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 unique N-terminal region of the cAMP-specific phosphodiesterase PDE4A5, which confers an ability to bind to certain protein SH3 domains, is cleaved during apoptosis in both Rat-1 fibroblasts and PC12 cells. Cleavage was abolished by the caspase-3-selective inhibitor, z-DEVD-CHO but not the caspase-1 selective inhibitor, z-YVAD-CHO. Caspase-3 treatment of PDE4A5, expressed either transiently in COS cells or generated in vitro by coupled transcription translation, generated a similar cleavage product of 100 kDa compared with the native 110-kDa PDE4A5. This product could be detected immunochemically with an antibody raised to a C-terminal PDE4A5 peptide but not an antibody raised to the N terminus of PDE4A5, indicating that caspase-3 caused N-terminal cleavage of PDE4A5. Deletion of the putative caspase-3 cleavage site, (69)DAVD(72), in PDE4A5, or generation of either the D72A or the D69A mutants, ablated the ability of caspase-3 to cause cleavage. The N-terminal truncate PDE4A5-DeltaP3 was engineered to mimic the caspase-cleaved product of PDE4A5. This showed altered catalytic activity and, unlike PDE4A5, was unable to interact with the SH3 domain of the tyrosyl kinase, LYN. Although both PDE4A5 and PDE4A5-DeltaP3 were localized at cell cortical regions (ruffles), the distinct perinuclear association noted for both PDE4A5 and LYN was not seen for PDE4A5-DeltaP3. Staurosporine-induced apoptosis caused a marked redistribution of PDE4A5 but not PDE4A8 in stably transfected Rat-1 cells. The PDE4-selective inhibitor, rolipram together with the adenylyl cyclase activator forskolin, caused a synergistic increase in the apoptosis of Rat-1 cells. Overexpression of PDE4A5 in Rat-1 cells protected against staurosporine-induced apoptosis in contrast to overexpression of PDE4A8, which potentiated apoptosis. PDE4A5 may be the sole PDE4 family member to provide a substrate for caspase-3 cleavage and this action serves to remove the SH3 binding domain that is unique to this isoform within the PDE4A family and to alter its intracellular targeting.
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PMID:The cAMP-specific phosphodiesterase PDE4A5 is cleaved downstream of its SH3 interaction domain by caspase-3. Consequences for altered intracellular distribution. 1082 34

A crucial function of the BCR-ABL chimeric gene in chronic myeloid leukemia is the prolongation of cell survival by inhibition of apoptosis. BCR-ABL expression confers cross-resistance to multiple genotoxic anticancer drugs by inhibition of the apoptotic response to DNA damage in association with cell cycle arrest at the G2-M restriction point. Previous reports indicated that BCR-ABL exerts its antiapoptotic effect against various apoptotic stimuli upstream to the cleavage and activity of caspase-3. Here we show that the adenovirus E1A protein induces substantial apoptosis in BCR-ABL expressing K562 and LAMA-84 leukemia cells. This apoptotic activity of E1A is accompanied by processing of caspase-3 and cleavage of poly(ADP-ribose) polymerase and can be significantly blocked by z-VAD-fmk Z-Val-Ala-Asp(OCH3)-CH2F and the caspase-3-specific inhibitor Z-DEVD-FMK Z-Asp(OCH3)-Glu-Val-Asp(OCH3)-CH2F. Moreover, E1A renders K562 cells, which are particularly resistant to cell death irrespective of the inducing agent, susceptible to induction of apoptosis by the chemotherapeutic agents etoposide and daunorubicin. Counteracting the DNA damage-induced inactivation of cdc2 kinase, E1A reverses the drug-induced G2-M arrest These results indicate that solitary delivery of E1A significantly antagonizes BCR-ABL-induced antiapoptotic functions and circumvents the inherent resistance to DNA damage-induced apoptosis, supporting the use of E1A in combination with chemotherapeutic agents as a promising therapeutic strategy for successful treatment of Philadelphia chromosome-positive leukemia in vivo.
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PMID:E1A overcomes the apoptosis block in BCR-ABL+ leukemia cells and renders cells susceptible to induction of apoptosis by chemotherapeutic agents. 1091 74

