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 signaling pathways of endothelin-1-induced contraction, including the role of protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), protein kinase C (PKC) and RhoA/Rho-kinase were studied using rabbit basilar arteries by isometric tension and Western blot. The following results were observed: (1) endothelin-1 produced phosphorylation of MAPK and RhoA and contraction by activation of endothelin-A but not endothelin-B receptors; (2) MAPK inhibitors, PD 98059 and U0126, PTK inhibitor, genistein, Src kinase inhibitor, damnacanthal, and Janus tyrosine kinase (JAK2) inhibitor, AG-490, abolished endothelin-1-induced contraction and MAPK immunoreactivity; (3) PTK inhibitor, staurosporine, and phosphatidylinositol 3-kinase (PI- 3K) inhibitor wortmannin abolished endothelin-1 induced contraction but not MAPK immunoreactivity; (4) Rho-kinase inhibitor, Y-27632, reduced endothelin-1-induced contraction; (5) PI-3K inhibitor, wortmannin, but not PKC and PTK inhibitors, reduced endothelin-1-induced RhoA activation; (6) endothelin-1 increased the level of myosin light chain (MLC) phosphorylation, and Rho-kinase inhibitor, Y-27632, reduced the effect of endothelin- 1 on MLC phosphorylation. This study demonstrated that three signaling pathways Src-JAK2-PTK-MAPK, PI-3K-RhoA-Rhokinase- MLC and PKC all contribute to endothelin-1-induced contraction in the rabbit basilar artery. MAPK is downstream of PTK, Src and JAK pathways. PI-3 kinase and MLC might be the upstream and downstream factors of RhoA activation.
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PMID:Signal transduction of ET-1 in contraction of cerebral arteries. 1583 90

The retractile type IV pilus participates in a number of fundamental bacterial processes, including motility, DNA transformation, fruiting body formation and attachment to host cells. Retraction of the N. gonorrhoeae type IV pilus requires a functional pilT. Retraction generates substantial force on its substrate (> 100 pN per retraction event), and it has been speculated that epithelial cells sense and respond to these forces during infection. We provide evidence that piliated, Opa non-expressing Neisseria gonorrhoeae activates the stress-responsive PI-3 kinase/Akt (PKB) pathway in human epithelial cells, and activation is enhanced by a functional pilT. PI-3 kinase inhibitors wortmannin and LY294002 reduce cell entry by 81% and 50%, respectively, illustrating the importance of this cascade in bacterial invasion. PI-3 kinase and its direct downstream effectors [PI(3,4,5)P3] and Akt are concentrated in the cell cortex beneath adherent bacteria, particularly at the periphery of the bacterial microcolonies. Furthermore, [PI(3,4,5)P3] is translocated to the outer leaflet of the plasma membrane. Finally, we show that [PI(3,4,5)P3] stimulates microcolony formation and upregulates pilT expression in vitro. We conclude that N. gonorrhoeae activation of PI-3 kinase triggers the host cell to produce a lipid second messenger that influences bacterial behaviour.
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PMID:PilT is required for PI(3,4,5)P3-mediated crosstalk between Neisseria gonorrhoeae and epithelial cells. 1609 15

The generation of reactive oxygen species (ROS) has been implicated in the perturbation of endothelial function and cell death. However, the specific signaling pathways which mediate and modifying this response have not been fully elucidated. Therefore, in this study we tested the hypothesis that activation of JAK2 is involved in the aortic endothelial cell (EC) response to ROS. When ECs were exposed to HG (25 mM) for 6 h or ROS (i.e., H(2)O(2) (100 microM)) for 1 h and returned to normal medium we found a decrease in cell density and morphologic signs of apoptosis. Furthermore, incubation of ECs with HG and H(2)O(2) also resulted in the tyrosine phosphorylation of JAK2. In addition, pretreatment of ECs with AG-490, an inhibitor of JAK2, prevented nuclear fragmentation, whereas inhibitors of Jun kinase (SP 600125), MAP kinase (PD 98059), Src kinase (PP2) or PI-3 kinase (wortmannin) were without effect. Finally, immunoblot analysis of caspase-3 and PARP cleavage confirmed a role for activation of JAK2 in both HG- or ROS-induced apoptosis, based on inhibition by either AG-490 or adenoviral transfection with a dominant-negative JAK2 mutant. In conclusion the activation of JAK2 plays a pivotal role in oxidant stress-induced commitment of ECs to apoptosis, based on studies with HG and H(2)O(2).
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PMID:Hyperglycemia and reactive oxygen species mediate apoptosis in aortic endothelial cells through Janus kinase 2. 1625 69

