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 T cell costimulatory molecule CD28 is important for T cell survival, yet both the signaling pathways downstream of CD28 and the apoptotic pathways they antagonize remain poorly understood. Here we demonstrate that CD4(+) T cells from CD28-deficient mice show increased susceptibility to Fas-mediated apoptosis via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. Protein kinase B (PKBalpha/Akt1) is an important serine/threonine kinase that promotes survival downstream of PI3K signals. To understand how PI3K-mediated signals downstream of CD28 contribute to T cell survival, we examined Fas-mediated apoptosis in T cells expressing an active form of PKBalpha. Our data demonstrate that T cells expressing active PKB are resistant to Fas-mediated apoptosis in vivo and in vitro. PKB transgenic T cells show reduced activation of caspase-8, BID, and caspase-3 due to impaired recruitment of procaspase-8 to the death-inducing signaling complex (DISC). Similar alterations are seen in T cells from mice which are haploinsufficient for PTEN, a lipid phosphatase that regulates phosphatidylinositol-3,4,5-trisphosphate (PIP(3)) and influences PKBalpha activity. These findings provide a novel link between CD28 and an important apoptosis pathway in vivo, and demonstrate that PI3K/PKB signaling prevents apoptosis by inhibiting DISC assembly.
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PMID:CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly. 1216 62

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) have been implicated in antitumor immunity and therapy. In the present study, we investigated the sensitivity of Philadelphia chromosome (Ph1)-positive leukemia cell lines to TRAIL- or FasL-induced cell death to explore the possible contribution of these molecules to immunotherapy against Ph1-positive leukemias. TRAIL, but not FasL, effectively induced apoptotic cell death in most of 5 chronic myelogenous leukemia-derived and 7 acute leukemia-derived Ph1-positive cell lines. The sensitivity to TRAIL was correlated with cell-surface expression of death-inducing receptors DR4 and/or DR5. The TRAIL-induced cell death was caspase-dependent and enhanced by nuclear factor kappa B inhibitors. Moreover, primary leukemia cells from Ph1-positive acute lymphoblastic leukemia patients were also sensitive to TRAIL, but not to FasL, depending on DR4/DR5 expression. Fas-associated death domain protein (FADD) and caspase-8, components of death-inducing signaling complex (DISC), as well as FLIP (FLICE [Fas-associating protein with death domain-like interleukin-1-converting enzyme]/caspase-8 inhibitory protein), a negative regulator of caspase-8, were expressed ubiquitously in Ph1-positive leukemia cell lines irrespective of their differential sensitivities to TRAIL and FasL. Notably, TRAIL could induce cell death in the Ph1-positive leukemia cell lines that were refractory to a BCR-ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI571; Novartis Pharma, Basel, Switzerland). These results suggested the potential utility of recombinant TRAIL as a novel therapeutic agent and the possible contribution of endogenously expressed TRAIL to immunotherapy against Ph1-positive leukemias.
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PMID:TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells. 1250 34

The hepatic stellate cell (HSC), the pericyte of the liver sinusoids belongs to the mesenchymal cells of the liver. Damaging noxae induce a transformation from the quiescent (vitamin A-storing cell) to the activated (connective tissue-producing cell) state. The balance between proapoptotic and surviving factors decides about the fate of the activated HSC. Interferon-alpha (IFN-alpha) has been shown to elicit antiproliferative and/or antifibrogenic effects in various cell types of mesenchymal origin. We therefore investigated the effect of IFN-alpha on primary cultured rat HSC in their quiescent (day 2) and activated state (day 7). IFN-alpha significantly inhibited spontaneous apoptosis in activated HSC in vitro and simultaneously inhibited cell cycle progression by inducing a G1 arrest. The effect of IFN-a is not accompanied by a modulation of CD95, CD95L, p53, p21(WAF1), p27, bcl-2, bcl-xL, bax, NFkappaB, or IkappaB gene expression. Surprisingly, the IFN-alpha effect could be abolished completely by blocking JAK2 activity or JAK2 translation. The downregulating effect of IFN-alpha on the activity of caspase-8 and caspase-3 could also be neutralized using tyrphostin AG490 or JAK-2 antisense. Taken together IFN-alpha inhibits apoptosis of activated HSC by activation of JAK2 which inhibits the caspase-8 apoptosis pathway.
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PMID:Antiapoptotic effect of interferon-alpha on hepatic stellate cells (HSC): a novel pathway of IFN-alpha signal transduction via Janus kinase 2 (JAK2) and caspase-8. 1260 46

