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

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

Hybridization with cDNA arrays was used to obtain expression profiles of 214 protein-tyrosine kinase, protein-tyrosine phosphatase, dual-specific phosphatase, and other genes for kidney carcinomas (KC) and normal kidney tissues of 34 patients and for seven carcinoma cell lines. Computer analysis revealed three clusters of genes coexpressed in KC. A proliferating-cell gene cluster included MET, VIM, MYC, TOP2A, PCNA, etc. A neoangiogenesis and blood-cell gene cluster included LCK, HCK, FGR, MMP9, CSFR1, VEGF, FLT1, and KDR. A cluster corresponding to normal, differentiated kidney cells included ERBB2 (HER2) for receptor protein-tyrosine kinase, several phosphatase genes (PTPRE, PTPRB, DUSP9), and EGF. The results suggested that MET, DUSP9, PCNA, TOP2A, and VIM may serve as diagnostic and prognostic markers in KC. Tubulin and topoisomerase II were assumed to be promising targets for cell proliferation inhibitors in KC.
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PMID:[Molecular portrait of human kidney carcinomas: the gene expression profiling of protein-tyrosine kinases and tyrosine phosphatases which controlled regulatory signals in the cells]. 1206 34

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.
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PMID:[Gene expression profiles of protein kinases and phosphatases obtained by hybridization with cDNA arrays: molecular portrait of human prostate carcinoma]. 1262 52

Transendothelial migration of monocytes followed by their differentiation into macrophages involves interaction of monocytes with subendothelial matrix. The influence of extracellular matrix on monocyte-macrophage differentiation was studied using an in vitro model system with human PBMC maintained on different matrix protein substrata. Upregulation of macrophage specific marker activities such as endocytosis of modified proteins, changes in expression of cell surface antigen, and production of matrix metalloproteinases was studied. Cells maintained on Fibronectin (Fn) showed significantly higher rate of endocytosis and production of MMP2 and MMP9 when compared to other matrix protein substrata. Immunoblot analysis, ELISA, and zymography showed that Fn-dependent upregulation of MMPs was blocked by antibodies to alpha(5)beta(1) integrin indicating that the Fn effect was mediated by integrins. The Fn effect on mo-mPhi was blocked by genistein and herbimycin. As monocytes differentiate to macrophages there was an increase in the rate of production of Fn. These results indicate the influence of the microenvironment of the cell, particularly Fn, on mo-mPhi differentiation and integrin-mediated downstream signaling through focal adhesion kinase and Src type tyrosine kinase is involved in this.
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PMID:Monocyte macrophage differentiation in vitro: Fibronectin-dependent upregulation of certain macrophage-specific activities. 1711 76

This study used a first-trimester human extravillous trophoblast (EVT) cell line, HTR-8/SVneo, to investigate whether sodium arsenite (AsNaO(2)) reduces human EVT migration and invasion. Treatments with 2.5 microM AsNaO(2) or less (< or =187.3 microg/L), concentrations that are relevant to human exposures in drinking water, were sublethal to HTR-8/SVneo cells. A 72-h exposure to sodium arsenite inhibited cell migration in a concentration-dependent manner at 0.625, 1.25 and 2.5 microM. Significant changes in cell proliferation were not observed under these treatment conditions. Moreover, inhibition of cell migration was unrelated to phosphorylation of focal adhesion kinase Tyr397. In contrast to cell migration, 72-h exposures to AsNaO(2) (0.3125-2.5 microM) had no significant effects on cell invasion, nor on the activities and protein expression of matrix metalloproteinase (MMP) 2 and MMP9. Because trophoblast migration is important for placentation, these results suggest an effect that could contribute to insufficiency of placental development and adverse pregnancy outcomes.
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PMID:Sodium arsenite inhibits migration of extravillous trophoblast cells in vitro. 1764 79

