Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PTEN tumor suppressor is frequently mutated in human cancers and is a negative regulator of PI3'K/PKB/Akt-dependent cellular survival. Investigation of the human genomic PTEN locus revealed a p53 binding element directly upstream of the PTEN gene. Deletion and mutation analyses showed that this element is necessary for inducible transactivation of PTEN by p53. A p53-independent element controlling constitutive expression of PTEN was also identified. In contrast to p53 mutant cell lines, induction of p53 in primary and tumor cell lines with wild-type p53 increased PTEN mRNA levels. PTEN was required for p53-mediated apoptosis in immortalized mouse embryonic fibroblasts. Our results reveal a unique role for p53 in regulation of cellular survival and an interesting connection in tumor suppressor signaling.
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PMID:Regulation of PTEN transcription by p53. 1154 34

Previous studies demonstrate that interleukin-6 (IL-6) mediates growth and survival in human multiple myeloma (MM) cells via the MEK/MAPK and JAK/STAT signaling pathways, respectively. IL-6 also confers protection against Dexamethasone (Dex)-induced apoptosis via activation of protein tyrosine phosphatase (SHP2). In the current study, we characterized IL-6 triggered phophatidylinositol-3 kinase/Akt kinase (PI3-K/Akt) signaling in MM cells. IL-6 induces Akt/PKB phosphorylation in a time and dose dependent manner in MM.1S MM cells. IL-6 also induced phosphorylation of downstream targets of Akt, including Bad, GSK-3beta, and FKHR, confirming Akt activation. Inhibition of Akt activation by the PI3-K inhibitor LY294002 partially blocked IL-6 triggered MEK/MAPK activation and proliferation in MM.1S cells, suggesting cross-talk between PI3-K and MEK signaling. We demonstrate that Dex-induced apoptosis in MM.1S cells is mediated by downstream activation of caspase-9, with resultant caspase-3 cleavage; and conversely, that IL-6 triggers activation of PI3-K and its association with SHP2, inactivates caspase-9, and protects against Dex-induced apoptosis. LY294002 completely abrogates this signaling cascade, further confirming the importance of PI3-K/Akt signaling in conferring the protective effect of IL-6 against Dex-induced apoptosis. Finally, we show that IL-6 triggered PI3-K/Akt signaling in MM.1S cells inactivates forkhead transcriptional factor (FKHR), with related G1/S phase transition, whereas LY294002 blocks this signaling, resulting in upregulation of p27(KIP1) and G1 growth arrest. Our data therefore suggest that PI3-K/Akt signaling mediates growth, survival, and cell cycle regulatory effects of IL-6 in MM.
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PMID:Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. 1159 6

P210BCR-ABL counteracted against the complementary effect of XPB on DNA repair when ultraviolet (UV)-sensitive 27-1 cells were treated with UV or cisplatin but not with hydrogen peroxide. Wortmannin, an inhibitor of PI3 kinase did not affect its anti-repair effect. Enhanced recruitment of p44 with TFIIH after cisplatin treatment is inhibited by the expression of P210BCR-ABL in a kinase activity-dependent manner. Although purified TFIIH from P210BCR-ABL expressor and non-expressor showed almost no difference in molar ratio of each component, the in vitro activity of TFIIH was decreased by 5-10% in repair assay but was increased by more than two-fold in transcription assay.
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PMID:TFIIH functions are altered by the P210BCR-ABL oncoprotein produced on the Philadelphia chromosome. 1160 Jan 36

