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

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Imatinib mesylate is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. Imatinib stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients.
...
PMID:Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells. 1588 38

Aldosterone is currently recognized as a risk hormone for cardiovascular disease. However, the cellular mechanism by which aldosterone acts on vasculature has not been well understood. In the present study, we investigated whether aldosterone affects angiotensin-converting enzyme (ACE) gene expression in rat endothelial cells. Cultured rat aortic endothelial cells (RAECs) from Sprague-Dawley rats were used in the study. ACE mRNA levels and its enzyme activities in RAECs were examined by real-time RT-PCR and enzyme assay using hippuryl-His-Leu as substrates, respectively. Aldosterone significantly increased steady-state ACE mRNA levels and its enzymatic activities. This effect was dose dependent and time dependent and abolished by mineralocorticoid receptor antagonist spironolactone or transcription inhibitor actinomycin D. Dexamethasone also increased steady-state ACE mRNA levels, whose effect was completely blocked by glucocorticoid receptor antagonist RU486, but not by spironolactone. By contrast, the aldosterone-induced ACE mRNA expression was only partially blocked by RU486. The stimulatory effect of aldosterone on ACE mRNA expression was completely blocked by a protein tyrosine kinase inhibitor (genistein) and JAK2 inhibitor (AG490), partially by Src kinase inhibitor (PP2) and epidermal growth factor receptor kinase inhibitor (AG1478), but not by platelet-derived growth factor receptor kinase inhibitor (AG1296). Transfection of dominant-negative JAK2 construct, but not wild-type construct, significantly blocked the aldosterone-induced ACE mRNA up-regulation. Furthermore, aldosterone induced phosphorylation of JAK2, whose effect was blocked by spironolactone and actinomycin D. In conclusion, the present study demonstrates for the first time that aldosterone induces ACE gene expression and its enzyme activity mainly via a mineralocorticoid receptor-mediated and JAK2-dependent pathway in rat endothelial cells. This may constitute a positive feedback loop for a local renin-angiotensin system, possibly involved in the development of aldosterone-induced endothelial dysfunction and vascular injury.
...
PMID:Aldosterone induces angiotensin converting enzyme gene expression via a JAK2-dependent pathway in rat endothelial cells. 1593 31

Imatinib mesylate (STI571) is an oral 2-phenylaminopyrimidine derivative that acts as a selective inhibitor against several receptor tyrosine kinases and has been viewed as one of the therapeutic success stories of the 21st century. Imatinib was first shown to inhibit the causative molecular translocation in chronic myelogenous leukemia, BCR-ABL. Because imatinib could also inhibit the activity of KIT, a 145-kD transmembrane glycoprotein, and because gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the digestive tract, are characterized by expression of a gain-of-function mutation in KIT, imatinib was used in therapeutic trials of GISTs beginning in 1999. The initial success has now resulted in more widespread use of imatinib for the treatment of patients with GIST. Molecular genetic studies have shown that most GISTs possess a KIT mutation in exon 9, 11, 13, or 17. Clinically, GIST patients with KIT exon 11 mutations (ie, the juxtamembrane region) are the most prevalent and sensitive to imatinib. In addition to the inhibitory effect on KIT, imatinib also inhibits the activity of mutant platelet-derived growth factor receptor-alpha (PDGFRalpha) found in a subset of GIST. What is becoming evident is that there are patients with GIST who lack mutations in KIT or PDGFRalpha, or possess "imatinib-resistant" mutations (such as exon 17 mutations in KIT and exon 18 mutations in PDGFRalpha). These patients typically do not respond well to imatinib therapy. Therefore, identifying additional genetic factors that contribute to the pathogenesis of GIST, independent of KIT and PDGFRalpha, will be important in developing additional anti-GIST therapies. As one might suspect from previous experiences with antitumor therapies, primary and secondary resistance to imatinib is also becoming a major clinical problem in the treatment of this disease. Therefore, new drugs that can serve as alternative therapies in imatinib-resistant patients with GIST or that can be used in combination with imatinib will be needed. As with most recent efforts to derive novel molecular target therapies to treat cancer, improved therapy of GIST will continue to benefit from advances in the molecular characterization of this disease.
...
PMID:Molecular research directions in the management of gastrointestinal stromal tumors. 1624 52