The protein kinase Akt (protein kinase B) can be activated by numerous growth factors via PI-3 kinase-generated phosphoinositides and is thought to have anti-apoptotic properties. Activated Akt/PKB boosts the activity of endothelial NO synthase (NOS III), which has been found in the key areas of the inner ear (e.g., hair cells and stria vascularis). In order to localize activated Akt/PKB (phospho-Akt) in the cochlea of guinea pigs, sections of ten temporal bones were observed immunohistochemically. The strongest immunoreactivity was found in and underneath inner hair cells (IHC). Within the organ of Corti, reactivity was found in supporting cells, while outer hair cells remained unstained. Spiral ganglion cells, the endothelium of the lateral wall and the vascular area of the modiolus showed moderate staining. The results give evidence that activated Akt/PKB influences the activity of the NO/cGMP pathway in the cochlea. Because of the antiapoptotic properties, activated Akt should now be examined under non-physiological conditions.
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PMID:Evidence for an Akt-kinase/NO/cGMP pathway in the cochlea of guinea pigs. 1628 96

Focal adhesion kinase (FAK) is up-regulated in a variety of cancers, including breast cancer, in association with poor disease prognosis. In the present study, we examined the role of FAK in the control of anticancer drug-induced apoptosis of mammary adenocarcinoma MTLn3 cells. Doxorubicin caused the formation of well defined focal adhesions and stress fibers early after treatment, which was later followed by their loss in association with the onset of apoptosis. Phosphorylation of FAK on tyrosine 397 decreased only during the onset of doxorubicin-induced apoptosis in a Bcl-2 and caspase-independent manner. Doxorubicin also caused an early activation of protein kinase B (PKB). Expression of the dominant-negative acting focal adhesion kinase-related nonkinase (FRNK) sensitized MTLn3 cells to apoptosis caused by doxorubicin. FRNK inhibited the doxorubicin-induced activation of PKB. In addition, inhibition of phosphatidylinositide-3 (PI-3) kinase with wortmannin inhibited the activation of PKB by doxorubicin. Both wortmannin and transient overexpression of the dual lipid/protein phosphatase and tensin homolog deleted on chromosome 10 enhanced doxorubicin-induced cell death. Altogether, these data fit with a model wherein FAK is involved in the doxorubicin-induced activation of the PI-3 kinase/PKB signaling route, thereby suppressing the onset of apoptosis caused by doxorubicin.
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PMID:Focal adhesion kinase and protein kinase B cooperate to suppress doxorubicin-induced apoptosis of breast tumor cells. 1682 86

Several markers have been used to detect circulating tumor cells (CTC) in the peripheral blood of patients with breast cancer. However, analysis of activated signaling kinases in CTC implicated in cellular transformation, migration, and survival has not been addressed so far. In the present study, we focused on the phenotypic profile of micrometastatic cells in peripheral blood mononuclear cells (PBMC) preparations from 45 breast cancer patients. PBMC cytospins from 28 cytokeratin (CK)-positive and 17 CK-negative samples were assessed for the expression of phosphorylated FAK (p-FAK), phosphorylated PI-3 kinase (p-PI-3K), and HER2 using confocal laser scanning microscopy. The expression of p-FAK was documented in all 28 CK-positive samples, while all 17 CK-negative samples were tested negative for p-FAK. Immunomagnetic separation using EpCAM antibody fully confirmed these findings, implying a sound correlation for the co-expression of the two molecules. Interestingly, 15 of 28 CK- and p-FAK-positive samples also expressed the HER2 oncoprotein. p-PI-3K was documented in 15 of 17 CK- and p-FAK-positive samples. Immunoblot analysis of micrometastatic cells in co-culture with PBMC confirmed the specific expression of both p-FAK and p-PI-3K. Finally, impaired actin organization was apparent in CK- and p-FAK/p-PI-3K-positive samples, comparable to that observed in MCF-7 human breast cancer cells. Our findings provide strong evidence that micrometastatic cells express activated signaling kinases, which may regulate migration mechanisms, supporting the presumption of their malignant and metastatic nature.
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PMID:Phosphorylation of FAK, PI-3K, and impaired actin organization in CK-positive micrometastatic breast cancer cells. 1751 59