The role of adhesion molecules, such as alphav integrins, in the control of the survival of quiescent tumor cells is unclear. We used S 34961, a novel small molecule alphav integrin antagonist, to investigate the role of integrin-signaling in the survival of populations of quiescent human HT-29 and HCT 116 colon carcinoma cells. S 34961 at 1 microM induced detachment, but cells retained viability, existing as clusters. Nonligated beta-integrins may recruit and activate caspase-8 [J Cell Biol 155:459-470, 2001]. However, congruent with the absence of apoptosis, no activation of caspase-8 in these cells was detected after incubation with S 34961. A rapid (2 h) change in conformation of the N terminus of proapoptotic Bak was observed before detachment, together with a decrease in phosphorylation of focal adhesion kinase (2 h) and subsequent (8 h) decreases in phosphorylation of extracellular signal-regulated kinase-1/2 and Akt. Together, these results suggested that although treatment with S 34961 has no effect on survival per se, it may reduce the survival threshold of the tumor cells, with Bak in an activated state. Indeed, concomitant incubation of S 34961 with 10 microM U-0126 (a mitogen-activated protein kinase kinase inhibitor) was found to lead to apoptosis (at 24 h), whereas U-0126 alone had no effect. Together, these observations could guide the use of combination therapy with integrin antagonists in the clinic.
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PMID:Decrease in survival threshold of quiescent colon carcinoma cells in the presence of a small molecule integrin antagonist. 1276 37

FLICE-inhibitory protein (FLIP) is a homolog of caspase-8 that lacks catalytic activity and has been shown to be important in protecting endothelial cells from apoptosis. The serine/threonine kinase Akt/PKB was recently reported to promote FLIP expression in endothelial and tumor cells. Here we examined the role of the forkhead transcription factor FOXO3a, a downstream target of Akt, in controlling FLIP regulation in endothelial cells. FOXO3a nuclear translocation was regulated by Akt in human umbilical vein endothelial cells. Transduction of a nonphosphorylatable, constitutively active mutant of FOXO3a (TM-FOXO3a) led to the down-regulation of FLIP levels. Transduction with TM-FOXO3a also increased caspase-8 activity and promoted apoptosis in endothelial cells. Conversely, transduction of a dominant-negative mutant of FOXO3a up-regulated FLIP levels and protected endothelial cells from apoptosis under serum deprivation conditions. Restoration of intracellular FLIP blocked caspase-8 activation and inhibited apoptosis in TM-FOXO3a-transduced cells. These data suggest that FOXO3a is a downstream target of Akt in endothelial cells that can promote apoptosis via FLIP down-regulation and activation of the extrinsic apoptotic pathway.
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PMID:The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP. 1455 Dec 7

Glomerular epithelial cell (GEC) injury and apoptosis may contribute to sclerosis in glomerulonephritis. The present study addresses signals that regulate survival of GEC in culture and in the acute puromycin aminonucleoside nephrosis (PAN) model of GEC injury in vivo. Compared with GEC on plastic substratum, adhesion to collagen increased activation of focal adhesion kinase (FAK), c-Src, and ERK and facilitated survival (prevented apoptosis). GEC on plastic exhibited increased caspase-8 and -9 activities, increased expression of the proapoptotic protein, Bax, and decreased the antiapoptotic protein, Bcl-XL, compared with collagen. Stable expression of constitutively active mutants of FAK (CD2-FAK) or MEK (R4F-MEK) activated the ERK pathway and supplanted the requirement of collagen for survival. In contrast, expression of a Ras mutant that activates phosphatidylinositol 3-kinase but blocks ERK activation or pharmacological inhibition of the ERK pathway decreased survival on collagen. Glomeruli isolated from rats with PAN revealed increased beta1-integrin expression, along with increased activation of FAK, c-Src, and ERK, compared with controls. EGF receptor activation was undetectable in PAN. Therefore, adhesion to collagen, resulting in activation of FAK and the Ras-ERK pathway, supports GEC survival. Analogous signals for GEC survival are activated in PAN.
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PMID:Extracellular matrix regulates glomerular epithelial cell survival and proliferation. 1455 18

PPARgamma is known to induce apoptosis in malignant tumor cells, but the mechanism of this induction is not well understood. We investigated induction of apoptosis with 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a PPARgamma ligand, in cholangio cell carcinoma (CCC) cells (RBE, ETK-1 or HuCCT-1). Apoptosis was induced in RBE and ETK-1 cells with 15d-PGJ2, but not in HuCCT-1 cells, although PPARgamma was expressed in all CCC cells. Apoptosis-related proteins were also expressed, including FLIP, bclx, Apaf-1 and XIAP, but expression levels differed among the three cell lines. RBE cells treated with 15d-PGJ2 showed caspase activation, and it appeared that PPARgamma-induced apoptosis was dependent on caspase activation. However, neither ETK-1 nor HuCCT-1 cells showed significant activation of caspase-8 or -3 with 15d-PGJ2 treatment, raising the possibility of a caspase-independent apoptosis induction pathway. XIAP was down-regulated by 15d-PGJ2 in all three CCC cell lines. Therefore, 15d-PGJ2 induces apoptosis in CCC cells via caspase-dependent or independent pathways. 15d-PGJ2 may also induce down-regulation of XIAP and may promote caspase cascade activation through TNF-family receptor signaling pathways.
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PMID:The PPARgamma ligand, 15-Deoxy-Delta12,14-PGJ2, regulates apoptosis-related protein expression in cholangio cell carcinoma cells. 1461 59

