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)

Because conventional chemotherapy is not specific for cancer cells leading to toxic side effects there is a need for novel agents with high grade antitumor specificity. The major prerequisite to develop such drugs is to understand the targets that these agents should attack. In recent years a number of promising new anticancer drugs have been developed which target intracellular pathways or extracellular cell molecules. The clinically most effective compounds function as tyrosine kinase inhibitors. In the past, various tyrosine kinase receptors have been identified as regulators of tumor or tumor vessel growth. Having shown their expression characteristics in different tumor entities, specific inhibitors of the ATP binding sites of these receptors or antibodies were developed and entered clinical trials. The pathognomonic role of the tyrosine kinase defines the way of action of the inhibiting drug, whereas the amount of expression in tumor tissue defines the rationale to use the inhibitor to treat a specific protein. The future will define indications for such drugs by tumor kinase profiles instead of tumor entities. Gleevec, inhibiting the BCR-ABL tyrosine kinase; Iressa, inhibiting the EGF-receptor tyrosine kinase; Herceptin, inhibiting the Her2/neu tyrosine kinase and PTK787/ZK222584, inhibiting the VEGF-receptor tyrosine kinase will be discussed as representatives of selective tyrosine kinase inhibitors whereas ZD6474 and SU6668 will be discussed as representatives of multitarget tyrosine kinase inhibitors.
...
PMID:Receptor tyrosine kinases: the main targets for new anticancer therapy. 1255 64

Hybridization with cDNA arrays was used to obtain expression profiles of 263 protein-tyrosine kinase (PTK), protein-tyrosine phosphatase (PTP), dual-specific phosphatase (DuSP), and other genes for the normal prostate tissue, primary prostate carcinomas (PC) of 84 patients, 7 xenografts, and 5 carcinoma cell lines. Analysis of 96 profiles revealed eight clusters of genes coexpressed in PC (coefficient of correlation r > 0.7). According to the known functions of their genes, the clusters were designated as proliferating-cell (CDC42, TOP2A, FGFR3, MYC, etc.), neoangiogenesis and blood-cell (LCK, VAV1, KDR, VEGF, MMP9, SYK, PTPRS, and FLT4), invasion-1 and invasion-2 (ADAM17, TRPM2, DUSP6, VIM, CAV1, CAV2, JAK1, PTPNS1, FYN, and PDGFB), HER2, and PSA/PSM/HER3. Basing on expression profiles of 66 genes, a molecular classification of PC was constructed and allowed discrimination between PC and cell lines or xenografts at 98.9% probability. The results suggested that, along with PSA, PSM (FOLH1), kallikrein-2, and a-2-macroglobulin, cell signaling genes EGFR, HER2, HER3, TOP2, KRT8, KRT18, VEGF, CD44, VIM, CAV1, and CAV2 may serve as diagnostic and prognostic markers in PC. The HER2, VEGF, and CD44 genes and the MMP and ADAM families were assumed to be promising targets for inhibitors of PC cell proliferation and metastasis.
...
PMID:[Gene expression profiles of protein kinases and phosphatases obtained by hybridization with cDNA arrays: molecular portrait of human prostate carcinoma]. 1262 52

Understanding transcriptional changes in brain after ischemia may provide therapeutic targets for treating stroke and promoting recovery. To study these changes on a genomic scale, oligonucleotide arrays were used to assess RNA samples from periinfarction cortex of adult Sprague-Dawley rats 24 h after permanent middle cerebral artery occlusions. Of the 328 regulated transcripts in ischemia compared with sham-operated animals, 264 were upregulated, 64 were downregulated, and 163 (49.7%) had not been reported in stroke. Of the functional groups modulated by ischemia: G-protein-related genes were the least reported; and cytokines, chemokines, stress proteins, and cell adhesion and immune molecules were the most highly expressed. Quantitative reverse transcription polymerase chain reaction of 20 selected genes at 2, 4, and 24 h after ischemia showed early upregulated genes (2 h) including Narp, Rad, G33A, HYCP2, Pim-3, Cpg21, JAK2, CELF, Tenascin, and DAF. Late upregulated genes (24 h) included Cathepsin C, Cip-26, Cystatin B, PHAS-I, TBFII, Spr, PRG1, and LPS-binding protein. Glycerol 3-phosphate dehydrogenase, which is involved in mitochondrial reoxidation of glycolysis derived NADH, was regulated more than 60-fold. Plasticity-related transcripts were regulated, including Narp, agrin, and Cpg21. A newly reported lung pathway was also regulated in ischemic brain: C/EBP induction of Egr-1 (NGFI-A) with downstream induction of PAI-1, VEGF, ICAM, IL1, and MIP1. Genes regulated acutely after stroke may modulate cell survival and death; also, late regulated genes may be related to tissue repair and functional recovery.
...
PMID:Genomics of the periinfarction cortex after focal cerebral ischemia. 1284 83

