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)

The mechanisms involved in the epithelial to mesenchymal transition (EMT) are integrated in concert with master developmental and oncogenic pathways regulating in tumor growth, angiogenesis, metastasis, as well as the reprogrammation of specific gene repertoires ascribed to both epithelial and mesenchymal cells. Consequently, it is not unexpected that EMT has profound impacts on the neoplastic progression, patient survival, as well as the resistance of cancers to therapeutics (taxol, vincristine, oxaliplatin, EGF-R targeted therapy and radiotherapy), independent of the "classical" resistance mechanisms linked to genotoxic drugs. New therapeutic combinations using genotoxic agents and/or EMT signaling inhibitors are therefore expected to circumvent the chemotherapeutic resistance of cancers characterized by transient or sustained EMT signatures. Thus, targeting critical orchestrators at the convergence of several EMT pathways, such as the transcription pathways NF-kappaB, AKT/mTOR axis, MAPK, beta-catenin, PKC and the AP-1/SMAD factors provide a realistic strategy to control EMT and the progression of human epithelial cancers. Several inhibitors targeting these signaling platforms are already tested in preclinical and clinical oncology. In addition, upstream EMT signaling pathways induced by receptor and nonreceptor tyrosine kinases (e.g. EGF-R, IGF-R, VEGF-R, integrins/FAK, Src) and G-protein-coupled receptors (GPCR) constitute practical options under preclinical research, clinical trials or are currently used in the clinic for cancer treatment: e.g. small molecule inhibitors (Iressa: targeting selectively the EGF-R; CP-751,871, AMG479, NVP-AEW541, BMS-536924, PQIP, AG1024: IGF-R; AZD2171, ZD6474: VEGF-R; AZD0530, BMS-354825, SKI606: Src; BIM-46174: GPCR; rapamycin, CCI-779, RAD-001: mTOR) and humanized function blocking antibodies (Herceptin: ErbB2; Avastin: VEGF-A; Erbitux: EGF-R; Abegrin: alphavbeta3 integrins). We can assume that silencing RNA and adenovirus-based gene transfer of therapeutic miR and dominant interferring expression vectors targeting EMT pathways and signaling elements will bring additional ways for the treatment of epithelial cancers. Identification of the factors that initiate, modulate and effectuate EMT signatures and their underlying upstream oncogenic pathways should provide the basis of more efficient strategies to fight cancer progression as well as genetic and epigenetic forms of drug resistance. This goal can be accomplished using global screening of human clinical tumors by EMT-associated cDNA, proteome, miRome, and tissue arrays.
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PMID:Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. 1871 6

Bone sialoprotein (BSP) is an abundant protein in the extracellular matrix of bone that has been suggested to have several different physiological functions, including the nucleation of hydroxyapatite (HA), promotion of cell attachment and binding of collagen. Studies in our lab have demonstrated that increased expression of BSP in osteoblast cells can increase expression of the osteoblast-related genes Runx2 and Osx as well as alkaline phosphatase and osteocalcin and increase matrix mineralization. To determine the molecular mechanisms responsible for the BSP-mediated increase in osteoblastic differentiation, several functional domain mutants of BSP were expressed in primary rat bone osteoblastic cells, including the contiguous glutamic acid sequences (polyGlu) and the arginine-glycine-aspartic acid (RGD) motif. Markers of osteoblast differentiation, including matrix mineralization and alkaline phosphatase staining, were increased in cells expressing BSP mutants of the polyGlu sequences but not in cells expressing RGD-mutated BSP. We also determined the dependence on integrin-associated pathways in promoting BSP-mediated differentiation responses in osteoblasts by demonstrating the activation of focal adhesion kinase, MAP kinase-associated proteins ERK1/2, ribosomal s6 kinase 2 and the AP-1 protein cFos. Thus, the mechanism regulating osteoblast differentiation by BSP was determined to be dependent on integrin-mediated intracellular signaling pathways.
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PMID:Activation of the mitogen-activated protein kinase pathway by bone sialoprotein regulates osteoblast differentiation. 1872 50

