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)

c-Src is a proto-oncogene involved in the genesis of and invasion by many cancers. This non-receptor tyrosine kinase also plays a crucial role in bone homeostasis, since inhibition or deletion of c-Src impairs the function of osteoclasts, the bone resorbing cells. It is thus conceivable that c-Src could be a suitable target for the pharmacological treatment of cancers, skeletal metastases and diseases of bone loss, such as osteoporosis. The pyrrolo-pyrimidines CGP77675 and CGP76030 proved to be effective in preventing bone loss in animal models, while the effect of AZD0530, a dually active inhibitor of c-Src and Bcr-ABL, on bone resorption, has been tested in a Phase I clinical trials with promising results. As far as the metastatic bone disease is concerned, c-Src inhibitors could potentially have inhibitory effects both on osteoclasts and on tumour cells, and could disrupt the vicious circle established between these cell types in the bone microenvironment. In accord with this idea, CGP76030 is able to reduce the incidence of osteolytic lesions and of visceral metastases, and to suppress morbidity and lethality in a bone metastasis mouse model without obvious adverse effects. The purine-based c-Src inhibitor AP23451 and the dual c-Src/Abl inhibitors AP22408 and AP23236 proved efficacious in reducing bone metastases in preclinical studies. These results open a new avenue for the development of innovative therapies for the treatment of bone metastatic disease.
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PMID:Inhibition of protein kinase c-Src as a therapeutic approach for cancer and bone metastases. 1839 92

Migration and adhesion of tumor cells are essential prerequisites for the formation of metastases in malignant diseases. Protein kinase C (PKC) has been shown to regulate cell migration, adhesion and proliferation. In order to identify a connection between PKC isoforms and tumor progression in renal cell carcinoma (RCC), the influence of PKC isoforms on cell migration, adhesion and proliferation and possible influences of the activity of integrins and focal adhesion kinase (FAK) were analyzed in RCC cells. The experiments were performed in the RCC cell line CCF-RC1 after pre-incubation of the cells with the PKC inhibitors GF109203X, GO6976, RO31-8220 and rottlerin. Cell migration and adhesion were assessed through chemotaxis analysis and adhesion to an endothelial monolayer, respectively. Cell proliferation was analysed by a BrdU incorporation assay. The expression and activity of beta1 integrins and FAK were analysed by Western blot analysis. GF109203X reduced cell migration to 69%, the activity of beta1 integrins to 63% and FAK expression to 82% compared to untreated cells. Rottlerin reduced cell migration in a concentration-dependent manner to 36%, cell proliferation to 81%, expression and activity of beta1 integrins to 72 and 79%, and expression and activity of FAK to 56 and 76% of untreated cells, respectively. RO31-8220 also reduced the expression and activity of beta1 integrins as well as the expression of FAK to 84, 66 and 66% of untreated cells, respectively. GO6976 reduced the expression of FAK to 60% of untreated cells. Cell migration was only slightly reduced by GO6976 to 84% of untreated cells, and cell adhesion remained uninfluenced. These findings show a critical role of PKCdelta in the regulation of tumor cell migration, which seems to be caused by affecting the expression and activity of beta1 integrins and FAK. These results can provide a basis for new strategies in preventing metastases of renal cell carcinoma.
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PMID:Migration of renal carcinoma cells is dependent on protein kinase Cdelta via beta1 integrin and focal adhesion kinase. 1842 41