RhoC is a member of the Ras-homologous family of genes which have been implicated in tumorigenesis and tumor progression. However, the exact role of RhoC is controversial and is yet to be clarified. We have examined the effect of RhoC on prostate tumor cells and found that RhoC had no effect on cell proliferation in vitro or on tumor growth in mice. However, RhoC significantly enhanced the metastatic ability of the tumor cells in these animals, suggesting that RhoC affects only the metastasis but not the growth of prostate tumor cells. The results of our immunohistochemical analyses on tumor specimens from 63 patients with prostate cancer indicate that RhoC expression had no significant correlation with Gleason grade. However, the expression of RhoC showed significant positive correlation with both lymph node and distant metastasis, and it was inversely correlated with patient survival. We also found that RhoC significantly augmented the invasion and motility of prostate tumor cells by activating matrix metalloproteinases 2 and 9 (MMP2 and MMP9) in vitro. The results of our antibody array analysis for signal molecules revealed that RhoC significantly activated kinases including mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK), Akt, and Pyk2. Inhibition of Pyk2 kinase blocked the RhoC-dependent activation of FAK, MAPK, and Akt, followed by the suppression of MMP2 and MMP9. Inhibitors of both MAPK and Akt also significantly blocked the activities of these MMPs. Therefore, our results indicate that RhoC promotes tumor metastasis in prostate cancer by sequential activation of Pyk2, FAK, MAPK, and Akt followed by the up-regulation of MMP2 and MMP9, which results in the stimulation of invasiveness of tumor cells.
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PMID:RhoC promotes metastasis via activation of the Pyk2 pathway in prostate cancer. 1879 50

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is involved in several biological processes including cell adhesion, invasion, and angiogenesis. HB-EGF also plays a pivotal role in the progression of ovarian cancer. To investigate the significance of HB-EGF in peritoneal dissemination, we examined the roles of HB-EGF in cell adhesion, invasion, and angiogenesis in ovarian cancer. Through the suppression of focal adhesion kinase and EGF receptor activation, cell adhesive properties mediated by integrin beta(1) were diminished by the inhibition of HB-EGF expression. The reduction of HB-EGF expression attenuated the chemotactic invasive ability and the expression of matrix metalloprotease (MMP)-2 and vascular endothelial growth factor (VEGF), leading to the inhibition of cell invasion and angiogenesis. Suppression of the Snail family, which regulates the epithelial-mesenchymal transition, blocked the cell adhesion properties on extracellular matrices, the chemotactic invasive ability, and the expression of MMP9 and VEGF through the reduction of HB-EGF expression. The volume of tumor burden in the peritoneal cavity was dependent on the expression of HB-EGF. According to these results, HB-EGF contributes to cell adhesion, invasion, and angiogenesis, which are integral to transcoelomic metastasis in ovarian cancer. CRM197, an inhibitor of HB-EGF, resulted in a significant decrease of tumor burden in peritoneal dissemination, accompanied with a reduction in both cellular spreading, when assayed on an extracellular matrix, and invasive ability, when assayed in a chemotaxis chamber, as well as decreased expression of MMP9 and VEGF. Thus, HB-EGF is a mutual validating target in the peritoneal dissemination of ovarian cancer, and CRM197 may be useful as a anticancer agent for advanced ovarian cancer.
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PMID:Heparin-binding epidermal growth factor-like growth factor promotes transcoelomic metastasis in ovarian cancer through epithelial-mesenchymal transition. 1885 47

The PRL (phosphatase of regenerating liver) phosphatases represent a distinct class of protein tyrosine phosphatases, which are implicated in tumorigenesis and metastasis processes. Accumulating evidence indicates that alteration of PRL1 expression affects cell motility and tumor metastasis, although the biochemical pathways regulated by PRL1 remain less well defined. We find that elevated expression of PRL1 increases the levels of the matrix metalloproteinases MMP2 and MMP9. We have studied whether MMP2 and MMP9 are regulated by PRL1 and participate in PRL1-dependent cell migration and invasion. To this end, knockdown or inhibition of MMP2 and MMP9 by either siRNA or a specific small molecule inhibitor blocks PRL1-mediated cell migration and invasion. In addition, we report that upregulation of PRL1 activates the Src kinase through increased Tyr416 phosphorylation, which culminates in the phosphorylation of focal adhesion proteins FAK and p130(Cas), as well as ERK1/2 activation. We provide evidence that both the Src and ERK1/2 pathways contribute to the increased motility of the PRL1 cells. We further demonstrate that Src and ERK1/2 activities are required for the PRL1-induced increase in the levels of MMP2 and MMP9, likely through activation of transcription factors AP1 and Sp1. Accordingly, increased PRL1 expression results in activation of Src and ERK1/2, which stimulates MMP2 and MMP9 production, leading to increased cell migration and invasion.
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PMID:PRL1 promotes cell migration and invasion by increasing MMP2 and MMP9 expression through Src and ERK1/2 pathways. 1919 80