Accumulating evidence strongly implicates angiotensin II (AngII) intracellular signaling in mediating cardiovascular diseases such as hypertension, atherosclerosis and restenosis after vascular injury. In vascular smooth muscle cells (VSMCs), through its G-protein-coupled AngII Type 1 receptor (AT(1)), AngII activates various intracellular protein kinases, such as receptor or non-receptor tyrosine kinases, which includes epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Src, PYK2, FAK, JAK2. In addition, AngII activates serine/threonine kinases such as mitogen-activated protein kinase (MAPK) family, p70 S6 kinase, Akt/protein kinase B and various protein kinase C isoforms. In VSMCs, AngII also induces the generation of intracellular reactive oxygen species (ROS), which play critical roles in activation and modulation of above signal transduction. Less is known about endothelial cell (EC) AngII signaling than VSMCs, however, recent studies suggest that endothelial AngII signaling negatively regulates the nitric oxide (NO) signaling pathway and thereby induces endothelial dysfunction. Moreover, in both VSMCs and ECs, AngII signaling cross-talk with insulin signaling might be involved in insulin resistance, an important risk factor in the development of cardiovascular diseases. In fact, clinical and pharmacological studies showed that AngII infusion induces insulin resistance and AngII converting enzyme inhibitors and AT(1) receptor blockers improve insulin sensitivity. In this review, we focus on the recent findings that suggest the existence of novel signaling mechanisms whereby AngII mediates processes, such as activation of receptor or non-receptor tyrosine kinases and ROS, as well as cross-talk between insulin and NO signal transduction in VSMCs and ECs.
...
PMID:Angiotensin II regulates vascular and endothelial dysfunction: recent topics of Angiotensin II type-1 receptor signaling in the vasculature. 1647 78

Standard antineoplastic treatment for metastatic melanoma is ineffective in the large majority of patients. Therefore, alternative approaches need to be investigated. STI571 is a new antineoplastic compound, which selectively inhibits the tyrosine kinase activity of ABL, c-Kit and platelet-derived growth factor receptor (PDGFR). Melanoma may express all of these proteins. The aim of this study was to investigate whether STI571 inhibits the in-vitro growth of melanoma cells. Nineteen cell lines were obtained from four primary and 15 metastatic melanomas of cutaneous origin. The percentages of positive cells for the putative targets of STI571 were as follows: ABL, 41-100%; c-Kit, 8-97%; PDGFR-alpha, 41-98%; PDGFR-beta, 51-99%. 3-(4,5-Dimethylthiazol-yl)-2,5-diphenyltetrazolium (MTT) and viability assays showed that STI571 clearly inhibits the proliferation of eight of the 19 (42.1%) cell lines. No relationship could be established between the expression of c-Kit, ABL, PDGFR-alpha or PDGFR-beta and the response of cell lines to STI571. Our study shows, for the first time, an antiproliferative effect of STI571 on human melanoma cell lines of cutaneous origin, raising the possibility of the future clinical use of STI571. The identification of the target of STI571 in human cutaneous melanoma cells would allow the selection of patients who could benefit from this treatment.
...
PMID:Antiproliferative effect of STI571 on cultured human cutaneous melanoma-derived cell lines. 1656 68

STI571 is a specific inhibitor of tyrosine kinases, such as BCR-ABL, platelet-derived growth factor receptor, and c-KIT, and has recently been approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors (GISTs). This study demonstrated that STI571 induces cell death in the gastrointestinal stromal tumor cell line, GIST-T1. In these cells, STI571 induced pro-caspase-12 or pro-caspase-7 cleavage and it affected caspase-3 activity and induced the endoplasmic reticulum (ER)-resident chaperone, glucose-regulated protein 78. The STI571-induced cell death was blocked by the protein synthesis inhibitor, cycloheximide. Together, these results suggest that STI571 induces cell death in GIST-T1 cells, at least in part, via the ER stress response.
...
PMID:STI571 (Glivec) induces cell death in the gastrointestinal stromal tumor cell line, GIST-T1, via endoplasmic reticulum stress response. 1659 77