Detachment of adherent epithelial cells from the extracellular matrix induces apoptosis, known as anoikis. Integrin stimulation protects cells from anoikis, but the responsible mechanisms are not well known. Here, we demonstrated that a pro-apoptotic GTP-binding protein, DAP3 (death-associated protein 3), is critical for induction of anoikis. Down-regulation of DAP3 expression by antisense oligonucleotides inhibited anoikis. Conversely, overexpression of DAP3 augmented cell death and caspase activation induced by cell detachment. Furthermore, the association of DAP3 with FADD and the activation of caspase-8 were induced by cell detachment. We also showed that DAP3 is phosphorylated by kinase Akt (PKB), and active Akt can nullify apoptosis induction by DAP3. Mutation of a consensus Akt phosphorylation site in DAP3 renders it resistant to suppression by active Akt in cells. Integrin ligation stimulates Akt activation and phosphorylation of DAP3 in intact cells, as well as suppresses the ability of DAP3 overexpression to augment anoikis. Involvement of DAP3 in anoikis signaling demonstrates a novel role for this GTP-binding protein in apoptosis induction caused by cell detachment.
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PMID:Functional role of death-associated protein 3 (DAP3) in anoikis. 1530 71

We have demonstrated that focal adhesion kinase (FAK)-overexpressed (HL-60/FAK) cells have marked resistance against various apoptotic stimuli such as hydrogen peroxide, etoposide, and ionizing radiation compared with the vector-transfected (HL-60/Vect) cells. HL-60/FAK cells are highly resistant to TRAIL-induced apoptosis, while original HL-60 or HL-60/Vect cells were sensitive. TRAIL at 500 ng/ml induced significant DNA fragmentation, activation of caspase-8 and 3, the processing of a proapoptotic BID, and mitochondrial release of cytochrome c in HL-60/Vect cells, whereas no such events were observed in the HL-60/FAK cells. In particular, the expression of procaspase-8 gene and subsequent cleavage of caspase-8 were markedly reduced in HL-60/FAK cells, while expression of TRAIL-receptor 2 and 3, TRADD, and FADD was equivalent in both types of cells. In HL-60/FAK cells, the phosphoinositide 3 (PI3)-kinase/Akt survival pathway was constitutively activated, accompanied by significant induction of inhibitor-of-apoptosis proteins, XIAP, RIP, and Bcl-XL. The introduction of FAK siRNA in HL-60/FAK cells sensitized them against TRAIL-induced apoptosis, confirming that overexpressed FAK downregulates procaspase-8 expression, which subsequently inhibits downstream apoptosis pathway in the HL-60/FAK cells.
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PMID:Down-regulation of procaspase-8 expression by focal adhesion kinase protects HL-60 cells from TRAIL-induced apoptosis. 1536 72

Molecular hardwiring of the cell cycle to the apoptotic machinery is a critical tumor suppressor mechanism for eliminating hyperproliferative cells. Deregulation of the Rb-E2F repressor complex by genetic deletion or functional inhibition of Rb triggers apoptosis through both the intrinsic (caspase-9 mediated) and extrinsic (caspase-8 mediated) death pathways. Induction of the intrinsic pathway has been studied extensively and involves release of free E2F and direct transcriptional activation of E2F-responsive apoptotic genes such as ARF, APAF1, and CASP9. In contrast, the mechanisms leading to activation of the extrinsic pathway are less well understood. There is growing evidence that Rb-E2F perturbation induces the extrinsic pathway, at least in part, through derepression (as opposed to transactivation) of apoptotic genes. Here, we explore this possibility using cells in which Rb-E2F complexes are displaced from promoters without stimulating E2F transactivation. This derepression of Rb-E2F-regulated genes leads to apoptosis through inactivation of focal adhesion kinase and activation of caspase-8. These findings reveal a new mechanistic link between Rb-E2F and the extrinsic (caspase 8-mediated) apoptotic pathway.
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PMID:Loss of Rb-E2F repression results in caspase-8-mediated apoptosis through inactivation of focal adhesion kinase. 1564 Jan 64


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