Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over-expression of EGFR, as in most cases of ovarian cancer, is associated with advanced-stage disease and poor prognosis. Activation of EGFR signaling pathway is involved in increased cell proliferation, angiogenesis, metastasis and decreased apoptosis. Tyrosine kinase activity is essential for signal transduction and receptor down-regulation. However, we found in this study that tyrosine kinase activity is not necessary in ligand-induced EGFR down-regulation in ovarian cancer cell line CaOV3 cells. EGFR tyrosine kinase inhibitors, such as PD153035, AG1478, as well as non-specific tyrosine kinase inhibitor PP2 cannot reverse EGF-induced down-regulation of EGFR. These findings thus permit us to develop the following exciting but unconventional strategy to sensitize cancer cells, namely, by priming ovarian cancer cells with EGF and EGFR inhibitor PD153035, before chemotherapy. This priming procedure down-regulates EGFR without induction of mitogenic signals such as ERK and PI3K/AKT. EGF plus EGFR inhibitor-primed ovarian cancer cells display increased sensitivity to taxol-induced cell death, resistant to EGF-induced cell migration and cell proliferation as well as ERK and PI3K/AKT activation. Further studies showed that PD153035, which does not reverse ligand-induced EGFR down-regulation, blocks EGF-induced EGFR activation as well as EGFR's binding to c-cbl and Grb2. Taken together, we contend that priming with EGFR inhibitors plus EGF inhibits cell signaling pathways leading to cell proliferation and survival, while down-regulating EGFR. This priming approach sensitizes ovarian cancer cells and would ultimately result in better chemotherapeutical outcome.
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PMID:Priming with EGFR tyrosine kinase inhibitor and EGF sensitizes ovarian cancer cells to respond to chemotherapeutical drugs. 1840 Mar 75

The aim of this study was to investigate whether Shp2 (Src homology region 2, phosphatase 2) controls focal adhesion kinase (FAK) activity and its trophic actions in cardiomyocytes. We show that low phosphorylation levels of FAK in nonstretched neonatal rat ventricular myocytes (NRVMs) coincided with a relatively high basal association of FAK with Shp2 and Shp2 phosphatase activity. Cyclic stretch (15% above initial length) enhanced FAK phosphorylation at Tyr397 and reduced FAK/Shp2 association and phosphatase activity in anti-Shp2 precipitates. Recombinant Shp2 C-terminal protein tyrosine phosphatase domain (Shp2-PTP) interacted with nonphosphorylated recombinant FAK and dephosphorylated FAK immunoprecipitated from NRVMs. Depletion of Shp2 by specific small interfering RNA increased the phosphorylation of FAK Tyr397, Src Tyr418, AKT Ser473, TSC2 Thr1462, and S6 kinase Thr389 and induced hypertrophy of nonstretched NRVMs. Inhibition of FAK/Src activity by PP2 {4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine} abolished the phosphorylation of AKT, TSC2, and S6 kinase, as well as the hypertrophy of NRVMs induced by Shp2 depletion. Inhibition of mTOR (mammalian target of rapamycin) with rapamycin blunted the hypertrophy in NRVMs depleted of Shp2. NRVMs treated with PP2 or depleted of FAK by specific small interfering RNA were defective in FAK, Src, extracellular signal-regulated kinase, AKT, TSC2, and S6 kinase phosphorylation, as well as in the hypertrophic response to prolonged stretch. The stretch-induced hypertrophy of NRVMs was also prevented by rapamycin. These findings demonstrate that basal Shp2 tyrosine phosphatase activity controls the size of cardiomyocytes by downregulating a pathway that involves FAK/Src and mTOR signaling pathways.
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PMID:Shp2 negatively regulates growth in cardiomyocytes by controlling focal adhesion kinase/Src and mTOR pathways. 1884 15