Emodin (1,3,8-trihydroxy-6-methylanthaquinone), an active component present in the root and rhizome of Rheum palmatum L. (Polygonaceae) has anti-bacterial, anti-tumor, diuretic and vasorelaxant effects. However, its mechanism of action on the cell migration and invasion of human neuroblastoma cancer SH-SY5Y cells is not fully understood. In this study, firstly, the effects of emodin on the percentage of viable cells were examined by using MTT assay and it was found that emodin induced dose-and time-dependent inhibition in human neuroblastoma SH-SY5Y cells. Second, the effects of emodin on the migration and invasion of SH-SY5Y cells were examined by using wound assay and matrigel counting and the results showed that emodin suppressed the migration and invasion of SH-SY5Y cells. Third, we examined the effect of emodin on the levels of associated proteins by using Western blotting and the results indicated that emodin inhibited the levels of GRB2, RhoA, HIF-1alpha, VEGF, FAK, iNOS, COX2, p-p38, p-c-jun, MMP2, MMP9 and MMP7 but promoted the levels of PKC, PI3K, MEKK3 and NF-kappaB p65 that led to the inhibition of migration and invasion of SH-SY5Y cells in vitro.
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PMID:Involvement of matrix metalloproteinases on the inhibition of cells invasion and migration by emodin in human neuroblastoma SH-SY5Y cells. 1929 97

During disease progression the cells that comprise solid malignancies undergo significant changes in gene copy number and chromosome structure. Colorectal cancer provides an excellent model to study this process. To indentify and characterize chromosomal abnormalities in colorectal cancer, we performed a statistical analysis of 299 expression and 130 SNP arrays profiled at different stages of the disease, including normal tissue, adenoma, stages 1-4 adenocarcinoma, and metastasis. We identified broad (> 1/2 chromosomal arm) and focal (< 1/2 chromosomal arm) events. Broad amplifications were noted on chromosomes 7, 8q, 13q, 20, and X and broad deletions on chromosomes 4, 8p, 14q, 15q, 17p, 18, 20p, and 22q. Focal events (gains or losses) were identified in regions containing known cancer pathway genes, such as VEGFA, MYC, MET, FGF6, FGF23, LYN, MMP9, MYBL2, AURKA, UBE2C, and PTEN. Other focal events encompassed potential new candidate tumor suppressors (losses) and oncogenes (gains), including CCDC68, CSMD1, POLR1D, and PMEPA1. From the expression data, we identified genes whose expression levels reflected their copy number changes and used this relationship to impute copy number changes to samples without accompanying SNP data. This analysis provided the statistical power to show that deletions of 8p, 4p, and 15q are associated with survival and disease progression, and that samples with simultaneous deletions in 18q, 8p, 4p, and 15q have a particularly poor prognosis. Annotation analysis reveals that the oxidative phosphorylation pathway shows a strong tendency for decreased expression in the samples characterized by poor prognosis.
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PMID:Association of survival and disease progression with chromosomal instability: a genomic exploration of colorectal cancer. 1935 72

The epigenetic silencing of tumor suppressor genes is a crucial event during carcinogenesis and metastasis. Here, in a human genome-wide survey, we identified scavenger receptor class A, member 5 (SCARA5) as a candidate tumor suppressor gene located on chromosome 8p. We found that SCARA5 expression was frequently downregulated as a result of promoter hypermethylation and allelic imbalance and was associated with vascular invasion in human hepatocellular carcinoma (HCC). Furthermore, SCARA5 knockdown via RNAi markedly enhanced HCC cell growth in vitro, colony formation in soft agar, and invasiveness, tumorigenicity, and lung metastasis in vivo. By contrast, SCARA5 overexpression suppressed these malignant behaviors. Interestingly, SCARA5 was found to physically associate with focal adhesion kinase (FAK) and inhibit the tyrosine phosphorylation cascade of the FAK-Src-Cas signaling pathway. Conversely, silencing SCARA5 stimulated the signaling pathway via increased phosphorylation of certain tyrosine residues of FAK, Src, and p130Cas; it was also associated with activation of MMP9, a tumor metastasis-associated enzyme. Taken together, these data suggest that the plasma membrane protein SCARA5 can contribute to HCC tumorigenesis and metastasis via activation of the FAK signaling pathway.
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PMID:Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling. 2003 95


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