The ubiquitously expressed Src tyrosine kinases (c-Src, c-Yes, and c-Fyn) regulate intestinal cell growth and differentiation. Src activity is also elevated in the majority of malignant and premalignant tumors of the colon. The development of fibroblasts with the three ubiquitously expressed kinases deleted (SYF cells) has identified the role of Src proteins in the regulation of actin dynamics associated with increased cell migration and invasion. Despite this, unexpectedly nothing is known about the role of the individual Src kinases on intestinal cell cytoskeleton and/or cell migration. We have previously reported that villin, an epithelial cell-specific actin-modifying protein that regulates actin reorganization, cell morphology, cell migration, cell invasion, and apoptosis, is tyrosine-phosphorylated. In this report using the SYF cells reconstituted individually with c-Src, c-Yes, c-Fyn, and wild type or phosphorylation site mutants of villin, we demonstrate for the first time the absolute requirement for c-Src in villin-induced regulation of cell migration. The other major finding of our study is that contrary to previous reports, the nonreceptor tyrosine kinase, Jak3 (Janus kinase 3), does not regulate phosphorylation of villin or villin-induced cell migration and is, in fact, not expressed in intestinal epithelial cells. Further, we identify SHP-2 and PTP-PEST (protein-tyrosine phosphatase proline-, glutamate-, serine-, and threonine-rich sequence) as negative regulators of c-Src kinase and demonstrate a new function for these phosphatases in intestinal cell migration. Together, these data suggest that in colorectal carcinogenesis, elevation of c-Src or down-regulation of SHP-2 and/or PTP-PEST may promote cancer metastases and invasion by regulating villin-induced cell migration and cell invasion.
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PMID:Potential molecular mechanism for c-Src kinase-mediated regulation of intestinal cell migration. 1848 83

The phosphatidylcholine-using phospholipase D (PLD) isoform PLD2 is widely expressed in mammalian cells and is activated in response to a variety of promitogenic agonists. In this study, active and inactive hemagglutinin-tagged human PLD2 (HA-PLD2) constructs were stably expressed in an EL4 cell line lacking detectable endogenous PLD1 or PLD2. The overall goal of the study was to examine the roles of PLD2 in cellular signal transduction and cell phenotype. HA-PLD2 confers PLD activity that is activated by phorbol ester, ionomycin, and okadaic acid. Proliferation and Erk activation are unchanged in cells transfected with active PLD2; proliferation rate is decreased in cells expressing inactive PLD2. Basal tyrosine phosphorylation of focal adhesion kinase (FAK) is increased in cells expressing active PLD2, as is phosphorylation of Akt; inactive PLD2 has no effect. Expression of active PLD2 is associated with increased spreading and elongation of cells on tissue culture plastic, whereas inactive PLD2 inhibits cell spreading. Inactive PLD2 also inhibits cell adhesion, migration, and serum-induced invasion. Cells expressing active PLD2 form metastases in syngeneic mice, as do the parental cells; cells expressing inactive PLD2 form fewer metastases than parental cells. In summary, active PLD2 enhances FAK phosphorylation, Akt activation, and cell invasion in EL4 lymphoma cells, whereas inactive PLD2 exerts inhibitory effects on adhesion, migration, invasion, and tumor formation. Overall, expression of active PLD2 enhances processes favorable to lymphoma cell metastasis, whereas expression of inactive PLD2 inhibits metastasis.
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PMID:Effects of active and inactive phospholipase D2 on signal transduction, adhesion, migration, invasion, and metastasis in EL4 lymphoma cells. 1852 40

EMT and MET in carcinoma-clinical observations, regulatory pathways and new models.
Clin Exp Metastasis 2008
PMID:EMT and MET in carcinoma--clinical observations, regulatory pathways and new models. 1856 98

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.
Clin Exp Metastasis 2008
PMID:E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. 1860 Mar 5

