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Insulin-stimulated phosphorylation of endothelial nitric oxide synthase at Ser615 contributes to nitric oxide synthesisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Insulin stimulates endothelial nitric oxide synthesis via protein kinase B/Akt-mediated phosphorylation and activation of endothelial nitric oxide synthase at Ser1177. In previous studies, we have demonstrated that stimulation of endothelial nitric oxide synthase phosphorylation at Ser1177 may be required, yet is not sufficient for insulin-stimulated nitric oxide synthesis. We therefore investigated the role of phosphorylation of endothelial nitric oxide synthase at alternative sites to Ser1177 as candidate parallel mechanisms contributing to insulin-stimulated nitric oxide synthesis. Stimulation of human aortic endothelia...
Source: BJ Signal - November 20, 2009 Category: Biochemistry Authors: S A Ritchie, C F Kohlhaas, A R Boyd, K C Yalla, K Walsh, J MC Connell, I P Salt Tags: BJ Signal Source Type: journals

The adaptor protein EBP50 is important for localization of the protein kinase A{-}Ezrin complex in T cells and the immunomodulating effect of cAMPEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We recently reported that the dual-specific A kinase anchoring protein (AKAP) Ezrin targets type I protein kinase A (PKA) to the vicinity of the T cell receptor (TCR) in T cells and together with phosphoprotein associated with glycosphingolipid-enriched membrane microdomains (PAG) and Ezrin/Radixin/Moesin (ERM) binding phosphoprotein 50 (EBP50) forms a scaffold that positions PKA close to its substrate the C-terminal Src kinase (Csk). This complex is important for controlling the activation state of the T cell. Ezrin binds to the adaptor protein EBP50 which again contacts PAG. In this work we show that Ezrin and EBP50 inte...
Source: BJ Signal - October 26, 2009 Category: Biochemistry Authors: A Jorun Stokka, R Mosenden, A Ruppelt, B Lygren, K Taskén Tags: BJ Signal Source Type: journals

Development of an intracellularly-acting inhibitory peptide selective for PKNEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PKNs form a subfamily of the AGC serine/threonine protein kinases, and have a catalytic domain homologous to that of protein kinase C (PKC) in the carboxyl-terminal region and three characteristic antiparallel coiled coil (ACC) domain repeats in the amino-terminal region. The preferred peptide phosphorylation motif for PKNs determined by a combinatorial peptide library method was highly similar to that of PKCs within a 10 amino acid stretch. Previously reported PKN inhibitory compounds also inhibit PKCs to a similar extent, and no PKN selective inhibitors have been commercially available. We have identified a 15 amino acid...
Source: BJ Signal - October 26, 2009 Category: Biochemistry Authors: K Shiga, K Takayama, S Futaki, J E Hutti, L C Cantley, K Ueki, Y Ono, H Mukai Tags: BJ Signal Source Type: journals

G-protein coupled receptor kinases mediate TNF{alpha}-induced NF{kappa}B signaling via direct interaction with and phosphorylation of I{kappa}B{alpha}Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Tumor necrosis factor-α (TNFα) is a multifunctional cytokine involved in the pathophysiology of many chronic inflammatory diseases. TNFα activation of the nuclear factor κB (NFκB) signaling pathway particularly in macrophages has been implicated in many diseases. We demonstrate here that G-protein coupled receptor kinase-2 and 5 (GRK2 and 5) regulate TNFα-induced NFκB signaling in Raw264.7 macrophages. RNAi knockdown of GRK2 or 5 in macrophages significantly inhibits TNFα-induced IκBα phosphorylation and degradation, NFκB activation, and expressio...
Source: BJ Signal - October 1, 2009 Category: Biochemistry Authors: S Patial, J Luo, K J. Porter, J L. Benovic, N Parameswaran Tags: BJ Signal Source Type: journals

IRAK1-independent pathways required for the interleukin 1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The protein kinase Tpl2 is activated by LPS, TNFα and IL-1. Activation of the native Tpl2 complex by these agonists requires the IKKβ-catalysed phosphorylation of the p105/NFκB1 subunit and is accompanied by the release of the catalytic subunit from both p105/NFκB1 and another subunit ABIN2. Here we report that IL-1 activates the transfected Tpl2 catalytic subunit in an HEK293 cell line that stably expresses the IL-1 receptor, but does not express the protein kinase IRAK1. In these cells IL-1 does not activate IKKβ or induce the phosphorylation of p105/NFκB1, and nor does the IKK...
Source: BJ Signal - September 14, 2009 Category: Biochemistry Authors: H Saputro Handoyo, M Stafford, D Baltzis, E McManus, M Peggie, P Cohen Tags: BJ Signal Source Type: journals

