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

---

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

Resistance to anoikis is a characteristic of malignant cells with increased tumorigenesis and metastasis. Altered FAK activity has been strongly implicated in the development, growth, progression, and metastasis of human cancers, but the mechanism of FAK in regulating anoikis is unknown. In this study, the resistance anoikis role of FAK and its downstream mediators was evaluated in the human lung cancer cell line A549. It has been shown that down regulation of FAK stimulates the apoptosis of cells and the down-regulation of p-ERK, p-PI3K, p-Src, and p-p38. Furthermore, in detached A549 cells, increased FAK phosphorylations (Tyr397, Tyr861, Tyr925) were detected in a time-dependent manner, and the specific inhibitors of MEK1, PI3K, and Src (PD98059, LY294002, and PP2) partly abolished the resistance to the anoikis characteristic of cancer cells. Altogether, our data suggested that Src is involved in the progress of detachment-induced FAK activation in lung tumor cells. PI3K/AKT, MAPK-ERK, and perhaps MAPK-p38 but not MAPK-JNK, appear to be the key downstream effectors of FAK in mediating cell survival. The increased FAK activity upon cell detachment may contribute to the metastasis potential of malignant tumors.
...
PMID:Inhibitory role of focal adhesion kinase on anoikis in the lung cancer cell A549. 1834 94

Aspirin is used as chemopreventive agents in a variety of human cancer cells including those of colon, lung, breast, and leukemia. Sodium salicylate (NaSal, the natural deacetylated form of aspirin) induced cell cycle arrest and apoptosis in a dose-dependent manner in A549 cells; high dose (20mM) of NaSal-induced apoptosis, whereas low dose (2-10mM) induced cell cycle arrest. We found that NaSal-activated Akt/PKB, ERK1/2, and p38MAPK signal cascades. Twenty micromolar of NaSal-induced apoptotic response of A549 cells was enhanced by the PI3K inhibitors (LY294002 and wortmannin) and in a less extent by the MEK1/2 inhibitors (U0126 and PD98059), whereas it was suppressed by the p38MAPK inhibitor (SB203580). Furthermore, simultaneous inhibition of the Akt/PKB and ERK1/2 signal cascades could lower the dose of NaSal to induce apoptosis to 2mM in A549 lung cancer cells. Similar enhancement was observed in cells treated with 2mM NaSal and 100muM genistein, an inhibitor of receptor tyrosine kinases (RTKs) that are upstream of PI3K and MEK1/2 signaling. We further demonstrated that NAG-1 plays a key role in apoptosis by NaSal-based combined treatment. Collectively, our findings indicate that inhibition of the pro-survival Akt/PKB and ERK1/2 signaling may increase the chemopreventive effects of NaSal and combined treatment of two natural compounds (NaSal and genistein) results in a highly synergistic induction of apoptosis, thereby increasing the chemopreventive effects of NaSal against cancer.
...
PMID:Implication of NAG-1 in synergistic induction of apoptosis by combined treatment of sodium salicylate and PI3K/MEK1/2 inhibitors in A549 human lung adenocarcinoma cells. 1835 53

The 190 kD (p190) and 210 kD (p210) Bcr-Abl proteins are responsible for the pathophysiology of Philadelphia chromosome (Ph)(+) leukemia. We applied RNA interference (RNAi) to specific killing of p190(+) cells, and determined the optimal sequences for gene silencing in the BCR, junctional and ABL regions of p190, respectively. Then, p190(+) and p210(+) cells were infected with lentiviral vectors encoding these shRNAs, resulting in efficient killing of p190(+) cells, while p210(+) cells were only sensitive to shBCR and shABL. In p190-transformed Ba/F3 cells, silencing of p190 specifically inhibited tyrosine phospohorylation of Stat5 prior to their death, but did not affect phosphorylation of Jak2, Akt or MEK1/2. In contrast, downregulation of p190 by their treatment with 17-allylamino-17-demetoxygeldanamycin (17-AAG) was associated with reduced protein levels of Jak2, Akt and MEK1/2. shRNA targeting p190 collaborated additively with imatinib and 17-AAG in growth inhibition of Ba/F3-p190wt and imatinib-resistant Ba/F3-p190Y253 H cells. Collectively, RNAi-mediated silencing of p190 is a promising option both for delineating signal transduction and for therapeutic application in 190(+) leukemia.
...
PMID:RNAi-mediated silencing of p190Bcr-Abl inactivates Stat5 and cooperates with imatinib mesylate and 17-allylamino-17-demetoxygeldanamycin in selective killing of p190Bcr-Abl-expressing leukemia cells. 1836 71

