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)

Cancer metastasis follows a sequential series of events, and many of the critical steps are distinctly similar to EMT-like transformations that occur during normal embryonic development. A current area of focus is the similarities between how cancer cells interact with the ectopic parenchyma after metastatic spread, and secondary developmental MET events that occur in epithelial tissues that have re-assembled within the embryo from mesenchymal cells. Accumulating evidence suggests a critical role for these secondary events, termed mesenchymal-epithelial transitions (MET) in development and mesenchymal-epithelial reverting transitions (MErT) in cancer. In this situation, metastatic seed cancer cells may inertly become part of the ectopic tissue and therefore surmount the metastatic inefficiencies to which most disseminated cancer cells succumb. Just as a critical EMT event is the downregulation or silencing of E-cadherin, we discuss the role of E-cadherin in cancer-associated MErT at distant metastatic sites and speculate on the implications for the fate of micrometastases that undergo a transition to being E-cadherin positive.
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PMID:E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. 1860 Mar 5

Targeted therapy against epidermal growth factor receptor (EGFR) represents a major therapeutic advance in lung cancer treatment. Somatic mutations of the EGFR gene, most commonly L858R (exon 21) and short in-frame exon 19 deletions, have been found to confer enhanced sensitivity toward the inhibitors gefitinib and erlotinib. We have recently identified an EGFR mutation E884K, in combination with L858R, in a patient with advanced lung cancer who progressed on erlotinib maintenance therapy, and subsequently had leptomeningeal metastases that responded to gefitinib. The somatic E884K substitution appears to be relatively infrequent and resulted in a mutant lysine residue that disrupts an ion pair with residue R958 in the EGFR kinase domain C-lobe, an interaction that is highly conserved within the human kinome as demonstrated by our sequence analysis and structure analysis. Our studies here, using COS-7 transfection model system, show that E884K works in concert with L858R in-cis, in a dominant manner, to change downstream signaling, differentially induce Mitogen-activated protein kinase (extracellular signaling-regulated kinase 1/2) signaling and associated cell proliferation and differentially alter sensitivity of EGFR phosphorylation inhibition by ERBB family inhibitors in an inhibitor-specific manner. Mutations of the conserved ion pair E884-R958 may result in conformational changes that alter kinase substrate recognition. The analogous E1271K-MET mutation conferred differential sensitivity toward preclinical MET inhibitors SU11274 (unchanged) and PHA665752 (more sensitive). Systematic bioinformatics analysis of the mutation catalog in the human kinome revealed the presence of cancer-associated mutations involving the conserved E884 homologous residue, and adjacent residues at the ion pair, in known proto-oncogenes (KIT, RET, MET and FAK) and tumor-suppressor gene (LKB1). Targeted therapy using small-molecule inhibitors should take into account potential cooperative effects of multiple kinase mutations, and their specific effects on downstream signaling and inhibitor sensitivity. Improved efficacy of targeted kinase inhibitors may be achieved by targeting the dominant activating mutations present.
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PMID:Disruption of the EGFR E884-R958 ion pair conserved in the human kinome differentially alters signaling and inhibitor sensitivity. 1901 41

Hepatocyte growth factor (HGF) plays a definitive role in invasive, angiogenic, and metastatic activities of tumor cells by binding to the c-Met receptor. NK4, a competitive antagonist for HGF and the c-Met receptor, prevents tumor cell growth and metastasis via its bifunctional properties to act as an HGF antagonist and angiogenesis inhibitor. In the present study, we investigated the inhibitory effectiveness of NK4 on hematogenous pulmonary metastasis of the CT26 murine colon cancer cell line, focusing on tumor cell adhesion to endothelial cells. In an in vitro adhesion assay, HGF facilitated adhesion of CT26 cells to a murine endothelial cell line (F-2) in a dose-dependent manner. Furthermore, the enhancing effect of HGF on CT26-F-2 cell interaction was blocked by NK4 as well as by anti-HGF antibody. Similarly, HGF-induced phosphorylation of focal adhesion kinase (FAK), downstream of integrin signaling, was reduced by NK4 and by anti-HGF antibody. However, distinct integrin expression on the surface of CT26 cells was not altered by HGF. In an in vivo experimental pulmonary metastasis assay, stable NK4 expression potently decreased the number of pulmonary metastatic foci. The NK4-induced suppression of pulmonary metastasis was partially reversed when HGF was intraperitoneally administered in an adhesive phase. These results suggest that NK4 could act on tumor cells to inhibit CT26 adhesion to endothelial cells by reducing FAK phosphorylation, which is regulated by inside-out HGF/c-Met signaling, and thereby suppress hematogenous pulmonary metastasis.
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PMID:NK4, an HGF antagonist, prevents hematogenous pulmonary metastasis by inhibiting adhesion of CT26 cells to endothelial cells. 1923 48