Resistance to chemotherapy is believed to be a major cause of treatment failure in pancreatic cancer. Thus, it is necessary to explore alternative therapeutic modalities to overcome drug resistance in pancreatic cancer treatment. We tested the hypothesis that Src tyrosine kinase inhibition could augment the chemosensitivity of 5-fluorouracil (5-FU)-resistant human pancreatic cancer cells to 5-FU. As detected by MTT proliferation assay, propidium iodide and annexin V staining, a combination of 5-FU+Src kinase inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) reflected the chemotherapeutic sensitivity and restored the 5-FU-induced apoptosis in 5-FU-resistant cells. Furthermore, when small-interfering RNA approach to silence Src gene expression was applied, the degree of 5-FU-induced apoptosis was increased in all cell lines independently of the chemoresistance status. Western blotting and RT-PCR analysis revealed that the expression of thymidylate synthase (TS) was higher in 5-FU-resistant cells, however, decreased significantly after pretreatment with PP2. Furthermore, the combination of 5-FU+PP2 decreased the 5-FU-induced activation of epidermal growth factor receptor (EGFR)-AKT pathway. Finally, PP2 in combination with 5-FU substantially decreased the in vivo tumor growth and inhibited distant metastases. Taken together, 5-FU chemoresistance can be reversed through indirect TS regulation by inhibiting Src tyrosine kinase. A potential mechanism of action of Src kinase inhibitors on 5-FU chemosensitivity might be linked to the inhibition of 5-FU-induced EGFR-AKT activation.
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PMID:Inhibition of Src tyrosine kinase reverts chemoresistance toward 5-fluorouracil in human pancreatic carcinoma cells: an involvement of epidermal growth factor receptor signaling. 1879 7

Repetitive strain stimulates intestinal epithelial migration across fibronectin via focal adhesion kinase (FAK), Src, and extracellular signal-related kinase (ERK) although how these signals act and interact remains unclear. We hypothesized that PI3K is central to this pathway. We subjected Caco-2 and intestinal epithelial cell-6 cells to 10 cycles/min deformation on flexible fibronectin-coated membranes, assayed migration by wound closure, and signaling by immunoblots. Strain stimulated PI3K, AKT, glycogen synthase kinase (GSK), and p38 phosphorylation. Blocking each kinase prevented strain stimulation of migration. Blocking PI3K prevented strain-stimulated ERK and p38 phosphorylation. Blocking AKT did not. Downstream, blocking PI3K, AKT, or ERK inhibited strain-induced GSK-Ser9 phosphorylation. Upstream of AKT, reducing FAK or Rac1 by siRNA blocked strain-stimulated AKT phosphorylation, but inhibiting Src by PP2 or siRNA did not. Transfection with FAK point mutants at Tyr397, Tyr576/577, or Tyr925 demonstrated that only FAK925 phosphorylation is required for strain-stimulated AKT phosphorylation. Myosin light chain activation by strain required FAK, Rac1, PI3K, AKT, GSK, and ERK but not Src or p38. Finally, blebbistatin, a nonmuscle myosin II inhibitor, blocked the motogenic effect of strain downstream of myosin light chain. Thus strain stimulates intestinal epithelial migration across fibronectin by a complex pathway including Src, FAK, Rac1, PI3K, AKT, GSK, ERK, p38, myosin light chain, and myosin II.
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PMID:Delineating the signals by which repetitive deformation stimulates intestinal epithelial migration across fibronectin. 1917 20

We previously reported that prolactin (PRL) induces chitotriosidase (CHIT-1) mRNA expression in human macrophages. In this investigation we determined the signaling pathways involved in CHIT-1 induction in response to PRL. The CHIT-1 induction PRL-mediated was reduced by wortmannin and LY-294002, inhibitors of phosphatidylinositol 3-kinase (PI3-K) and by genistein an inhibitor of protein tyrosine kinase (PTK). Pre-treatment of macrophages with SB203580, a specific inhibitor of the mitogen-activated kinases (MAPK) p38, or with U0126, an inhibitor of MAPK p44/42, prevented both basal and exogenous PRL-mediated CHIT-1 expression. No significant effects on CHIT-1 induction PRL-mediated were observed with a protein kinase C inhibitor (PKC), rottlerin, or with an Src inhibitor, PP2, or with JAK2 inhibitor, AG490. In addition, PRL induced a phosphorylation of AKT that was prevented both by the two MAPK inhibitors SB203580 and U0126 and by the PI3-K inhibitors wortmannin and LY-294002. In conclusion, our results indicate that PRL up-regulated CHIT-1 expression via PTK, PI3-K, MAPK, and signaling transduction components.
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PMID:Prolactin induces chitotriosidase expression in human macrophages through PTK, PI3-K, and MAPK pathways. 1941 92