Overexpression and activation of the steroid receptor coactivator amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) have been shown to have a critical role in oncogenesis and are required for both steroid and growth factor signaling in epithelial tumors. Here, we report a new mechanism for activation of SRC coactivators. We demonstrate regulated tyrosine phosphorylation of AIB1/SRC-3 at a C-terminal tyrosine residue (Y1357) that is phosphorylated after insulin-like growth factor 1, epidermal growth factor, or estrogen treatment of breast cancer cells. Phosphorylated Y1357 is increased in HER2/neu (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2) mammary tumor epithelia and is required to modulate AIB1/SRC-3 coactivation of estrogen receptor alpha (ERalpha), progesterone receptor B, NF-kappaB, and AP-1-dependent promoters. c-Abl (v-Abl Abelson murine leukemia viral oncogene homolog 1) tyrosine kinase directly phosphorylates AIB1/SRC-3 at Y1357 and modulates the association of AIB1 with c-Abl, ERalpha, the transcriptional cofactor p300, and the methyltransferase coactivator-associated arginine methyltransferase 1, CARM1. AIB1/SRC-3-dependent transcription and phenotypic changes, such as cell growth and focus formation, can be reversed by an Abl kinase inhibitor, imatinib. Thus, the phosphorylation state of Y1357 can function as a molecular on/off switch and facilitates the cross talk between hormone, growth factor, and intracellular kinase signaling pathways in cancer.
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PMID:Tyrosine phosphorylation of the nuclear receptor coactivator AIB1/SRC-3 is enhanced by Abl kinase and is required for its activity in cancer cells. 1876 37

The metastatic nature of breast cancer has been well recognized, yet the mechanisms through which breast cancer cells acquire their invasive properties have not been clearly elucidated. Our previous study indicates that BMP-6 restores E-cadherin-mediated EMT through repressing deltaEF1 in breast cancer. However, the mechanism by which BMP-6 regulates deltaEF1 expression remains unclear. In this study, we confirmed the significant role of BMP-6 in inhibiting MDA-MB-231 migration through decreasing deltaEF1 expression which subsequently relieves deltaEF1-mediated invasion. The inhibitory effect of BMP-6 through deltaEF1 regulation was supported by an inverse correlation of BMP-6/miR-192 and deltaEF1 expressions observed in both MDA-MB-231 and MCF-7 cells and clinical tumor specimens. Moreover, BMP-6 treatment or miR-192 transfection decreased the reporter activity of the deltaEF1 3'-UTR-luc, validating that deltaEF1 is a target of miR-192. Meanwhile, we also found that BMP-6 acted as a potent transcriptional repressor of the human deltaEF1 promoter. Mutation of the AP-1 binding site on this promoter abolished BMP-6-induced transrepression of deltaEF1. Depletion of BMP-6 expression by RNAi resulted in a significant increase in the promoter activity of deltaEF1. Our study has provided novel findings of a dual mechanism for BMP-6-regulated deltaEF1 expression in breast cancer cells, involving cross-talks between AP-1-mediated transcriptional repression and miRs-mediated translational inhibition.
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PMID:Dual mechanism of deltaEF1 expression regulated by bone morphogenetic protein-6 in breast cancer. 1880 2

One of the possible mechanisms of the angiogenic effect of laminin (Ln) involves modulation of the biological activity of VEGF by regulating poly ADP ribosylation (PAR). PAR modification of VEGF was found to be related with the changes in NAD(+) associated with a shift in LDH isoenzymes. Further investigations on LDH gene expression in HUVECs suggested that the effect of Ln was mediated through alpha(6)beta(4) integrin-FAK-src-p38 MAPK pathway. This was evidenced by (a) co-immunoprecipitation of beta(4) integrin with alpha(6) subunit, (b) activation by tyrosine phosphorylation of beta(4) integrin and FAK, (c) co-immunoprecipitation of FAK with beta(4) and with adapter protein, src, (d) increased phosphorylation of p38 MAPK in cells maintained on Ln and (e) blocking of effect of Ln on LDH-B gene expression by inhibition of p38 MAPK. Increase in serine phosphorylation of c-fos and c-jun and higher levels of heterodimers of AP-1 in the nucleus in cells maintained on Ln suggested activation of AP-1 transcription factor. These results provide evidence for modulation of endothelial cell function relevant to angiogenesis by Ln through alpha(6)beta(4) integrin.
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PMID:Endothelial cell-laminin interaction: modulation of LDH expression involves alpha6beta4 integrin-FAK-p38MAPK pathway. 1881 27