Mapping the ligand-binding pocket of integrin {alpha}5{beta}1 using a gain-of-function approachEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Integrin α5β1 is a key receptor for the extracellular matrix protein fibronectin.Antagonists of human α5β1 have therapeutic potential as anti-angiogenic agents in cancer and diseases of the eye. However, the structure of the integrin is unsolved and the atomic basis of fibronectin and antagonist binding by α5β1 is poorly understood. Here we demonstrate that zebrafish α5β1 integrins do not interact with human fibronectin or the human α5β1 antagonists JSM6427 and cyclic peptide CRRETAWAC. Zebrafish α5β1 integrins do bind zebrafish fibronectin...
Source: BJ Signal - September 13, 2009 Category: Biochemistry Authors: A Paul Mould, E Joanna Koper, A Byron, G Zahn, M J Humphries Tags: BJ Signal Source Type: journals

Myosin is reversibly inhibited by S-nitrosylationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study reveals a new link between exercise and S-nitrosylation of skeletal muscle contractile proteins that may be important under (patho)physiological conditions. (Source: BJ Signal)
Source: BJ Signal - September 10, 2009 Category: Biochemistry Authors: L Nogueira, C Figueiredo-Freitas, G Casimiro-Lopes, M H. Magdesian, J Assreuy, M M. Sorenson Tags: BJ Metabolism Source Type: journals

Differential regulation of adipocyte PDE3B in distinct membrane compartments by insulin and the {beta}3-receptor agonist CL316243: Effects of caveolin-1 knockdown on formation/maintenance of macromolecular signaling complexesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In adipocytes, Phosphodiesterase 3B (PDE3B) is an important regulatory effector in signaling pathways controlled by insulin and cAMP-increasing hormones. Stimulation of 3T3-L1 adipocytes with insulin or the β3-receptor agonist CL316243 (CL) indicated that insulin preferentially phosphorylated /activated PDE3B associated with internal membranes (endoplasmic reticulum/Golgi), whereas CL preferentially phosphorylated/ activated PDE3B associated with caveolae. siRNA-mediated knock-down (KD) of caveolin-1 (cav-1) in 3T3-L1 adipocytes resulted in down-regulation of expression of membrane- associated PDE3B. Insulin-induced...
Source: BJ Signal - September 10, 2009 Category: Biochemistry Authors: F Ahmad, R Lindh, Y Tang, L Ruishalme, A Öst, P Strålfors, E Degerman, V C. Manganiello Tags: BJ Signal Source Type: journals

Regulation of RND3 localization and function by PKC{alpha}-mediated phosphorylationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The Rnd proteins (Rnd1, Rnd2 and Rnd3/RhoE) form a distinct branch of the Rho family of small GTPases. Altered Rnd3 expression causes changes in cytoskeletal organization and cell cycle progression. Rnd3 functions to decrease RhoA activity, but how Rnd3 itself is regulated to cause these changes is still under investigation. Unlike other Rho family proteins, Rnd3 is regulated not by GTP/GDP cycling, but at the level of expression and by posttranslational modifications such as prenylation and phosphorylation. We show here that, upon PKC agonist stimulation, Rnd3 undergoes an electrophoretic mobility shift and its subcellula...
Source: BJ Signal - August 31, 2009 Category: Biochemistry Authors: J P Madigan, B O Bodemann, D C Brady, B J Dewar, P J Keller, M Leitges, M R Philips, A J Ridley, C J. Der, A D Cox Tags: BJ Signal Source Type: journals

Nutrient isothiocyanates covalently modify and inhibit the inflammatory cytokine macrophage migration inhibitory factor (MIF)Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Dietary isothiocyanates (ITCs) prevent cancer and show other bioactivities in vivo. As electrophiles, ITCs may covalently modify cellular proteins. Using a novel proteomics screen, we identified the Macrophage Migration Inhibitory Factor (MIF) as the principal target of nutrient ITCs in intact cells. ITCs covalently modify the amino-terminal proline residue of MIF and extinguish its catalytic tautomerase activity. MIF deficiency does not prevent induction of Phase 2 gene expression, a hallmark of many cancer chemopreventives including ITCs. Due to the emerging role of MIF in control of malignant cell growth and its clear i...
Source: BJ Signal - August 31, 2009 Category: Biochemistry Authors: J V Cross, J M Rady, F W Foss Jr., C Lyons, T L Macdonald, D J Templeton Tags: BJ Cell Source Type: journals