Transforming growth factor beta (TGF-beta)-mediated apoptosis is one of the major death processes in the liver. We have previously shown that epidermal growth factor (EGF) is an important survival signal for TGF-beta-induced apoptosis in fetal hepatocytes (Fabregat et al., FEBS Lett 1996;384:14-18). In this work we have studied the intracellular signaling implicated in the protective effect of EGF. We show here that EGF activates p42 and p44 mitogen-activated protein kinases (MAPK). However, mitogen extracellular kinase (MEK) inhibitors do not block the survival effect of EGF. EGF also activates phosphoinositide 3-kinase (PI 3-kinase) and protein kinase B (PKB/AKT) in these cells. The presence of PI 3-kinase inhibitors blocks the protective effect of EGF on cell viability, DNA fragmentation, and caspase-3 activity. We have found that TGF-beta disrupts the mitochondrial transmembrane potential (DeltaPsi(m))( )and activates the release of cytochrome c, this effect being blocked by EGF, via a PI 3-kinase-dependent pathway. A detailed study on bcl-2 superfamily gene expression shows that TGF-beta produces a decrease in the messenger RNA (mRNA) and protein levels of bcl-x(L), an antiapoptotic member of this family, capable of preventing cytochrome c release. EGF is able to maintain bcl-x(L) levels even in the presence of TGF-beta. PI 3-kinase inhibitors completely block the protective effect of EGF on TGF-beta-induced bcl-x(L )down-regulation. We conclude that PI 3-kinase mediates the survival effect of EGF on TGF-beta-induced death by acting upstream from the mitochondrial changes, i.e., preventing bcl-x(L) down-regulation, cytochrome c release, and activation of caspase-3.
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PMID:Epidermal growth factor impairs the cytochrome C/caspase-3 apoptotic pathway induced by transforming growth factor beta in rat fetal hepatocytes via a phosphoinositide 3-kinase-dependent pathway. 1096 Apr 45

The v-Cbl oncogene induces myeloid and B-cell leukemia; however, the mechanism by which transformation occurs is not understood. An oncogenic form of c-Cbl (Cbl-DeltaY371) was expressed in the interleukin-3 (IL-3)-dependent cell line 32Dcl3 to determine whether it was able to induce growth factor-independent proliferation. We were unable to isolate clones of transfected 32Dcl3 cells expressing Cbl-DeltaY371 that proliferated in the absence of IL-3. In contrast, 32Dcl3/Cbl-DeltaY371 cells did not undergo apoptosis like parental 32Dcl3 cells when cultured in the absence of IL-3. Both 32Dcl3 and 32D/CblDeltaY371 cells arrested in G(1) when cultured in the absence of IL-3. Approximately 18% of the 32Dcl3 cells cultured in the absence of IL-3 for 24 h were present in a sub-G(1) fraction, while only 4% of the 32D/Cbl-DeltaY371 and 2% of the 32D/Bcl-2 cells were found in a sub-G(1) fraction. There was no difference in the pattern of tyrosine-phosphorylated proteins observed following stimulation of either cell type with IL-3. The phosphorylation of JAK2, STAT5, and endogenous c-Cbl was identical in both cell types. No differences were detected in the activation of Akt, ERK1, or ERK2 in unstimulated or IL-3-stimulated 32D/Cbl-DeltaY371 cells compared with parental 32Dcl3 cells. Likewise, there was no difference in the pattern of phosphorylation of JAK2, STAT5, ERK1, ERK2, or Akt when 32Dcl3 and 32D/CblDY371 cells were withdrawn from medium containing IL-3. The protein levels of various Bcl-2 family members were examined in cells grown in the absence or presence of IL-3. We observed a consistent increased amount of Bcl-2 protein in five different clones of 32D/Cbl-DeltaY317 cells. These data suggest that the Cbl-DeltaY371 mutant may suppress apoptosis by a mechanism that involves the overexpression of Bcl-2. Consistent with this result, activation of caspase-3 was suppressed in 32D/Cbl-DeltaY371 cells cultured in the absence of IL-3 compared with 32Dcl3 cells cultured under the same conditions.
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PMID:Suppression of apoptosis induced by growth factor withdrawal by an oncogenic form of c-Cbl. 1111 40