T cell responses are determined by the environment in which antigen is encountered. In the absence of proper costimulation, anergizing stimuli induce the activation of a specific program of gene expression. Proteins encoded by these genes impose a state of functional unresponsiveness in anergic T cells through the activation of different mechanisms that include dampening of the T cell receptor signaling and direct inhibition of cytokine expression. Anergy can be reversed by stimulating T cells in the presence of interleukin (IL-)2. Signaling through the IL-2 receptor has been shown to activate mTOR, which plays an important role in the integration of signals that determine the fate of T cells. The mechanisms underlying the IL-2-dependent regulation of T cell tolerance are still not fully elucidated. In this study we show that IL-2 receptor signaling mediated through JAK3 and mTOR inhibits the expression of anergy-inducing genes independently of any effect on cell cycle progression. Interestingly, we also show that this effect is likely due to changes on the levels of AP-1 activation induced by IL-2 receptor signaling in T cells. Our data identifies a mechanism that can explain how IL-2 may prevent or reverse the establishment of anergy in T cells and, therefore, helps to understand how the cytokine environment can be determinant to shape the outcome of T cell responses - tolerance or activation - when antigen is encountered.
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PMID:IL-2 signaling prevents T cell anergy by inhibiting the expression of anergy-inducing genes. 1899 Apr 50

Our laboratories have previously identified the alpha7 nAChR-JAK2 pathway as playing a central role in nicotine-induced neuroprotection. We have also reported that the angiotensin II (Ang II) AT(2) receptor induced activation of SHP-1 induces the tyrosine dephosphorylation of JAK2 that results in a complete neutralization of the alpha7 nAChR-JAK2 pro-survival cascade. In this study, we investigated the effects of inhibiting the alpha7 nAChR-JAK2 pro-survival cascade on the nicotine-induced production of the survival factor Bcl-2 and the transcriptional activation of NF-kappaB, AP-1, STAT1, STAT3, and STAT5. We report that nicotine induced the production of Bcl-2 and increased the transcriptional activation of NF-kappaB, AP-1, STAT1, and STAT3, and with the exception of AP-1, the other transcription factors (NF-kappaB, STAT1, and STAT3) were significantly reduced by JAK2 inhibition. We also demonstrate that, via transfection of either Bcl-2 antisense or NF-kappaB, STAT1 and STAT3 transcription factor decoys oligodeoxyribonucleotides into PC12 cells, nicotine induces its neuroprotection in PC12 cells via activation of the alpha7 nAChR-JAK2-(NF-kappaB; STAT3)-Bcl-2 pro-survival pathway. Finally, the neuroprotective nicotine-induced production of Bcl-2 appears to fully counteract the Abeta (1-42)-induced apoptosis of PC12 cells by blocking Abeta (1-42)-induced mitochondrial release of cytosolic cytochrome C.
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PMID:Convergence of alpha 7 nicotinic acetylcholine receptor-activated pathways for anti-apoptosis and anti-inflammation: central role for JAK2 activation of STAT3 and NF-kappaB. 1906 68

IFNgamma is strongly related to mast cell-associated diseases. There are many reports that IFNgamma inhibits mast cell degranulation. However, inflammatory cytokine production in mast cells stimulated with IFNgamma has not yet been clearly investigated. Therefore, we aimed to investigate the signaling pathways of cytokine production in mast cells stimulated with IFNgamma. Human mast cell line (HMC)-1 or mouse bone marrow-derived mast cells (BMMCs) were stimulated with IFNgamma (100 units) for time periods indicated. Expressions of proteins and mRNAs of cytokines were determined by ELISA and RT-PCR, respectively, activities of MAP kinases, PKC, JAK1/2, and STAT1 on tyrosine 701 and serine 727 by immunoblotting, the DNA-binding activity of the transcription factors by electrophoretic mobility shift assay. IFNgamma-stimulated mast cells showed increase in expressions of proteins and mRNAs of inflammatory cytokines, phosphorylations of MAP kinases, PKCalpha and betaI, JAK1/2, and STAT1 on tyrosine 701 and serine 727. JAK inhibitor or PKC inhibitors inhibited the phosphorylations of p38 kinase, STAT1 on serine 727, and activities of NF-kappaB and AP-1 compared to IFNgamma stimulation alone. These data suggest that IFNgamma-stimulated mast cells induce productions of inflammatory cytokines through PKC/p38/NF-kappaB and AP-1 pathways, not through classical JAK/STAT1 pathway, in both mast cells.
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PMID:Cytokine production through PKC/p38 signaling pathways, not through JAK/STAT1 pathway, in mast cells stimulated with IFNgamma. 1923 Dec 33