According to recently published data, the epithelial-mesenchymal transition--a process important for embryonic development, may be involved in many pathological processes such as wound healing, tissue fibrosis or cancer progression. The EMT process in cell is driven by growth factors (EGF, PDGF, HGF) or other signaling proteins such as TGF-beta, sonic hedgehog (Shh), Wnt/beta-catenin and extracellular matrix (ECM) components that may stimulate cellular growth and migration. During cancer progression, the EMT process is necessary to the conversion of benign tumor to aggressive and highly invasive cancer. This is due to complex changes in cancer cells and their microenvironment that lead to dissolution of intracellular junctions and their detachment from basolateral membrane, and changes in the interactions between cancer cells and ECM. The loss of adhesion is accompanied by molecular and morphologic changes in cancer cells that are essential for the phenotypic change from epithelial to mesenchymal one, and the acquirement of higher migration and invasion potential. During the colonization of distant sites, a reverse process mesenchymal-epithelial transition (MET) takes place and metastatic cancer cells again acquire the epithelial phenotype. The EMT in cancer progression is not only specific for cancer cells. It has been suggested that also cells within tumor microenvironment e.g. cancer associated fibroblasts (CAF) are generated in part from normal epithelial cells in EMT process. The understanding of the role of EMT and MET processes in cancer progression and their relationship with cancer stem cells, cancer associated fibroblasts and other stroma cells might lead to the discovery of new, targeted cancer therapies.
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PMID:[Epithelial-mesenchymal transition in cancer progression]. 1982 67

Akt (also known as PKB) signaling orchestrates many aspects of biological functions and, importantly, its deregulation is linked to cancer development. Akt activity is well-known regulated through its phosphorylation at T308 and S473 by PDK1 and mTOrC2, respectively. Although in the last decade the research has been primarily focused on Akt phosphorylation and its role in Akt activation and functions, other posttranslational modifications on Akt have never been reported. Until very recently, a novel posttranslational modification on Akt termed ubiquitination was identified and shown to play an important role in Akt activation. The cancer-associated Akt mutant recently identified in a subset of human cancers displays enhanced Akt ubiquitination, in turn contributing to Akt hyperactivation, suggesting a potential role of Akt ubiquitination in cancers. Thus, this novel posttranslational modification on Akt reveals an exciting avenue that has advanced our current understandings of how Akt signaling activation is regulated.
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PMID:Regulation of Akt signaling activation by ubiquitination. 2008 74

Biocompatible Au nanoparticles with surfaces modified by PEG (polyethylene glycol) were developed in view of possible applications for the enhancement of radiotherapy. Such nanoparticles exhibit preferential deposition at tumor sites due to the enhanced permeation and retention (EPR) effect. Here, we systematically studied their effects on EMT-6 and CT26 cell survival rates during irradiation for a dose up to 10 Gy with a commercial biological irradiator (E(average) = 73 keV), a Cu-Kalpha(1) x-ray source (8.048 keV), a monochromatized synchrotron source (6.5 keV), a radio-oncology linear accelerator (6 MeV) and a proton source (3 MeV). The percentage of surviving cells after irradiation was found to decrease by approximately 2-45% in the presence of PEG-Au nanoparticles ([Au] = 400, 500 or 1000 microM). The cell survival rates decreased as a function of the dose for all sources and nanoparticle concentrations. These results could open the way to more effective cancer irradiation therapies by using nanoparticles with optimized surface treatment. Difficulties in applying MTT assays were also brought to light, showing that this approach is not suitable for radiobiology.
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PMID:Enhancement of cell radiation sensitivity by pegylated gold nanoparticles. 2009 Jan 83

Extract: Approximately one person a minute dies of cancer in the United States. Normalized per population size, this corresponds to a current mortality rate that is essentially identical to what it was in 1950 -- a very counterintuitive finding, given the exceptional progress recorded in the fundamental scientific understanding of malignant disease in the last 50 years. Dominant among the reasons for the unsatisfactory progress in the treatment of cancer is our general inability to treat metastatic colonies, when surgical intervention and radiation therapy are no longer available options. Systemic injection with chemical and biological agents is then the choice, with the yet-unsolved problem of selectivity in the intervention on cancer cell population, or the ability to kill cancer without causing intolerable levels of unwanted collateral effects on the patient. This treatment selectivity problem breaks down into three major, related components: the ability for the therapeutic substances to reach the cancer lesion, to recognize it as the target of its action, and to perform the therapeutic intervention solely at the site of the lesion. Many approaches have been developed to address these questions, and have met with different degrees of success. Particularly promising are the recent clinical advances recorded in the field of the so-called molecularly targeted therapies, which intervene in an exquisitely selective fashion on cancer-associated biological features, such as mutations in the receptor of epidermal growth factor in cancers of epithelial origin, or the activation of the BCR-ABL tyrosine kinase pathway in chronic myelogenous leukemia.
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PMID:Nanotechnology-enabled medicine. 2070 73

