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 mechanisms of cell proliferation and transformation are intrinsically linked to the process of apoptosis: the default of proliferating cells is to die unless specific survival signals are provided. Platelet-derived growth factor (PDGF) is a principal survival factor that inhibits apoptosis and promotes proliferation, but the mechanisms mediating its anti-apoptotic properties are not completely understood. Here we show that the transcription factor NF-kappaB is important in PDGF signalling. NF-kappaB transmits two signals: one is required for the induction of proto-oncogene c-myc and proliferation, and the second, an anti-apoptotic signal, counterbalances c-Myc cytotoxicity. We have traced a putative pathway whereby PDGF activates NF-kappaB through Ras and phospatidylinositol-3-kinase (PI(3)K) to the PKB/Akt protein kinase and the IkappaB kinase (IKK); NF-kappaB thus appears to be a target of the anti-apoptotic Ras/PI(3)K/Akt pathway. We show that, upon PDGF stimulation, Akt transiently associates in vivo with IKK and induces IKK activation. These findings establish a role for NF-kappaB in growth factor signalling and define an anti-apoptotic Ras/PI(3)K/Akt/IKK/NF-kappaB pathway, thus linking anti-apoptotic signalling with transcription machinery.
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PMID:NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. 1048 1

Mutations in the gene encoding Bruton's tyrosine kinase (btk) cause the B cell deficiency diseases X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. In vivo and in vitro studies indicate that the BTK protein is essential for B cell survival, cell cycle progression, and proliferation in response to B cell antigen receptor (BCR) stimulation. BCR stimulation leads to the activation of transcription factor nuclear factor (NF)-kappaB, which in turn regulates genes controlling B cell growth. We now demonstrate that a null mutation in btk known to cause the xid phenotype prevents BCR-induced activation of NF-kappaB. This defect can be rescued by reconstitution with wild-type BTK. This mutation also interferes with BCR-directed activation of IkappaB kinase (IKK), which normally targets the NF-kappaB inhibitor IkappaBalpha for degradation. Taken together, these findings indicate that BTK couples IKK and NF-kappaB to the BCR. Interference with this coupling mechanism may contribute to the B cell deficiencies observed in XLA and xid.
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PMID:Bruton's tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement. 1081 67

Mutations in the gene encoding Bruton's tyrosine kinase (BTK) interfere with B cell proliferation and lead to an X-linked immunodeficiency in mice characterized by reduced B cell numbers. Recent studies have established that BTK transmits signals from the B cell antigen receptor (BCR) to transcription factor NF-kappaB, which in turn reprograms a set of genes required for normal B cell growth. We now demonstrate that induction of NF-kappaB via this pathway requires the intermediate action of the -gamma2 isoform of phospholipase C (PLC-gamma2), a potential phosphorylation substrate of BTK. Specifically, pharmacologic agents that block the action of either PLC-gamma2 or its second messengers prevent BCR-induced activation of IkappaB kinase. Moreover, activation of NF-kappaB in response to BCR signaling is completely abolished in B cells deficient for PLC-gamma2. Taken together, these findings strongly suggest that PLC-gamma2 functions as an integral component of the BTK/NF-kappaB axis following BCR ligation. Interference with this NF-kappaB cascade may account for some of the B cell defects reported for plc-gamma2(-/-) mice, which develop an X-linked immunodeficiency-like phenotype.
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PMID:Phospholipase C-gamma 2 couples Bruton's tyrosine kinase to the NF-kappaB signaling pathway in B lymphocytes. 1104 93