Oncostatin M (OSM) is an IL-6/LIF cytokine family member whose role has been identified in a range of biological activities in vitro, including upregulation of inflammatory gene expression and regulation of connective tissue metabolism. Previously, we identified murine OSM (mOSM) as an inducer of the eosinophil-chemoattractant protein eotaxin-1, both in vitro using fibroblast cell lines and in vivo from mouse lung tissues. Using the NIH 3T3 cell line, we demonstrate the requirement of PI3'K activation for mOSM induction of eotaxin-1 through inhibition of both mOSM-stimulated mRNA and protein expression using the PI3'K antagonist LY294002. By assessment of phosphorylation of the downstream mediator Akt, we show mOSM to be differentially capable of activating PI3'K relative to the related gp130-utilizing cytokine IL-6. Assessment of eotaxin-1 gene expression utilizing PKB/Akt mutant-transfected NIH 3T3 cell lines demonstrated Akt is not involved in upstream regulation of eotaxin-1 through mOSM, indicating an alternate kinase pathway downstream of PI3'K may be involved. We demonstrate that mOSM stimulation of expression of eotaxin-1 is reduced by PD98059, a MAPK kinase inhibitor selective for MEK1. Both LY294002 and PD98059 attenuated mOSM-induced phosphorylation of ERK1/2 MAP kinase and also reduced binding of an AP-1 responsive promoter element, a transcriptional complex known to be MAPK-sensitive. Further, LY294002 pretreatment reduced mOSM-stimulated expression of the downstream AP-1 co-factor JunB, while PD98059 reduced levels of JunB as well as c-Fos. These results provide evidence for a previously unidentified signaling mechanism utilized by mOSM for the induction of eotaxin-1.
...
PMID:Oncostatin M induction of eotaxin-1 expression requires the convergence of PI3'K and ERK1/2 MAPK signal transduction pathways. 1837 59

Kinex antibody microarray analyses was used to investigate the regulation of 188 protein kinases, 24 protein phosphatases, and 170 other regulatory proteins during meiotic maturation of immature germinal vesicle (GV+) pig oocytes to maturing oocytes that had completed meiosis I (MI), and fully mature oocytes arrested at metaphase of meiosis II (MII). Increases in apparent protein levels of protein kinases accounted for most of the detected changes during the GV to MI transition, whereas reduced protein kinase levels and increased protein phosphorylation characterized the MI to MII transition. During the MI to MII period, many of the MI-associated increased levels of the proteins and phosphosites were completely or partially reversed. The regulation of these proteins were also examined in parallel during the meiotic maturation of bovine, frog, and sea star oocytes with the Kinex antibody microarray. Western blotting analyses confirmed altered expression levels of Bub1A, IRAK4, MST2, PP4C, and Rsk2, and the phosphorylation site changes in the kinases Erk5 (T218 + Y220), FAK (S722), GSK3-beta (Y216), MEK1 (S217 + S221) and PKR1 (T451), and nucleophosmin/B23 (S4) during pig oocyte maturation.
...
PMID:Antibody microarray analyses of signal transduction protein expression and phosphorylation during porcine oocyte maturation. 1848 64