Ribosomal protein S6 kinase (S6K) is activated by an array of mitogenic stimuli and is a key player in the regulation of cell growth. The activation process of S6 kinase involves a complex and sequential series of multiple Ser/Thr phosphorylations and is mainly mediated via phosphatidylinositol 3-kinase (PI3K)-3-phosphoinositide-dependent protein kinase-1 (PDK1) and mTor-dependent pathways. Upstream regulators of S6K, such as PDK1 and protein kinase B (PKB/Akt), are recruited to the membrane via their pleckstrin homology (PH) or protein-protein interaction domains. However, the mechanism of integration of S6K into a multi-enzyme complex around activated receptor tyrosine kinases is not clear. In the present study, we describe a specific interaction between S6K with receptor tyrosine kinases, such as platelet-derived growth factor receptor (PDGFR). The interaction with PDGFR is mediated via the kinase or the kinase extension domain of S6K. Complex formation is inducible by growth factors and leads to S6K tyrosine phosphorylation. Using PDGFR mutants, we have shown that the phosphorylation is exerted via a PDGFR-src pathway. Furthermore, src kinase phosphorylates and coimmunoprecipitates with S6K in vivo. Inhibitors towards tyrosine kinases, such as genistein and PP1, or src-specific SU6656, but not PI3K and mTor inhibitors, lead to a reduction in tyrosine phosphorylation of S6K. In addition, we mapped the sites of tyrosine phosphorylation in S6K1 and S6K2 to Y39 and Y45, respectively. Mutational and immunofluorescent analysis indicated that phosphorylation of S6Ks at these sites does not affect their activity or subcellular localization. Our data indicate that S6 kinase is recruited into a complex with RTKs and src and becomes phosphorylated on tyrosine/s in response to PDGF or serum.
...
PMID:Receptor association and tyrosine phosphorylation of S6 kinases. 1664 May 65

Imatinib mesylate is a drug that has been recently approved for the treatment for chronic myeloid leukemia. It acts as a potent and selective inhibitor of BCR-ABL tyrosine kinase. It also inhibits both c-kit and platelet-derived growth factor receptor tyrosine kinases. Hypopigmentation of the skin in patients receiving this drug has been recently reported. We report a 17-year-old Caucasian patient affected by chronic myeloid leukemia in therapy with imatinib mesylate who developed hypopigmented vitiligo-like patches and generalized lightening of the skin. In order to evaluate the lightening observed clinically, we measured the progressive skin color hypopigmentation by using a colorimeter over several months. The colorimetric evaluation confirmed the generalized and gradual lightening of patient's skin over treatment with imatinib mesylate. We believe that this is the first reported instance of vitiligo-like lesions in a pediatric patient treated with imatinib mesylate, and the second in a Caucasian patient.
...
PMID:Vitiligo-like lesions and diffuse lightening of the skin in a pediatric patient treated with imatinib mesylate: a noninvasive colorimetric assessment. 1665 Feb 31

Most gastrointestinal stromal tumors (GISTs) possess a gain-of-function mutation in c-KIT. Imatinib mesylate, a small-molecule inhibitor against several receptor tyrosine kinases, including KIT, platelet-derived growth factor receptor-alpha, and BCR-ABL, has therapeutic benefit for GISTs both via KIT and via unknown mechanisms. Clinical evidence suggests that a potential therapeutic benefit of imatinib might result from decreased glucose uptake as measured by positron emission tomography using 18-fluoro-2-deoxy-d-glucose. We sought to determine the mechanism of and correlation to altered metabolism and cell survival in response to imatinib. Glucose uptake, cell viability, and apoptosis in GIST cells were measured following imatinib treatment. Lentivirus constructs were used to stably express constitutively active AKT1 or AKT2 in GIST cells to study the role of AKT signaling in metabolism and cell survival. Immunoblots and immunofluorescent staining were used to determine the levels of plasma membrane-bound glucose transporter Glut4. We show that oncogenic activation of KIT maximizes glucose uptake in an AKT-dependent manner. Imatinib treatment markedly reduces glucose uptake via decreased levels of plasma membrane-bound Glut4 and induces apoptosis or growth arrest by inhibiting KIT activity. Importantly, expression of constitutively active AKT1 or AKT2 does not rescue cells from the imatinib-mediated apoptosis although glucose uptake was not blocked, suggesting that the potential therapeutic effect of imatinib is independent of AKT activity and glucose deprivation. Overall, these findings contribute to a clearer understanding of the molecular mechanisms involved in the therapeutic benefit of imatinib in GIST and suggest that a drug-mediated decrease in tumor metabolism observed clinically may not entirely reflect therapeutic efficacy of treatment.
...
PMID:Therapeutic effect of imatinib in gastrointestinal stromal tumors: AKT signaling dependent and independent mechanisms. 1670 77

Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of BCR-ABL-negative chronic myeloproliferative disorders (CMPDs). These fusion genes encode constitutively activated receptor tyrosine kinases that can be inhibited by imatinib. Twelve patients with BCR-ABL-negative CMPDs and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses with normalization of peripheral-blood cell counts and disappearance of eosinophilia; 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRB fusion-positive, BCR-ABL-negative CMPDs.
...
PMID:Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders. 1696 Jan 51


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---