The serine/threonine kinase Akt/PKB is a potent regulator of cell survival and has oncogenic transformation potential. Previously, it has been shown that Akt can activate the transcription factor NF-kappaB and that this functions to block apoptosis induced by certain stimuli. The mechanism whereby Akt activates NF-kappaB has been controversial, with evidence supporting induction of nuclear translocation of NF-kappaB via activation of IkappaB kinase activity and/or the stimulation of the transcription function of NF-kappaB. Here we demonstrate that Akt targets the transactivation function of NF-kappaB by stimulating the transactivation domain of RelA/p65 in a manner that is dependent on IkappaB kinase beta activity and on the mitogen-activated protein kinase p38 (p38). Activation of RelA/p65 transactivation function requires serines 529 and 536, sites shown previously to be inducibly phosphorylated. Consistent with the requirement of p38 in the activation of NF-kappaB transcriptional function, expression of activated Akt induces p38 activity. Furthermore, the ability of IL-1beta to activate NF-kappaB is known to involve Akt, and we show here that IL-1beta induces p38 activity in manner dependent on Akt and IkappaB kinase activation. Interestingly, activated Akt and the transcriptional co-activators CBP/p300 synergize in the activation of the RelA/p65 transactivation domain, and this synergy is blocked by p38 inhibitors. These studies demonstrate that Akt, functioning through IkappaB kinase and p38, induces the transcription function of NF-kappaB by stimulating the RelA/p65 transactivation subunit of NF-kappaB.
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PMID:Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. 1125 36

Activation of the nuclear factor (NF)-kappaB transcription complex by signals derived from the surface expressed B cell antigen receptor controls B cell development, survival, and antigenic responses. Activation of NF-kappaB is critically dependent on serine phosphorylation of the IkappaB protein by the multi-component IkappaB kinase (IKK) containing two catalytic subunits (IKKalpha and IKKbeta) and one regulatory subunit (IKKgamma). Using mice deficient for protein kinase C beta (PKCbeta) we show an essential role of PKCbeta in the phosphorylation of IKKalpha and the subsequent activation of NF-kappaB in B cells. Defective IKKalpha phosphorylation correlates with impaired B cell antigen receptor-mediated induction of the pro-survival protein Bcl-xL. Lack of IKKalpha phosphorylation and defective NF-kappaB induction in the absence of PKCbeta explains the similarity in immunodeficiencies caused by PKCbeta or IKKalpha ablation in B cells. Furthermore, the well established functional cooperation between the protein tyrosine kinase Bruton's tyrosine kinase (Btk), which regulates the activity of NF-kappaB and PKCbeta, suggests PKCbeta as a likely serine/threonine kinase component of the Btk-dependent NF-kappaB activating signal transduction chain downstream of the BCR.
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PMID:Protein kinase C beta controls nuclear factor kappaB activation in B cells through selective regulation of the IkappaB kinase alpha. 1207 Feb 92

The action mechanisms of several chemopreventive agents derived from herbal medicine and edible plants have become attractive issues in cancer research. Tea is the most widely consumed beverage worldwide. Recently, the cancer chemopreventive actions of tea have been intensively investigated. It have been demonstrated that the active principles of tea were attributed to their tea polyphenols. Recently, tremendous progress has been made in elucidating the molecular mechanisms of cancer chemoprevention by tea and tea polyphenols. The suppression of various tumor biomarkers including growth factor receptor tyrosine kinases, cytokine receptor kinases, PI3K, phosphatases, ras, raf, MAPK cascades, N x FB, I x B kinase, PKA, PKB, PKC, c-jun, c-fos, c-myc, cdks, cyclins, and related transducing proteins by tea polyphenols has been studied in our laboratory and others. The I x B kinase (IKK) activity in LPS-activated murine macrophages (RAW 264.7 cells) was found to be inhibited by various tea polyphenols including (-) epigallocatechin-3-gallate (EGCG), theaflavin (TF-1), theaflavin-3-gallate (TF-2) and theaflavin-3,3'-digallate (TF-3). TF-3 inhibited IKK activity in activated macrophages more strongly than did the other tea polyphenols. TF-3 inhibited both IKK1 and IKK2 activity and prevented the degradation of I x B x and I x B x in activated macrophage cells. The results suggested that the inhibition of IKK activity by TF-3 and other tea polyphenols could occur by a direct effect on IKKs or on upstream events in the signal transduction pathway. TF-3 and other tea polyphenols blocked phosphorylation of IB from the cytosolic fraction, inhibited NFB activity and inhibited increases in inducible nitric oxide synthase levels in activated macrophage. TF-3 and other tea polyphenols also inhibited strongly the activities of xanthine oxidase, cyclooxygenase, EGF-receptor tyrosine kinase and protein kinase C. These results suggest that TF-3 and other tea polyphenols may exert their cancer chemoprevention through suppressing tumor promotion and inflammation by blocking signal transduction. The mechanisms of this inhibition may be due to the blockade of the mitogenic and differentiating signals through modulating EGFR function, MAPK cascades, NFkappaB activation as well as c-myc, c-jun and c-fos expression.
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PMID:Cancer chemoprevention by tea polyphenols through modulating signal transduction pathways. 1243 85

