal adhesion sites. Haptotactic stimulation through VN led to a dose-dependent increase in cell migration and concomitantly to enhanced tyrosine phosphorylation of focal adhesion kinase. Both events were completely blocked by a specific inhibitor of integrin alpha(v). Additionally, the integrin alpha(v) inhibitor abolished PDGF-BB-stimulated chemotactic migration. Confocal microscopy confirmed the increased tyrosine phosphorylation at VN-initiated focal contact sites in hCASMC, that was abolished upon alpha(v) inhibition. In vitro invasion of hCASMC was severely compromised in the presence of the integrin alpha(v) inhibitor paralleled by decreased levels of secreted matrix metalloprotease 2 (MMP-2). Together, integrin alpha(v) inhibition abrogates tyrosine phosphorylation at focal adhesion sites and diminishes MMP-2 secretion leading to reduced migration and invasion of hCASMCs.
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PMID:Targeting of alpha(v) integrins interferes with FAK activation and smooth muscle cell migration and invasion. 1585 Jul 74

Imatinib mesylate (IM) is a tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. It has proved beneficial in treating patients with chronic myeloid leukaemia (CML). In addition, IM demonstrates activity against malignant cells expressing c-kit and platelet-derived growth factor receptor (PDGF-R). The activity of IM in the blastic crisis of CML and against various myeloma cell lines suggests that this drug may also target other cellular components. In the light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on telomerase activity (TA) and regulation in various malignant cell lines. Imatinib mesylate caused a dose-dependent inhibition of TA (up to 90% at a concentration of 15 microM IM) in c-kit-expressing SK-N-MC (Ewing sarcoma), SK-MEL-28 (melanoma), RPMI 8226 (myeloma), MCF-7 (breast cancer) and HSC 536/N (Fanconi anaemia) cells as well as in ba/F3 (murine pro-B cells), which do not express c-kit, BCR-ABL or PDGF-R. Imatinib mesylate did not affect the activity of other DNA polymerases. Inhibition of TA was associated with 50% inhibition of proliferation. The inhibition of proliferation was associated with a decrease in the S-phase of the cell cycle and an accumulation of cells in the G2/M phase. No apoptosis was observed. Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. Other steps of telomerase regulation were not affected by IM. This study demonstrates an additional cellular target of IM, not necessarily mediated via known tyrosine kinases, that causes inhibition of TA and cell proliferation.
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PMID:Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines. 1587 Jul 11

PDGF and nitric oxide (NO) have been shown to participate in the progression of several forms of glomerulonephritis. A potential influence of NO on PDGF-mediated signaling cascades was therefore examined. Treatment of rat mesangial cells (MC) with the NO donors diethylenetriamine NO (DETA-NO) or spermine-NONOate resulted in a time- and dose-dependent upregulation of PDGF receptor alpha (PDGFRalpha) but not PDGFRbeta mRNA levels. Administration of DETA-NO also induced PDGFRalpha protein expression that was paralleled also by an enhanced receptor phosphorylation. Further experiments using 3-(5-hydroxymethyl-2-furyl)-1-benzylindazole (YC-1), an activator of the soluble guanylyl cyclase (sGC), the membrane-soluble cyclic GMP (cGMP) analog 8-Bromo-PET-cGMP, and the inhibitors of sGC ODQ and NS2028 suggest that elevated cGMP levels are responsible for the effects of NO. Importantly, NO-dependent autophosphorylation of PDGFRalpha drastically augmented PDGF-AA-evoked phosphorylation of PKB/Akt, a classical downstream target of PDGFRalpha signaling. Furthermore, in a rat model of anti-Thy-1 glomerulonephritis, expression and phosphorylation of PDGFRalpha but not PDGFRbeta expression was markedly reduced in nephritic animals that were treated with the inducible NO synthase inhibitor L-N6(1-iminoethyl)lysine(dihydrochloride) (L-NIL) compared with non-L-NIL-treated nephritic rats as demonstrated by Western blotting and immunohistochemistry. Taken together, the data suggest that NO modulates PDGFRalpha-triggered signaling in a cGMP-dependent manner by induction of PDGFRalpha expression in MC and in a rat model of mesangioproliferative glomerulonephritis. The mechanistic details of this regulation have to be elucidated in further experiments.
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PMID:Nitric oxide upregulates induction of PDGF receptor-alpha expression in rat renal mesangial cells and in anti-Thy-1 glomerulonephritis. 1587 77

Alphavbeta3 integrin is a crucial factor involved in a variety of physiological processes, such as cell growth and migration, tumor invasion and metastasis, angiogenesis, and wound healing. Alphavbeta3 integrin exerts its effect by regulating endothelial cell (EC) migration, proliferation, and survival. Inhibiting the function of alphavbeta3 integrin, therefore, represents a potential anti-cancer, anti-thrombotic, and anti-inflammatory strategy. In this study, we tested an RNA aptamer, Apt-alphavbeta3 that binds recombinant alphavbeta3 integrin, for its ability to bind endogenous alphavbeta3 integrin on the surface of cells in culture and to subsequently affect cellular response. Our data illustrate that Apt-alphavbeta3 binds alphavbeta3 integrin expressed on the surface of live HUVECs. This interaction significantly decreases both basal and PDGF-induced cell proliferation as well as inhibition of cell adhesion. Apt-alphavbeta3 can also reduce PDGF-stimulated tube formation and increase HUVEC apoptosis through inhibition of FAK phosphorylation pathway. Our results demonstrate that by binding to its target, Apt-alphavbeta3 can efficiently inhibit human EC proliferation and survival, resulting in reduced angiogenesis. It predicts that Apt-alphavbeta3 could become useful in both tumor imaging and the treatment of tumor growth, atherosclerosis, thrombosis, and inflammation.
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PMID:Targeted inhibition of alphavbeta3 integrin with an RNA aptamer impairs endothelial cell growth and survival. 1625 39


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