Oncogenic transformation of hematopoietic cells by the Bcr-Abl oncoprotein directly involves the activation Jak2 tyrosine kinase and the Stat5 transcription factor. Both proteins are normally linked to the interleukin (IL)-3/granulocyte-macrophage colony-stimulating factor receptors for growth and survival. Since fibroblastic cells are not targets of BCR-ABL-induced oncogenesis, we determined whether forced expression of the IL-3 receptor would allow oncogenic transformation of NIH 3T3 fibroblasts known to be resistant to transformation by BCR-ABL. NIH 3T3 cells transduced with the human IL-3 receptor alpha and beta chains were highly susceptible to oncogenic transformation by expression of BCR-ABL. Forced expression of both receptor chains but not either one alone allowed efficient foci formation of NIH 3T3 cells expressing BCR-ABL (triple positive cells), and these cells formed colonies in soft agar, whereas BCR-ABL+ NIH 3T3 cells lacking IL-3 receptor expression did not. Signaling studies indicate that the BCR-ABL/IL-3 receptor+ NIH 3T3 cells utilize the Gab2/PI-3 kinase pathway activated by Jak2, and the Stat5 pathway activated separately by Bcr-Abl, whereas BCR-ABL+ NIH 3T3 cells lacking the IL-3 receptor do not utilize the Jak2 pathway, but still maintain activation of Stat5. The Bcr-Abl kinase inhibitor imatinib mesylate (1 microM) and two Jak2 kinase inhibitors strongly inhibited agar colony formation and the activation of Gab2 caused by Jak2. All of these findings indicate that Bcr-Abl oncoprotein requires the IL-3 receptor/Jak2/Stat5 pathways for oncogenic transformation of NIH 3T3 fibroblasts.
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PMID:BCR-ABL oncogenic transformation of NIH 3T3 fibroblasts requires the IL-3 receptor. 1807 9

Interactions between tumour cells and the extracellular matrix (ECM) strongly influence tumour development, affecting cell survival, proliferation and migration. Many of these interactions are mediated through a family of cell surface receptors named integrins. Fibronectin and its integrin receptors play important roles in tumour development. The alpha5beta 1 integrin interacts with the central cell adhesive region of fibronectin and requires both the RGD and synergy sites for maximal binding. Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases. They are capable of digesting the different components of the ECM and basement membrane. The ECM gives structural support to cells and plays a central role in cell adhesion, differentiation, proliferation and migration. Binding of ECM to integrins modulates expression and activity of the different MMPs. Our experimental findings demonstrate that cultivation of human breast cancer cells, MCF-7, in serum free medium in the presence of fibronectin upregulates the activity of MMP-2 and MMP-9. Blocking of alpha5beta 1 integrin with anti-alpha5 monoclonal antibody inhibits the fibronectin-induced MMP activation response appreciably. This strongly indicates alpha5beta 1 mediated signalling events in activation of MMP-2 and MMP-9. Phosphorylation of FAK and PI-3 kinase and the nuclear translocation of ERK and NF-kappaB upon fibronectin binding demonstrate possible participation of the FAK/PI-3K/ERK signalling pathways in the regulation of MMP-2 activity.
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PMID:Rapid expression and activation of MMP-2 and MMP-9 upon exposure of human breast cancer cells (MCF-7) to fibronectin in serum free medium. 1824 46

Protein kinase B (PKB; also known as Akt kinase) is located downstream in the PI-3 kinase pathway. Overexpression and constitutive activation of PKB/Akt leads to human prostate, breast and ovarian carcinomas. A series of 69 PKB/Akt inhibitors were examined to explore their binding modes using FlexX, and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies based on comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed to provide structural insights into these compounds. CoMFA produced statistically significant results, with cross-validated q ( 2 ) and non-cross validated correlation r(2) coefficients of 0.53 and 0.95, respectively. For CoMSIA, steric, hydrophobic and hydrogen bond acceptor fields jointly yielded 'leave one out' q(2) = 0.51 and r(2) = 0.84. The predictive power of CoMFA and CoMSIA was determined using a test set of 13 molecules, which gave correlation coefficients, r(2)(predictive) of 0.58 and 0.62, respectively. Molecular docking revealed that the binding modes of these molecules in the ATP binding sites of the Akt kinase domain were very similar to those of the co-crystallized ligand. The information obtained from 3D contour maps will allow the design of more potent and selective Akt kinase inhibitors.
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PMID:Elucidation of binding mode and three dimensional quantitative structure-activity relationship studies of a novel series of protein kinase B/Akt inhibitors. 1904 47

Protein kinase B (PKB/Akt) is a serine-threonine kinase functioning downstream of phosphatidylinositol 3-kinase (PI-3 kinase) in response to mitogen or growth factor stimulation. In several cell types, it plays an important anti-apoptotic role. TPA is a potent regulator of the growth of many different cell types. Here, we detected that TPA could induce cell apoptosis in the gastric cancer cell line, BGC-823. We also found that TPA inhibited the expression of PKB/Akt in a TPA concentration- and time-dependent manner. Furthermore, TPA inhibited the phosphorylation of PKB at Ser473, but did not affect the phosphorylation of Thr308. It only attenuated the expression of PKB/Akt and the phosphorylation of Ser473 in the cell nucleus, whereas it did not change the PKB/Akt distribution in BGC-823 cells. These results suggest that PKB/Akt inhibition by TPA may be the important factor in the mechanism of effect of TPA on gastric cell lines.
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PMID:The expression of protein kinase B in gastric cancer cell apoptosis induced by 12-O-tetradecanoylphorbol-1, 3-acetate. 1923 32


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