Bone sialoprotein (BSP) is a secreted glycoprotein found in mineralized tissues however, BSP is aberrantly expressed in a variety of osteotropic tumors. Elevated BSP expression in breast and prostate primary carcinomas is directly correlated with increased bone metastases and tumor progression. In this study, the intracellular signaling pathways responsible for BSP-induced migration and tumor survival were examined in breast and prostate cancer cells (MDA-MB-231, Hs578T and PC3). Additionally, the effects of exogenous TGF-beta1 and EGF, cytokines associated with tumor metastasis and present in high-levels in the bone microenvironment, were examined in BSP-expressing cancer cells. Expression of BSP but not an integrin-binding mutant (BSP-KAE) in tumor cell lines resulted in increased levels of alpha(v)-containing integrins and number of mature focal adhesions. Adhesion of cells to recombinant BSP or the expression of BSP stimulated focal adhesion kinase and ERK phosphorylation, as well as activated AP-1-family proteins. Activation of these pathways by BSP expression increased the expression of the matrix metalloproteinases MMP-2, MMP-9, and MMP-14. The BSP-mediated activation of the FAK-associated pathway resulted in increased cancer cell invasion in a Matrigel-coated Boyden-chamber assay and increased cell survival upon withdrawal of serum. Addition of EGF or TGF-beta1 to the BSP-expressing cell lines significantly increased ERK phosphorylation, AP-1 activation, MMP-2 expression, cell migration and survival compared to untreated cells expressing BSP. This study thus defines the cooperative mechanisms by which BSP can enhance specific factors associated with a metastatic phenotype in tumor cell lines, an effect that is increased by circulating TGF-beta1 and EGF.
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PMID:Bone sialoprotein stimulates focal adhesion-related signaling pathways: role in migration and survival of breast and prostate cancer cells. 1949 34

IL-24 is a member of the IL-10 family of cytokines. In this study, we investigated IL-24 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for IL-24 expression in human colonic subepithelial myofibroblasts (SEMFs). IL-24 expression in the IBD mucosa was evaluated by immunohistochemical methods. IL-24 mRNA and protein expression was determined by real-time PCR and ELISA, respectively. AP-1 and C/EBP DNA-binding activity and IL-24 promoter activity were assessed by EMSA analysis and a reporter gene assay, respectively. IL-24 mRNA expression was significantly elevated in active lesions from patients who have ulcerative colitis and Crohn's disease. Colonic SEMFs were identified as a major source of IL-24 in the mucosa. IL-1beta, but not IL-17A, TNF-alpha, or IFN-gamma, significantly enhanced IL-24 mRNA and protein expression in isolated colonic SEMFs. The IL-1beta-induced IL-24 mRNA expression was mediated by the activation of the transcription factors, AP-1 and C/EBP-beta. Induction of IL-24 mRNA stabilization was also involved in the effects of IL-1beta. IL-24 induced JAK1/STAT-3 phosphorylation and SOCS3 expression in HT-29 colonic epithelial cells. IL-24 did not modulate the proliferation of HT-29 cells, but significantly increased the mRNA expression of membrane-bound mucins (MUC1, MUC3, and MUC4). IL-24 derived from colonic SEMFs acts on colonic epithelial cells to elicit JAK1/STAT-3 activation and the expression of SOCS3 and mucins, supporting their suppressive effects on mucosal inflammation in IBD.
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PMID:Expression of IL-24, an activator of the JAK1/STAT3/SOCS3 cascade, is enhanced in inflammatory bowel disease. 1953 21


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