Granulocyte-macrophage colony-stimulating factor (GMCSF) has a central role in proliferation and differentiation of hematopoetic cells. Furthermore, it influences the proliferation and migration of endothelial cells. GMCSF elicits these functions by activating a receptor consisting of a ligand-specific alpha-chain and a beta-chain, which is common for GMCSF, interleukin-3 (IL-3), and IL-5. It is known that various signaling molecules such as Janus kinase 2 or transcription factors of the signal transducer and activator of transcription (STAT) family bind to the common beta-chain and initiate signaling cascades. However, alpha-chain-specific signal transduction adapters have to be postulated given that IL-3, IL-5, and GMCSF induce partly distinct biologic responses. Using a yeast 2-hybrid system, we identified the alpha-chain of the GMCSF receptor (GMRalpha) as putative interaction partner of IkappaB kinase beta, one of the central signaling kinases activating the transcription factor nuclear factor-kappaB (NF-kappaB). Using endogenous protein levels of endothelial cell extracts, we could verify the interaction by coimmunoprecipitation experiments. Fluorescence resonance energy transfer (FRET) microscopy confirmed the direct interaction of CFP-IKKbeta and YFPGMRalpha in living cells. Functional studies demonstrated GMCSF-dependent activation of IkappaB kinase activity in endothelial cells, degradation of IkappaB, and activation of NF-kappaB. Further biologic studies using GMCSF-dependent TF-1 cells indicated that GMCSF-triggered activation of NF-kappaB is important for cell survival and proliferation.
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PMID:GMCSF activates NF-kappaB via direct interaction of the GMCSF receptor with IkappaB kinase beta. 1263 24

Activated hepatic stellate cells (HSCs) are the main producers of extracellular matrix in the fibrotic liver and are involved in the regulation of hepatic inflammation. The aim of this study was to characterize the role of regulated on activation, normal T-cell expressed, and presumably secreted (RANTES) in activated HSCs. RANTES mRNA and protein secretion were strongly induced after stimulating HSCs with TNF-alpha, IL-1beta, or CD40L. RANTES production was NF-kappaB dependent, because inhibitor-kappaB (IkappaB) superrepressor and dominant-negative IkappaB kinase-2 almost completely blocked RANTES expression. NF-kappaB activation was sufficient to drive RANTES expression as demonstrated by the strong induction of RANTES in HSCs expressing NF-kappaB-inducing kinase. The JNK/activator protein-1 pathway also contributed to RANTES expression as demonstrated by the blocking effects of the JNK inhibitor SP600125. HSCs responded to stimulation with recombinant human (rh)RANTES with an increase in intracellular calcium concentration and a rapid increase in free radical formation. Furthermore, rhRANTES induced ERK phosphorylation, ERK-dependent [3H]thymidine incorporation, and HSC proliferation. Additionally, rhRANTES induced focal adhesion kinase phosphorylation and a substantial increase in HSC migration. HSCs functionally expressed chemokine receptor-5 (CCR5), as shown by flow-cytometric analysis and RT-PCR, and the inhibitory effects of a blocking CCR5 antibody on rhRANTES-induced ERK activation, proliferation, and migration. Diphenylene iodonium and N-acetylcysteine inhibited rhRANTES-induced ERK activation and HSC proliferation, indicating that NADPH oxidase-dependent production of reactive oxygen species was required. In conclusion, RANTES and CCR5 represent potential mediators of 1) HSC migration and proliferation and 2) a cross-talk between HSCs and leukocytes during fibrogenesis.
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PMID:Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. 1282 40