Integrin receptors mediate several functions including prevention of matrix detachment-induced apoptosis (anoikis) of several adherent cell types. We report here that antagonists of beta1 integrins trigger an apoptotic signaling pathway in adherent differentiated LAN-5 human neuroblastoma cells, a cell line which represents a model system for the study of human neurons. The pathway is characterized by cytochrome c release into the cytoplasm, and activation of caspase-9 and caspase-3, 4-6h after treatment; cleavage products of caspase-8 and caspase-2 were not detectable in the cells. Coordinate inactivation of cell survival pathways, including cleavage of focal adhesion kinase, decreased expression of protein kinase B, and reduced phosphorylation of the pro-apoptotic protein, Bad, also characterized the signaling pathway. These events occurred in adherent cells; DNA fragmentation and detachment followed as late events 18-24h after addition of beta1 integrin antagonists. zDEVD-fmk, an irreversible inhibitor of caspase-3-like enzymes, and cytochalasin D, an actin depolymerizing agent, blocked caspase-3 cleavage and delayed cell death. In contrast to these results, undifferentiated, adherent and dividing LAN-5 cells did not die in response to beta1 integrin antagonists. These studies identify a distinct apoptotic pathway which is triggered by antagonists of beta1 integrins on differentiated adherent neuronal cells.
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PMID:beta1 integrin antagonism on adherent, differentiated human neuroblastoma cells triggers an apoptotic signaling pathway. 1111 63

Apoptotic proteases cleave and inactivate survival signaling molecules such as Akt/PKB, phospholipase C (PLC)-gamma1, and Bcl-2. We have found that treatment of A431 cells with tumor necrosis factor-alpha in the presence of cycloheximide resulted in the cleavage of epidermal growth factor receptor (EGFR) as well as the activation of caspase-3. Among various caspases, caspase-1, caspase-3 and caspase-7 were most potent in the cleavage of EGFR in vitro. Proteolytic cleavage of EGFR was inhibited by both YVAD-cmk and DEVD-fmk in vitro. We also investigated the effect of caspase-dependent cleavage of EGFR upon the mediation of signals to downstream signaling molecules such as PLC-gamma1. Cleavage of EGFR by caspase-3 significantly impaired the tyrosine phosphorylation of PLC-gamma1 in vitro. Given these results, we suggest that apoptotic protease specifically cleaves and inactivates EGFR, which plays crucial roles in anti-apoptotic signaling, to abrogate the activation of EGFR-dependent downstream survival signaling molecules.
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PMID:Proteolytic cleavage of epidermal growth factor receptor by caspases. 1122 7

Neutrophil apoptosis is an important event in the resolution of inflammation. The role of substance P (SP) in neutrophil apoptosis has not been previously investigated. We found that substance P delays apoptosis in neutrophils. Human neutrophils were isolated and cultured up to 24 hours. Apoptosis was detected by light and electron microscopy, as well as DNA-fragmentation assays. Substance P delayed the spontaneous apoptosis of neutrophils at 6, 12, 18 and 24 hours in a dose-dependent fashion in the range of 10-100 microM. Whereas the both peptide neurokinin-1 (NK-1) receptor antagonists [D-Pro(2), D-Trp(7,9)]-SP and GR 82334 inhibited the substance P effect on neutrophils, the nonpeptide NK(1) receptor antagonist L-703.606 itself, an analogue of CP-96,345, induced apoptosis of neutrophils. Surprisingly, the effect of L-703.606 could be prevented by substance P. Western blotting results showed that the neuropeptide substance P inhibited the spontaneous apoptosis-associated caspase-3 activation in the same concentration range as described above. Parallel the inhibition of cleavage of focal adhesion kinase (FAK), a substrate of caspases could be observed by substance P. In conclusion, our results extend the range of biological effects of the neuropeptide substance P and provide new insight to the role of this tachykinin in the modulation of the inflammatory response by the nervous system.
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PMID:Delay of neutrophil apoptosis by the neuropeptide substance P: involvement of caspase cascade. 1131 37