Growth hormone (GH) is a major growth-promoting and metabolic regulatory hormone. Interaction of GH with its cell surface GH receptor (GHR), by virtue of receptor dimerization, causes activation of the GHR-associated cytoplasmic tyrosine kinase, JAK2. Several signalling pathways, including the STAT5, PI3 kinase and MAP kinase pathways, are thereby accessed, resulting in various biochemical and biological cellular signalling outcomes which are rapidly becoming deciphered. Various mechanisms probably exist to terminate, modulate and prevent GH signalling. Some of these mechanisms regulate receptor abundance and/or availability while others may alter the responsiveness of downstream signalling molecules to receptor engagement. In this review, recent insights into modulation of GH signalling are discussed. Special emphasis is placed on mechanisms of homologous and heterologous desensitization and on the likelihood that inducible GHR proteolysis, in addition to causing GH binding protein generation, may also serve as an important mechanism of heterologous GHR downregulation.
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PMID:Growth hormone signalling and its regulation: preventing too much of a good thing. 1173 35

Protein kinase B (PKB, also termed Akt) is a phosphatidylinositol 3' kinase (PI3'K)-dependent enzyme implicated in survival signaling and human tumorigenesis. To identify potential targets of this protein kinase, we employed a genetic screen in Drosophila. Among several genes that genetically interacted with PKB was trachealess (trh), which encodes a bHLH-PAS domain transcription factor required for development of the trachea and other tubular organs. Trh activates expression of the fibroblast growth factor receptor Breathless, which, in turn, is required for directed migration of all tracheal branches. Using a combination of biochemical and transgenic approaches, we show that direct phosphorylation of Trh by PKB at serine 665 is essential for nuclear localization and functional activation of this regulator of branching morphogenesis.
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PMID:Regulation of Drosophila tracheal system development by protein kinase B. 1174 Sep 32

Cardiotrophin-1 protects cardiac myocytes from ischaemic re-oxygenation (IR) injury. CT-1 activates MEK1/2,p42/44MAPK as well as the phosphatidylinositol (PI) 3-OH kinase (PI3) protein kinase B (PKB/Akt) pathway. In this study we investigate the signalling pathways that mediate the anti-apoptotic cell survival effect of CT-1 in IR. Dominant negative gene based inhibitors of MEK1/2, PI3-kinase and Akt inhibited CT-1 mediated cardioprotection in re-oxygenation as did chemical inhibitors of the PI3-kinase pathway. Hence the PI3-kinase/Akt pathway is required in addition to MEK1/2 to mediate CT-1 cardioprotection in IR.
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PMID:CT-1 mediated cardioprotection against ischaemic re-oxygenation injury is mediated by PI3 kinase, Akt and MEK1/2 pathways. 1174 48

Primary cortical neurones exposed to an oxidative insult in the form of hydrogen peroxide (H(2)O(2)) for 30 min showed a concentration-dependent increase in oxidative stress followed by a delayed NMDA receptor-dependent cell death measured 24 h later. Extracellular signal-regulated protein kinase (ERK1/2), c-jun N-terminal kinase (JNK) and the kinase Akt/PKB may regulate neuronal viability in response to oxidative insults. Using phospho-specific antibodies, a 15-min stimulation of neurones with H(2)O(2) (100 microm - 1 mm) produced a concentration-dependent phosphorylation of ERK1/2 and Akt/PKB that was partly dependent on extracellular Ca(2+) and phosphatidylinositol 3-kinase (PI3-K). Higher concentrations of H(2)O(2) (1 mm) also stimulated a phosphorylation of JNK which was totally dependent on extracellular Ca(2+) but not PI3-K. H(2)O(2)-induced phosphorylation of ERK1/2, Akt/PKB or JNK were unaffected by the NMDA channel blocker MK801. Blocking ERK1/2 activation with the upstream inhibitor U0126 (10 microm) enhanced H(2)O(2)-induced (100-300 microm range) neurotoxicity and inhibited H(2)O(2)-mediated phosphorylation of the cyclic AMP regulatory binding protein (CREB), suggesting that ERK1/2 signals to survival under these conditions. At higher concentrations (mm), H(2)O(2)-stimulated a phosphorylation of c-jun. It is likely, therefore, that subjecting neurones to moderate oxidative-stress recruits pro-survival signals to CREB but during severe oxidative stress pro-death signals through JNK and c-jun are dominant.
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PMID:Hydrogen peroxide-mediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: dependence on Ca(2+) and PI3-kinase. 1179 40