Extensive data indicate that the transcription factor NF kappa B is activated by signals downstream of oncoproteins such as Ras or breakpoint cluster region (BCR)-ABL. Consistent with this, evidence has been presented that NF kappa B activity is required for Ras and BCR-ABL to transform cells. However, it remains unclear whether these oncoproteins activate a full spectrum of NF kappa B-dependent gene expression or whether they may augment or interfere with other stimuli that activate NF kappa B. The data presented here indicate that BCR-ABL expression in 32D myeloid cells or oncogenic Ras expression in murine fibroblasts blocks the ability of tumor necrosis factor (TNF) to activate NF kappa B. This suppression of NF kappa B is manifested by an inhibition of TNF-induced inhibitor of NF kappa B (IKK) activity and NF kappa B DNA binding potential but not by blocking TNF-induced nuclear accumulation of NF kappa B/p65. The inhibition of NF kappa B is not observed in oncogenic Raf-expressing cells and is not fully restored by the suppression of PI3-kinase or MEK pathways. Oncogenic Ras suppresses the ability of TNF to activate the expression of NF kappa B-dependent genes, such as iNOS (inducible nitric oxide synthase) and RANTES (regulated on activation normal T-cell expressed and secreted). These studies suggest that the ability of Ras and BCR-ABL to activate NF kappa B involves an uncharacterized pathway that does not involve classic IKK activity and that suppresses the TNF-induced IKK pathway through a Raf/MEK/Erk-independent mechanism.
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PMID:Oncoprotein suppression of tumor necrosis factor-induced NF kappa B activation is independent of Raf-controlled pathways. 1285 13

Reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are generated in increased amounts in pathological, biological processes and can play a role in signal transduction. Neutrophils often accumulate in acute inflammatory reactions, at sites where elevated concentrations of ROS are present. ROS have been demonstrated to participate in the activation of intracellular signaling pathways, including those involved in modulating nuclear accumulation and transcriptional activity of NF-kappaB. However, the role of ROS in affecting such events in neutrophils has not been examined. Using exposure of murine bone marrow neutrophils to H2O2 as a model of oxidative stress, we found both strong and persistent activation of ERK1/2, p38, JNK, and PKB, but not the p21-activated kinase. Stimulating the bone marrow-derived neutrophils with H2O2 did not affect nuclear translocation of NF-kappaB. However, production and secretion of the proinflammatory cytokine TNF-alpha in LPS-stimulated neutrophils were inhibited by H2O2. Exposure of LPS- or TNF-alpha-stimulated neutrophils to H2O2 decreased nuclear translocation of NF-kappaB. LPS-induced activation of the transcriptional factor AP-1 was also inhibited by H2O2. This inhibition of nuclear accumulation of NF-kappaB by H2O2 was not caused by an impaired capacity of LPS to stimulate the IKK pathway or to direct oxidative effects on NF-kappaB but rather reflected diminished degradation of IkappaB-alpha. These results indicate that oxidative stress, despite being able to selectively activate intracellular kinases in bone marrow-derived neutrophils, also inhibits NF-kappaB activation and associated TNF-alpha expression. Such inhibitory effects on neutrophil activation may limit tissue damage produced by oxidative stress.
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PMID:Modulation of bone marrow-derived neutrophil signaling by H2O2: disparate effects on kinases, NF-kappaB, and cytokine expression. 1465 21


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