Antagonists of alphavbeta3 and alphavbeta5 disrupt angiogenesis in response to bFGF and VEGF, respectively. Here, we show that these alphav integrins differentially contribute to sustained Ras-extracellular signal-related kinase (Ras-ERK) signaling in blood vessels, a requirement for endothelial cell survival and angiogenesis. Inhibition of FAK or alphavbeta5 disrupted VEGF-mediated Ras and c-Raf activity on the chick chorioallantoic membrane, whereas blockade of FAK or integrin alphavbeta3 had no effect on bFGF-mediated Ras activity, but did suppress c-Raf activation. Furthermore, retroviral delivery of active Ras or c-Raf promoted ERK activity and angiogenesis, which anti-alphavbeta5 blocked upstream of Ras, whereas anti-alphavbeta3 blocked downstream of Ras, but upstream of c-Raf. The activation of c-Raf by bFGF/alphavbeta3 not only depended on FAK, but also required p21-activated kinase-dependent phosphorylation of serine 338 on c-Raf, whereas VEGF-mediated c-Raf phosphorylation/activation depended on Src, but not Pak. Thus, integrins alphavbeta3 and alphavbeta5 differentially regulate the Ras-ERK pathway, accounting for distinct vascular responses during two pathways of angiogenesis.
...
PMID:Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis. 1295 43

The central role of VEGF (vascular endothelial growth factor A) in angiogenesis is dependent upon its ability to co-ordinately regulate multiple endothelial functions. The multifunctionality of VEGF at the cellular level results from its ability to initiate a diverse, complex and integrated network of signalling pathways via its major receptor, kinase-insert-domain-containing receptor (KDR). Activation of phospholipase C-gamma, protein kinase C, Ca(2+), ERK (extracellular-signal-regulated protein kinase), Akt, Src, focal adhesion kinase and calcineurin pathways has been implicated in mediating multiple VEGF functions, including survival, proliferation, migration, vascular permeability, tubulogenesis, NO and prostanoid synthesis, and gene expression. NO and prostanoids in turn play paracrine and autocrine roles in linking post-receptor signalling to biological functions. Integration between biologically important signalling cascades occurs at several points. Akt and ERK, for example, are key junction points linking together signal transduction involved in survival and NO generation, and proliferation and prostanoid biosynthesis. Together, the multiplicity, functional versatility and integration of VEGF signalling provide a useful framework for understanding the mechanisms underlying the endothelial biological response to this key factor.
...
PMID:VEGF signalling: integration and multi-tasking in endothelial cell biology. 1464 Oct 20

AG 879 has been widely used as a Tyr kinase inhibitor specific for ErbB2 and FLK-1, a VEGF receptor. The IC(50) for both ErbB2 and FLK-1 is around 1 microM. AG 879, in combination of PP1 (an inhibitor specific for Src kinase family), suppresses almost completely the growth of RAS-induced sarcomas in nude mice. In this paper we demonstrate that AG 879 even at 10 nM blocks the specific interaction between the Tyr-kinase ETK and PAK1 (a CDC42/ Rac-dependent Ser/Thr kinase) in cell culture. This interaction is essential for both the RAS-induced PAK1 activation and transformation of NIH 3T3 fibroblasts. However, AG 879 at 10 nM does not inhibit either the purified ETK or PAK1 directly in vitro, suggesting that this drug blocks the ETK-PAK1 pathway by targeting a highly sensitive kinase upstream of ETK. Although the Tyr-kinases Src and FAK are known to activate ETK directly, Src is insensitive to AG 879, and FAK is inhibited by 100 nM AG 879, but not by 10 nM AG879. The structure-function relationship analysis of AG 879 derivatives has revealed that both thio and tert-butyl groups of AG 879, but not (thio) amide group, are essential for its biological function (blocking the ETK-PAK1 pathway), suggesting that through the (thio) amide group, AG 879 can be covalently linked to agarose beads to form a bioactive affinity ligand useful for identifying the primary target of this drug.
...
PMID:The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation. 1473 83

We show that integrin-linked kinase (ILK) stimulates the expression of VEGF by stimulating HIF-1alpha protein expression in a PKB/Akt- and mTOR/FRAP-dependent manner. In human prostate cancer cells, knockdown of ILK expression with siRNA, or inhibition of ILK activity, results in significant inhibition of HIF-1alpha and VEGF expression. In endothelial cells, VEGF stimulates ILK activity, and inhibition of ILK expression or activity results in the inhibition of VEGF-mediated endothelial cell migration, capillary formation in vitro, and angiogenesis in vivo. Inhibition of ILK activity also inhibits prostate tumor angiogenesis and suppresses tumor growth. These data demonstrate an important and essential role of ILK in two key aspects of tumor angiogenesis: VEGF expression by tumor cells and VEGF-stimulated blood vessel formation.
...
PMID:Regulation of tumor angiogenesis by integrin-linked kinase (ILK). 1474 28