Differentiation of PC12 cells by nerve growth factor (NGF) requires the activation of various mitogen-activated protein kinases (MAPKs) including p38 MAPK. Accumulating evidence has suggested cross-talk regulation of NGF-induced responses by G protein-coupled receptors, thus we examined whether NGF utilizes G(i/o) proteins to regulate p38 MAPK in PC12 cells. Induction of p38 MAPK phosphorylation by NGF occurred in a time- and dose-dependent manner and was partially inhibited by pertussis toxin (PTX). NGF-dependent p38 MAPK phosphorylation became insensitive to PTX treatment upon transient expressions of Galpha(z) or the PTX-resistant mutants of Galpha(i2) and Galpha(oA). Moreover, Galpha(i2) was co-immunoprecipitated with the TrkA receptor from PC12 cell lysates. To discern the participation of various signaling intermediates, PC12 cells were treated with a panel of specific inhibitors prior to the NGF challenge. NGF-induced p38 MAPK phosphorylation was abolished by inhibitors of Src (PP1, PP2, and SU6656) and MEK1/2 (U0126). Inhibition of the p38 MAPK pathway also suppressed NGF-induced PC12 cell differentiation. In contrast, inhibitors of JAK2, phospholipase C, protein kinase C and Ca(2+)/calmodulin-dependent kinase II did not affect the ability of NGF to activate p38 MAPK. Collectively, these studies indicate that NGF-dependent p38 MAPK activity may be mediated via G(i2) protein, Src, and the MEK/ERK cascade.
...
PMID:Nerve growth factor-induced stimulation of p38 mitogen-activated protein kinase in PC12 cells is partially mediated via G(i/o) proteins. 1850 36

Bone marrow mesenchymal stem cells (BMMSCs) have the capacity for self-renewal, and differentiation into a variety of cell types. They thus represent an attractive source of material for cell therapy. However, little is known about the mechanisms underlying the proliferation of BMMSCs. The purpose of this study was to identify the factors and signaling pathways involved in the proliferation of stem cell antigen-1(+) (Sca-1(+)) BMMSCs. Among the cytokines and growth factors examined in this study, fibroblast growth factor-2 (FGF-2) and FGF-4 significantly stimulated the proliferation of Sca-1(+) BMMSCs, as determined by bromodeoxyuridine incorporation. PI3K-Akt, ERK1/2, and JAK/STAT3 pathways were investigated after stimulation with FGF-2 or FGF-4 via Western blot analysis. No changes were observed in the total ERK1/2 and Akt; however, the pERK1/2 and pAkt levels were upregulated early within 15 min in the FGF-2- or FGF-4-treated Sca-1(+) BMMSCs. Moreover, the pERK1/2 and pAkt upregulation induced by FGF-2 and -4 were completely abolished by treatment with the MEK1/2 inhibitor, U0126 and the PI3K inhibitor, LY294002. However, no change in pJAK2 or total JAK2 levels was observed in the Sca-1(+) BMMSCs induced by FGF-2 or FGF-4. As a consequence of PI3K-Akt and ERK1/2, the upregulation of c-Jun in the Sca-1(+) BMMSCs, after stimulation with FGF-2 or FGF-4, was observed after 12 and 24 h. Moreover, the activation of c-Jun in FGF-2- and FGF-4-treated Sca-1(+) BMMSCs was significantly reduced by U0126. Taken together, these data suggest that FGF-2 and -4 promote the proliferation of Sca-1(+) BMMSCs by activation of the ERK1/2 and PI3K-Akt signaling pathways.
...
PMID:Fibroblast growth factor-2 and -4 promote the proliferation of bone marrow mesenchymal stem cells by the activation of the PI3K-Akt and ERK1/2 signaling pathways. 1878 32

The mechanisms by which p210-BCR-ABL determines hematopoietic stem cells fate remain poorly understood. To better understand the behavior of BCR-ABL in pluripotent stem cells, we previously developed a murine embryonic stem (ES) cell model transformed by p210-BCR-ABL and reported that BCR-ABL activates STAT3, a major protein involved in ES cells self-renewal, which leads specifically to inhibition of ES cells differentiation. We show here that BCR-ABL either inhibits differentiation or, unexpectedly, induces a rapid commitment to differentiation of murine ES cells, according to the intracellular levels of activated STAT3. We show that inhibition of endogenous STAT3 activation with an inducible STAT3 protein with dominant-negative activity (STAT3F) results in an early, rapid and complete differentiation of BCR-ABL-expressing ES cells, whereas control ES cells retain a more undifferentiated phenotype. This phenomenon could be totally abrogated by PD98059, a specific MEK1 inhibitor, suggesting the involvement of mitogen-activated protein kinase (MAP-Kinase)/ERK1/2 pathway, which was found constitutively phosphorylated in BCR-ABL-expressing cells. In addition, BCR-ABL-expressing ES cells harboring low levels of activated STAT3 committed more rapidly through hematopoietic differentiation, since embryoid bodies (EBs) derived from these cells were able to generate numerous hematopoietic progenitors 2 days early. Moreover, BCR-ABL-expressing ES cells cultured first with low levels of activated STAT3 before EBs derivation displayed a more rapid loss of pluripotency than controls and failed to generate hematopoietic progenitors. This phenomenon was partially abrogated when ES cells were first exposed to PD98059 or to the tyrosine kinase inhibitor imatinib mesylate. From this predictive model, we suggest that variations of the activation levels in BCR-ABL substrates such as STAT3 may represent "instructive" secondary cooperating events involved in the transformation of the leukemic cell phenotype during the course of CML.
...
PMID:BCR-ABL induces opposite phenotypes in murine ES cells according to STAT3 activation levels. 1883 38