Prostaglandin E(2) (PGE(2)) is elevated in many tumor types, but PGE(2)'s contributions to tumor growth are largely unknown. To investigate PGE(2)'s roles, the contributions of one of its receptors, EP2, were studied using the mouse skin initiation/promotion model. Initial studies indicated that protein kinase A (PKA), epidermal growth factor receptor (EGFR) and several effectors-cyclic adenosine 3',5'-monophosphate response element-binding protein (CREB), H-Ras, Src, protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2-were activated in 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted papillomas and that PKA and EGFR inhibition (H89 and AG1478, respectively) decreased papilloma formation. EP2's contributions to the activation of these pathways and papilloma development were determined by inhibiting endogenous TPA-induced PGE(2) production with indomethacin (Indo) and concomitantly treating with the EP2 agonist, CAY10399 (CAY). CAY treatment restored papilloma formation in TPA/Indo-treated mice and increased cyclic adenosine 3',5'-monophosphate and PKA activation as measured by p-CREB formation. CAY treatment also increased EGFR and Src activation and their inhibition by AG1478 and PP2 indicated that Src was upstream of EGFR. CAY also increased H-Ras, ERK1/2 and AKT activation, and AG1478 decreased their activation indicating EGFR being upstream. Supporting EP2's contribution, EP2-/- mice exhibited 65% fewer papillomas and reduced Src, EGFR, H-Ras, AKT and ERK1/2 activation. G protein-coupled receptor (GPCR) activation of EGFR has been reported to involve Src's activation via a GPCR-beta-arrestin-Src complex. Indeed, immunoprecipitation of beta-arrestin1 or p-Src indicated the presence of an EP2-beta-arrestin1-p-Src complex in papillomas. The data indicated that EP2 contributed to tumor formation via activation of PKA and EGFR and that EP2 formed a complex with beta-arrestin1 and Src that contributed to signaling and/or EP2 desensitization.
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PMID:The prostaglandin receptor EP2 activates multiple signaling pathways and beta-arrestin1 complex formation during mouse skin papilloma development. 1958 94

We have recently shown that high glucose increased the expression of Gq/11alpha, PLCbeta and mediated signaling in A10 vascular smooth muscle cells (VSMC). Since high glucose has been shown to increase growth factor receptor activation, we investigated the role of epidermal growth factor receptor (EGF-R) and platelet-derived growth factor receptor (PDGF-R) transactivation in high glucose-induced enhanced expression of Gq/11alpha and PLCbeta. Pre-treatment of A10 VSMC with high glucose (26 mM) for 3 days, increased the levels of Gqalpha, G11alpha, PLCbeta-1 and PLCbeta-2 proteins which were restored to control levels by AG1478, an inhibitor of EGF-R, AG1295, an inhibitor of PDGF-R and PP2, an inhibitor of c-Src but not by PP3. In addition, endothelin-1 (ET-1)-stimulated production of IP(3) that was enhanced by high glucose was also restored towards control levels by AG1478, AG1295 and PP2. High glucose also increased the phosphorylation of EGF-R and PDGF-R which was abolished by AG1478, AG1295 and PP2. Furthermore, high glucose-induced enhanced levels of Gqalpha, G11alpha and PLCbeta were also attenuated by PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) and wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-K). In addition, AG1478 and AG1295, also attenuated high glucose-induced enhanced phosphorylation of ERK1/2 and AKT. Furthermore, high glucose augmented the phosphorylation of c-Src which was attenuated by antioxidant, DPI. These results suggest that oxidative stress through the activation of c-Src and resultant transactivation of growth factor receptor contributes to the high glucose-induced enhanced expression of Gq/11alpha/PLC and -mediated cell signaling through MAPK/PI3K pathway.
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PMID:Role of growth factor receptor transactivation in high glucose-induced increased levels of Gq/11alpha and signaling in vascular smooth muscle cells. 2003 47