In the absence of survival-inducing cytokines activated T cells and neutrophils enter apoptosis spontaneously. Phosphatidylinositol 3-kinase (PI3 K) activation and signaling through PKB/AKT have been widely linked to the inhibition of apoptosis by cytokines. Here we have investigated the role of PKB in the inhibition of spontaneous apoptosis of activated human CD4+ T cells and neutrophils. We used a range of cytokines known to induce survival and/or activation of PKB. We found activation of PKB in T cells treated with IL-2 and insulin, and neutrophils cultured with N-formyl-Met-Leu-Phe (fMLP), insulin or granulocyte-macrophage colony-stimulating factor. Insulin did not inhibit apoptosis in neutrophils or T cells and fMLP did not delay neutrophil apoptosis. Intriguingly, IFN-beta induced PI3 K-dependent survival in both cell types, but did not activate PKB. IL-2 mediated rescue of T cells from apoptosis but no induction of proliferation occurred in thepresence of LY294002, an inhibitor of PI3 K, which also blocked subsequent PKB activation. The main role of PI3 K in IL-2-mediated signaling may therefore be in the regulation of proliferation. These findings suggest that activation of PKB and inhibition of apoptosis can be dissociated in cytokine-mediated rescue of non-transformed CD4+ T cells and neutrophils.
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PMID:Cytokine-mediated inhibition of apoptosis in non-transformed T cells and neutrophils can be dissociated from protein kinase B activation. 1182 65

Phosphatidylinositol 3-kinase (PI3-K) is a growth factor-activated transforming lipid (and protein) kinase, involved in cell motility and invasion, that has multiple effectors. Relatively little is known about its expression and enzymatic activity in human breast cancer. Since growth factor receptors are amplified in breast cancer, and the tumor suppressor PTEN may be mutated in human breast cancer, it was hypothesized that PI3-K and its downstream effectors would be activated in this disease. In 11 resected tumors analyzed for expression of this kinase, a mean 3-fold increase in protein expression was observed over the corresponding adjacent control tissue. Using an in vitro lipid kinase assay of the immunoprecipitated PI3-K protein, a greater than 2-fold increase in activation was observed. These changes were observed in the absence of an activation of either protein kinase B (PKB, akt1) or p70 S6 kinase (p70 S6K). However, p21-activated kinase (Pak), p38 mitogen-activated protein kinase (p38 MAPK) and mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK 2) were all overexpressed and demonstrated increased enzyme activity. It may be concluded that aberrant mitogenic signaling in human breast cancer in vivo involves Pak, p38 MAPK and MAPKAPK2 downstream of PI3-K, but neither of PKB or p70 S6K. It is proposed that this pathway may serve as a useful targeting nexus for investigation of small molecule inhibitors in human breast cancer.
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PMID:Dysregulation of phosphatidylinositol 3-kinase and downstream effectors in human breast cancer. 1185 99

We have previously shown that microtubule disruption results in an increase in cell adhesion to ECM proteins. In this work we show that this enhanced cell attachment was completely abolished by specific inhibitors of tyrosine-kinases, PI3-K and PKCs. Microtubule depolymerisation was associated with an important increased in tyrosine phosphorylation of FAK and paxilline, as well as with subcellular localisation of PKCgamma, delta and epsilon. We also observed significant alterations in actin cytoskeleton leading to reduced cell spreading. Thus, microtubule depolymerisation appears to activate various intracellular kinases that lead to actin cytoskeletal changes and to an increase of integrin-dependent adhesion. Whether this enhanced attachment is due to intracellular events resulting in changes in integrin affinity or avidity remains to be determined.
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PMID:[Involvement of FAK, PI3-K and PKC in cell adhesion induced by microtubule disruption]. 1188 61


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