In glioblastoma cells, inhibition of focal adhesion kinase (FAK) by the focal adhesion targeting domain attenuated epidermal growth factor receptor (EGFR) signaling, inhibiting epidermal growth factor-dependent migration. Although the EGFR-specific antagonist PD153035 increased caspase-3 activity, this was independent of FAK activity. Instead, the increase in apoptosis upon inhibition of FAK induced the aggregation of an NH(2)-terminal FAK fragment normally present in the nucleus. A recombinant NH(2)-terminal FAK construct was also targeted to the nucleus and aggregated in apoptotic cells upon coexpression with the focal adhesion targeting domain. Therefore, loss of FAK from the focal adhesions inhibits EGFR signaling at the cell membrane and transmits a proapoptotic signal to an NH(2)-terminal variant of FAK present in the nucleus.
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PMID:Loss of focal adhesion kinase (FAK) inhibits epidermal growth factor receptor-dependent migration and induces aggregation of nh(2)-terminal FAK in the nuclei of apoptotic glioblastoma cells. 1143 28

Decreased phosphorylation of focal adhesion kinase (FAK) is associated with loss of focal adhesions and actin stress fibers and precedes the onset of apoptosis in renal epithelial cells caused by nephrotoxicants (Van de Water, B., Nagelkerke, J. F., and Stevens, J. L. (1999) J. Biol. Chem. 274, 13328-13337). The role of FAK in the control of apoptosis caused by nephrotoxicants was further investigated in LLC-PK1 cells that were stably transfected with either green fluorescent protein (GFP)-FAK or dominant negative acting deletion mutants of FAK, GFP-FAT, and GFP-FRNK. GFP-FAT and GFP-FRNK delayed the formation of focal adhesions and prevented the localization of endogenous (phosphorylated) FAK at these sites. GFP-FAT and GFP-FRNK overexpression potentiated the onset of apoptosis caused by the nephrotoxicant dichlorovinyl-cysteine. This was associated with an increased activation of caspase-3. GFP-FAT also potentiated apoptosis caused by doxorubicin but not cisplatin. The potentiation of apoptosis by GFP-FAT was related to an almost complete dephosphorylation of FAK; this did not occur in cells overexpressing only GFP. This dephosphorylation was associated with a pronounced loss of focal adhesion organization in GFP-FAT cells, in association with loss of tyrosine phosphorylation of paxillin. In conclusion, the data indicate an important role of cell-matrix signaling in the control of chemically induced apoptosis; loss of FAK activity caused by toxic chemicals results in perturbations of focal adhesion organization with a subsequent inactivation of associated (signaling) molecules and loss of survival signaling.
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PMID:Suppression of chemically induced apoptosis but not necrosis of renal proximal tubular epithelial (LLC-PK1) cells by focal adhesion kinase (FAK). Role of FAK in maintaining focal adhesion organization after acute renal cell injury. 1144 17

Increased expression of focal adhesion kinase (FAK) was consistently observed in low- and high-grade astrocytomas and during glioblastoma progression after radiotherapy, but not in the more benign oligodendroglioma. In glioblastoma cell lines deficient for p53, p16(INK4A), and p14(ARF), FAK was inhibited in a dominant-negative manner by the focal adhesion targeting (FAT) domain, reducing invasion. In addition, caspase-3 activity was increased after serum withdrawal, or by cisplatin in the presence of serum, or upon loss of substrate attachment, and was in each case independent of PTEN status. Our results identify FAK as a potential target for anti-invasive strategies against infiltrating glioma cells.
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PMID:PTEN-independent induction of caspase-mediated cell death and reduced invasion by the focal adhesion targeting domain (FAT) in human astrocytic brain tumors which highly express focal adhesion kinase (FAK). 1147 98


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