NSCLC cells with a mesenchymal phenotype have shown a marked reduction in sensitivity to EGFR inhibitors, though the molecular rationale has remained obscure. Here we find that in mesenchymal-like tumor cells both tyrosine phosphorylation of EGFR, ErbB2, and ErbB3 signaling networks and expression of EGFR family ligands were decreased. While chronic activation of EGFR can promote an EMT-like transition, once having occurred EGFR family signaling was attenuated. We investigated the mechanisms by which mesenchymal-like cells bypass EGFR signaling and acquire alternative routes of proliferative and survival signaling. Mesenchymal-like NSCLC cells exhibit aberrant PDGFR and FGFR expression and autocrine signaling through these receptors can activate the MEK-ERK and PI3K pathways. Selective pharmacological inhibition of PDGFR or FGFR receptor tyrosine kinases reduced cell proliferation in mesenchymal-like but not epithelial NSCLC cell lines. A metastable, reversible EMT-like transition in the NSCLC line H358 was achieved by exogenous TGFbeta, which served as a model EMT system. The H358/TGFbeta cells showed many of the attributes of established mesenchymal-like NSCLC cells including a loss of cell-cell junctions, a loss of EGF-family ligand expression, a loss of ErbB3 expression, increased EGFR-independent Mek-Erk pathway activation and reduced sensitivity to EGFR inhibition. Notably an EMT-dependent acquisition of PDGFR, FGFR and TGFbeta receptors in H358/TGFbeta cells was also observed. In H358/TGFbeta cells both PDGFR and FGFR showed functional ligand stimulation of their intrinsic tyrosine kinase activities. The findings of kinase switching and acquired PDGFR and FGFR signaling suggest investigation of new inhibitor combinations to target NSCLC metastases.
Clin Exp Metastasis 2008
PMID:Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy. 1869 32

In metastatic cancer, high expression levels of vitronectin (VN) receptors (integrins), FAK, and ERK5 are reported. We hypothesized that integrin-mediated ERK5 activation via FAK may play a pivotal role in cell adhesion, motility, and metastasis. ERK5 and FAK phosphorylation when metastatic MDA-MB-231 and PC-3 cells were plated on VN was enhanced. Further experiments showed co-immunoprecipitation of integrins beta1, alpha V beta 3, or alpha V beta 5 with ERK5 and FAK. To gain better insight into the mechanism of ERK5, FAK, and VN receptors in cell adhesion and motility, we performed loss-of-function experiments using integrin blocking antibodies, and specific mutants of FAK and ERK5. Ectopic expression of dominant negative ERK5/AEF decreased ERK5 and FAK (Y397) phosphorylation, cell adhesion, and haptotactic motility (micromotion) on VN. Additionally, DN FAK expression attenuated ERK5 phosphorylation, cell adhesion, and motility. This study documents the novel finding that in breast and prostate cancer cells, ERK5 is a critical target of FAK in cell adhesion signaling. Using different cancer cells, our experiments unveil a novel mechanism by which VN receptors and FAK could promote cancer metastasis via ERK5 activation.
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PMID:A novel role of ERK5 in integrin-mediated cell adhesion and motility in cancer cells via Fak signaling. 1908 93

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.
Clin Exp Metastasis 2009
PMID:NK4, an HGF antagonist, prevents hematogenous pulmonary metastasis by inhibiting adhesion of CT26 cells to endothelial cells. 1923 48

Sporadic colorectal cancer is a major cause of death worldwide. Development takes place in a sequential manner from benign adenomas leading to carcinomas. In 90% of tumours bearing a Ras mutation it is Ki-Ras that is mutated. We have developed a model cell system to study oncogenic Ras mutations in colorectal cancer cell lines. In this analysis two Caco-2 derived cell lines expressing Ha-RasV12 (Caco-H) and Ki-RasV12 (Caco-K), respectively, have been used in large-scale microarray profiling against a Caco-2 control. This was carried out using an Illumina microarray containing 24,000 genes. Genes have been identified as differentially expressed in each isoform as well as commonly regulated. In addition the Caco-H cell line has a strong epithelial-mesenchymal phenotype that is reflected in many of its differentially expressed genes. These include the known EMT markers Vimentin, E-cadherin and Slug. Other genes of interest include several members of the Claudin family, Forkhead transcription factors and GATA-factors. The Caco-K cell line shows strong downregulation of the Dickkopf transcriptional repressor implicating it in WNT signalling. Pathway and functional analysis has also been carried out for the differentially expressed genes for both cell lines using Ingenuity software. This genome wide microarray analysis has provided a molecular signature for EMT in a Caco-H colon cancer cell line. It has also revealed a number of key genes for Caco-K expression and identified novel markers for Ras expression that have been verified by PCR analysis.
Clin Exp Metastasis 2009
PMID:A molecular signature for Epithelial to Mesenchymal transition in a human colon cancer cell system is revealed by large-scale microarray analysis. 1934 May 93


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