We report here that in the mouse embryonic gonads in addition to gonadal somatic cells, primordial germ cells (PGCs) the precursors of adult gametes, express estrogen receptor alpha (ERalpha) and that through this receptor, 17-beta-estradiol (E2) is able to modulate in such cells molecular signalling known to be crucial for their development. We demonstrated that PGCs from 11.5 to 12.5 days post coitum (dpc) mouse embryos express ERalpha transcripts and protein and that at concentrations of 10(-8)M E2 stimulates rapid (within 20 min) about 4-fold AKT (Ser473) and 3-fold ERK2 (Thr202/Tyr204) and SRC (Tyr418) phosphorylation. In addition, the E2 stimulatory effects were associated with increased phosphorylation of the KIT receptor (Tyr568/570). While the ER antagonist ICI182780 was able to abolish these effects, AKT phosphorylation induced by E2 was also inhibited by the PI3K inhibitor LY294002 and the SRC family inhibitor PP2. This latter was also able to abolish the increased phosphorylation of KIT and ERKs caused by E2. Taken together these results suggest that E2 may modulate via ERalpha non-genomic signalling/phosphorylation cascade in mouse PGCs. This was also supported by the finding that PGCs express MNAR, a scaffold protein that regulate ER activation in other cell types. Finally, we found that when PGCs were cultured in the presence of 10(-8)M E2 a significant ICI inhibitable increase of their number occurred. The present study provides evidence for novel direct non-genomic actions of estrogens on PGCs and suggests that these cells can represent a potential target for estrogens and estrogenic compounds during the early stages of embryo development in mammals.
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PMID:Rapid estrogen signalling in mouse primordial germ cells. 2038 Aug 32

Exposure of the brain to sub-lethal concentrations of glutamate activates, through stimulation of the glutamate N-methyl-D: -aspartate (NMDA) receptors, an endogenous brain protective mechanism (NMDA preconditioning) against glutamate cytotoxicity and various other injurious stimuli. Selective drug activation of this mechanism is considered to be a promising neuroprotective treatment against the devastating consequences of stroke and other traumatic brain insults. Although some properties of this mechanism have been characterized, many aspects concerning it are yet to be elucidated. In order to improve our understanding of the NMDA preconditioning mechanism, we have established an experimental in vitro model of primary rat neuronal cultures, in which NMDA preconditioning completely abolishes the glutamic acid insult-induced neuronal damage. Employing this model, we have monitored in the present study the level of activation or expression of several signal transducing proteins, assumed to be involved in the NMDA-activated protective mechanism, at various time points during the three successive periods of the model, preconditioning, insult, and reperfusion. The results demonstrated that the NMDA preconditioning-induced neuroprotective mechanism is associated with inactivation of p66ShcA, prevention of the insult-induced inactivation of Src, activation of AKT, inactivation followed by reactivation of FKHR-L1, and with increased expression of p52ShcA, EGFR, and MnSOD. The essential role of Src activity in the protective mechanism was further indicated by the demonstration that decreasing Src activation level by the Src inhibitor PP2 attenuated the NMDA preconditioning-induced protection. The alterations detailed above in the activation status or level of expression of the studied proteins are suggested to be part of the NMDA preconditioning-induced neuroprotective mechanism.
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PMID:Molecular alterations associated with the NMDA preconditioning-induced neuroprotective mechanism against glutamate cytotoxicity. 2210 60

Burkitt lymphoma (BL) is a highly aggressive B cell neoplasm. Although intensive polychemotherapy regimens have proven very effective, they are associated with significant toxicities. Therefore, more rational therapies that selectively target the molecular abnormalities of BL are needed. Recent data suggest that the tyrosine kinase SRC could represent a therapeutic target for BL. We found that new pyrazolo[3,4-d]pyrimidine SRC inhibitors exerted a significant cytotoxic effect and induced apoptosis on two BL cell lines, as determined by MTS assays, cytofluorimetric analyses and caspase 3 assay. Notably, our SRC inhibitors proved to be more effective than the well-known SRC inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine] in BL cells. Moreover, our small molecules induced a G 2/M arrest in BL cells through a possible new mechanism, whereby SRC inhibition hinders an AKT-WEE1-cyclin-dependent kinase 1 (CDK1) axis, leading to inhibition of CDK1, the main trigger of entry into mitosis. By using a small-molecule inhibitor of WEE1, a crucial CDK1 negative regulator, we were able to shift the balance toward apoptosis rather than growth arrest and enhance the efficacy of the SRC inhibitors, suggesting a possible use of these selective drugs in combination for a safe and efficient treatment of BL.
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PMID:Antitumor activity of new pyrazolo[3,4-d]pyrimidine SRC kinase inhibitors in Burkitt lymphoma cell lines and its enhancement by WEE1 inhibition. 2233 92


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