Kinases play key roles in cell signaling and represent major targets for drug development, but the regulation of their activation and their associations with health and disease have not been systematically analyzed. Here, we carried out a bioinformatic analysis of the expression levels of 459 human kinase genes in 5681 samples consisting of 44 healthy and 55 malignant human tissues. Defining the tissues where the kinase genes were transcriptionally active led to a functional genomic taxonomy of the kinome and a classification of human tissues and disease types based on the similarity of their kinome gene expression. The co-expression network around each of the kinase genes was defined in order to determine the functional context, i.e. the biological processes that were active in the cells and tissues where the kinase gene was expressed. Strong associations for individual kinases were found for mitosis (69 genes, including AURKA and BUB1), cell cycle control (73 genes, including PLK1 and AURKB), DNA repair (49 genes, including CHEK1 and ATR), immune response (72 genes, including MATK), neuronal (131 genes, including PRKCE) and muscular (72 genes, including MYLK2) functions. We then analyzed which kinase genes gain or lose transcriptional activity in the development of prostate and lung cancers and elucidated the functional associations of individual cancer associated kinase genes. In summary, we report here a systematic classification of kinases based on the bioinformatic analysis of their expression in human tissues and diseases, as well as grouping of tissues and tumor types according to the similarity of their kinome transcription.
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PMID:Analysis of kinase gene expression patterns across 5681 human tissue samples reveals functional genomic taxonomy of the kinome. 2115 26

The dynamic turnover of integrin-mediated adhesions is important for cell migration. Paxillin is an adaptor protein that localizes to focal adhesions and has been implicated in cell motility. We previously reported that calpain-mediated proteolysis of talin1 and focal adhesion kinase mediates adhesion disassembly in motile cells. To determine whether calpain-mediated paxillin proteolysis regulates focal adhesion dynamics and cell motility, we mapped the preferred calpain proteolytic site in paxillin. The cleavage site is between the paxillin LD1 and LD2 motifs and generates a C-terminal fragment that is similar in size to the alternative product paxillin delta. The calpain-generated proteolytic fragment, like paxillin delta, functions as a paxillin antagonist and impairs focal adhesion disassembly and migration. We generated mutant paxillin with a point mutation (S95G) that renders it partially resistant to calpain proteolysis. Paxillin-deficient cells that express paxillin S95G display increased turnover of zyxin-containing adhesions using time-lapse microscopy and also show increased migration. Moreover, cancer-associated somatic mutations in paxillin are common in the N-terminal region between the LD1 and LD2 motifs and confer partial calpain resistance. Taken together, these findings suggest a novel role for calpain-mediated proteolysis of paxillin as a negative regulator of focal adhesion dynamics and migration that may function to limit cancer cell invasion.
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PMID:Calpain-mediated proteolysis of paxillin negatively regulates focal adhesion dynamics and cell migration. 2127 Jan 28

Drosophila modeling can be effectively used for comprehensive and refined analysis of tumorigenesis, including the discovery of therapeutic anti-cancer drugs and their testing [1]. The Drosophila lgl gene was the first animal tumor suppressor found and the first tumor-associated gene encoding cytoplasmic protein. We compared the gene ontology of two cancer associated cytoplasmic proteins, Lgl and DFak56 (ortholog of human focal adhesion kinase, FAK). On the molecular level, both Lgl and FAK are involved in protein binding and the formation of macromolecular complexes mediated by phosphorylation in specific sites. On the cellular level, Lgl and FAK participate in cytoskeletal structure/dynamics, cell/ESM and cell to cell adhesion, and cell/tissue polarity. The biological processes of both genes comprise protein transport, cell signaling, cell motility and proliferation. Surprisingly, we found that diverse lgl*- null variants are widespread in lgl*-/lgl+ haplozygotic state in distant populations. To address this paradox, we found that under permanent thermal stress the developmental viability and the life span of lgl*-/lgl+ heterozygotes increased compared to the control flies. The stress-protective haplo-adaptive effect was maternally mediated and sex-specific, as males are more sensitive. The exposure of virgin haplozygotic females with one functional lgl allele to pulse thermal stress at successive stages of oogenesis showed that the germ line - early oocyte stage appeared most sensitive. Pulse heating of this stage in the parental females with one lgl dose resulted in a transgenerational haplo-adaptive effect on the viability and life span of the next generation animals. These data are important for a comprehensive knowledge of cancer-associated gene effects and evaluation of the aftermath of cancer therapy.
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PMID:Cell contact/adhesion proteins Lgl and DFak56: tumorigenic and whole-organism vital effects studied in Drosophila. 2170 8


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