Nerve growth factor (NGF)-mediated activation of mitogen-activated protein kinases (MAPK) is critical for differentiation and apoptosis of PC12 cells. Since NGF employs stress-activated c-Jun N-terminal kinase (JNK) to regulate both programmed cell death and neurite outgrowth of PC12 cells, we examined NGF-regulated JNK activity and the role of G(i/o) proteins. Induction of JNK phosphorylation by NGF occurred in a time- and dose-dependent manner and was partially inhibited by pertussis toxin (PTX). To discern the participation of various signaling intermediates, PC12 cells were treated with specific inhibitors prior to NGF challenge. NGF-elevated JNK activity was abolished by inhibitors of JNK, p38 MAPK, Src, JAK3 and MEK1/2. NGF-dependent JNK phosphorylation became insensitive to PTX treatment upon transient expressions of Galpha(z) or the PTX-resistant mutants of Galpha(i1-3) and Galpha(oA). Collectively, these studies indicate that NGF-dependent JNK activity may be mediated via G(i1-3) proteins, JAK3, Src, p38 MAPK and the MEK/ERK cascade.
...
PMID:Multiple Gi proteins participate in nerve growth factor-induced activation of c-Jun N-terminal kinases in PC12 cells. 1900 46

The number of epidermal growth factor receptors (EGFRs) and their ligands are highly expressed in malignant tumor cells. The EGF signaling pathway is also activated in up to one-third of patients with breast cancer. In this study, we investigated the novel function of the JAK3 inhibitor, WHI-P131, on EGF-induced MMP-9 expression and the regulatory mechanism of EGF-induced MMP-9 expression in SKBR3 cells. We observed that EGF increased MMP-9 mRNA and protein expression in a dose-dependent manner. EGF also induced the phosphorylation of EGFR, ERK, and STAT-3, and these effects were inhibited by the EGFR inhibitor, AG1478.To investigate the involvement of the STAT-3 pathway on EGF-induced MMP-9 expression, we pretreatedSKBR3 cells with JAK1, JAK2, and JAK3 inhibitors prior to EGF treatment. The results showed that the JAK3 inhibitor, WHI-P131, as well as JAK3 siRNA transfection, but not the JAK1 and JAK2 inhibitors, significantly decreased EGF-induced MMP-9 expression. In addition, EGF-induced STAT-3 phosphorylation was only inhibited by WHI-P131. We then transfected cells with adenoviral STAT-3 (Ad-STAT-3), followed by treatment with EGF. Interestingly, EGF-induced MMP-9 expression was decreased by Ad-STAT-3 overexpression in a dose-dependent manner, while it was significantly increased by STAT-3 siRNA transfection. Our results also showed that basal levels of MMP-9 expression were significantly increased by constitutive active-MEK (CAMEK)overexpression. EGF-induced ERK phosphorylation was prevented by WHI-P131, but not by JAK1 andJAK2 inhibitors. On the other hand, EGF-induced MMP-9 expression was decreased by the MEK1/2 inhibitor,UO126. Therefore, for the first time, we suggest that the JAK3 inhibitor, WHI-P131, inhibits EGF-induced STAT-3 phosphorylation as well as ERK phosphorylation. The JAK3/ERK pathway may play an important role in EGFinduced MMP-9 expression in SKBR3 cells.
...
PMID:EGF-induced MMP-9 expression is mediated by the JAK3/ERK pathway, but not by the JAK3/STAT-3 pathway in a SKBR3 breast cancer cell line. 1938 51


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---