To evaluate the effect of Ligustrazine on the expression of VEGF in bone marrow stromal cells (BMSCs) of radiation injured mice and to explore the effect of VEGF on the recovery of hematopoiesis and the mechanism of signal transduction, the protein expression of VEGF, focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK) in BMSCs were assayed by Western blot, the cell cycle and apoptosis rate of BMSCs were tested by flow cytometry. The effect of Ligustrazine on the hematopoiesis was evaluated at the same time. The results showed that the protein expression of VEGF in BMSCs was decreased significantly after irradiation and increased slowly with the time. The value in Ligustrazine-treated group almost reached normal level, but it remained lower than that in control group on day 14. The changes of phosphorylated FAK and MAPK protein expression had the same tendency. After (60)Co gamma-irradiation, the BMSCs were arrested in G0-G1 phase and apoptosis rate increased; these values recovered slowly with the time and remained higher than that in normal control group on day 14. The recovery of these values in Ligustrazine-treated group was sooner than that in irradiated control group, and they almost reached to the normal levels on day 14. It is concluded that irradiation could inhibit the expression of VEGF in BMSCs and induce apoptosis. The Ligustrazine promotes the recovery of bone marrow microenvironment probably by increasing the expression of phosphorylated FAK and MAPK in BMSCs.
...
PMID:[Effect of Ligustrazine on the expression of vascular endothelial growth factor in bone marrow stromal cells of radiation injured mice]. 1498 77

An intact VEGF receptor/PI3K/PKB/Akt signaling cascade protects endothelial cells from apoptotic stress-stimuli and mediates the formation of new blood vessels in pathological conditions such as cancer. Therefore, downregulation of this signaling cascade is of clinical interest for antiangiogenic cancer therapy. In this report, we demonstrate that VEGF controls the protein stability of the serine-threonine kinase PKB/Akt via inhibition of PKB/Akt protein degradation. VEGF deprivation or blockage of the VEGF signal transduction cascade with the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 resulted in a specific decrease of the PKB/Akt protein level and subsequent cellular restimulation with VEGF rescued its stability. Real-time quantitative RT-PCR analysis demonstrated that VEGF does not regulate PKB/Akt gene expression. On the other hand, broad range inhibitors of caspases and the proteasome complex prevented VEGF-dependent downregulation of the PKB/Akt protein level indicating that PKB/Akt protein stability is regulated by VEGF-controlled proteolysis. Inhibition of the VEGF receptor and PKB/Akt-downstream PIK-related mTOR-kinase by rapamycin also neutralized the VEGF-protective effect in an PKB/Akt gene expression-independent way but results in proteolysis-dependent reduction of PKB/Akt protein stability. These results demonstrate a novel regulatory mechanism of the activated VEGF receptor/mTOR-signal transduction pathway to control the protein stability of PKB/Akt and survival threshold in endothelial cells.
...
PMID:Degradation of PKB/Akt protein by inhibition of the VEGF receptor/mTOR pathway in endothelial cells. 1506 12

We have recently shown that quinoxaline 1,4-dioxides (QdNOs) are potent hypoxia selective cytotoxins that modulate hypoxia inducible factor-1alpha (HIF-1alpha) expression. In this study, we evaluated the cytotoxicity, anti-angiogenic, and radiosensitization activities of the two quinoxaline 1,4-dioxides (QdNOs), BPQ and DCQ. Clonogenic survival, Matrigel, and radiosensitization assays were performed in vitro and in vivo using Lewis lung carcinoma (LLC) and EMT-6 mammary adenocarcinoma cells. Transcript and protein levels of HIF-1alpha and VEGF were determined using RT-PCR and Western blotting, respectively. DCQ showed cytotoxic effects under hypoxic conditions for both cell lines. Treatment with either drug inhibited HIF-1alpha and VEGF secretion, with DCQ being more potent than BPQ. DCQ also inhibited the formation of tube-like structures of ECV-304 endothelial cells in Matrigel by 60-80% and significantly reduced neoangiogenesis in vivo. When combined with radiation (200-1000 cGy), DCQ resulted in the death of 100% of LLC or EMT-6 cells. Using the C57BL/6 mouse model, combined treatment with DCQ and radiation delayed the growth of LLC tumors for 17 days and reduced mean tumor volume by 80% at day 20. However, BPQ combined with radiation did not induce significant tumor regression. Histological analyses revealed a significant increase in tissue necrosis in tumors treated by DCQ and radiation. These results indicate a potent anti-angiogenic and radiation modification effect of two quinoxaline dioxides. These findings should stimulate further research in other tumor models as these compounds could have potential clinical applications in cancer therapy.
...
PMID:Quinoxaline 1,4-dioxides are novel angiogenesis inhibitors that potentiate antitumor effects of ionizing radiation. 1506 33


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

---