Design of proteolytically stable RI anchoring disruptor peptidomimetics for in vivo studies of anchored type I protein kinase A-mediated signalingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We have previously reported the design of an RI anchoring disruptor peptide (RIAD) that specifically displaces protein kinase A (PKA) type I from the A-kinase anchoring protein Ezrin, which is present in the immunological synapse of T cells. This increases immune reactivity by reducing the threshold for activation, and may prove a feasible approach for improving immune function in patients with cAMP-mediated T-cell dysfunction. However, the use of RIAD in biological systems is restricted by its susceptibility to enzymatic cleavage and, consequently, its short half-life in presence of the ubiquitous serum peptidases. In the...
Source: BJ Signal - August 27, 2009 Category: Biochemistry Authors: E A. Torheim, E Jarnæss, B Lygren, K Taskén Tags: BJ Signal Source Type: journals

Active site determinants of substrate recognition by the metalloproteinases TACE and ADAM10Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The metalloproteinases TACE (ADAM17) and ADAM10 are the primary enzymes responsible for catalyzing release of membrane anchored proteins from the cell surface in metazoan organisms. While the repertoire of protein substrates for these two proteases is partially overlapping, each one appears to target a subset of unique proteins in vivo. The mechanisms by which the two proteases achieve specificity for particular substrates are not completely understood. We have used peptide libraries to define the cleavage site selectivity of TACE and ADAM10. The two proteases have distinct primary sequence requirements at multiple positio...
Source: BJ Signal - August 27, 2009 Category: Biochemistry Authors: C I. Caescu, G R. Jeschke, B E. Turk Tags: BJ Cell Source Type: journals

The human hypoxia-inducible factor (HIF)-3{alpha} gene is a HIF-1 target and may modulate hypoxic gene inductionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hypoxia-inducible factor (HIF)-3alpha is the third member of the HIF transcription factor family. Whereas HIF-1alpha and -2alpha play critical roles in the cellular and systemic adaptation to hypoxia, little is known about the regulation and function of HIF-3alpha. At least five different splice variants may be expressed from the human HIF-3alpha locus, which are suggested to exert primarily negative regulatory effects on hypoxic gene induction. Here we report that hypoxia induces the human HIF-3alpha gene at the transcriptional level in a HIF-1-dependent manner. HIF-3alpha2 and HIF-3alpha4 transcripts, the HIF-3alpha spli...
Source: BJ Signal - August 20, 2009 Category: Biochemistry Authors: T Tanaka, M S. Wiesener, W Bernhardt, K Uwe Eckardt, C Warnecke Tags: BJ Signal Source Type: journals

Urokinase receptor-mediated phenotypic changes of vascular smooth muscle cells require involvement of membrane raftsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this report, we provide evidence that the molecular machinery of uPAR-mediated VSMC differentiation employs lipid rafts. We show that the disruption of rafts in VSMC by membrane cholesterol depletion using methyl-β-cyclodextrin (MCD) or filipin leads to upregulation of uPAR and cell de-differentiation. uPAR silencing by means of interfering RNA resulted in an increased expression of contractile proteins. Consequently, disruption of lipid rafts impaired expression of these proteins and transcriptional activity of related genes. We provide evidence that this effect was mediated by uPAR. Similar effects were observe...
Source: BJ Signal - August 19, 2009 Category: Biochemistry Authors: J Kiyan, G Smith, H Haller, I Dumler Tags: BJ Cell Source Type: journals

Angiopoietin-1 induced ubiquitylation of Tie2 by c-Cbl is required for internalization and degradationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Tie2 is a receptor tyrosine kinase expressed predominantly on the surface of endothelial cells. Activated by its ligands, the Angiopoietins, Tie2 initiates signaling pathways that modulate vascular stability and angiogenesis. Deletion of either Tie2 or Angiopoietin-1 (Ang1) genes in mice results in lethal vascular defects signifying their importance in vascular development. The mechanism employed by the Tie2 signalling machinery to attenuate or cause receptor trafficking is not well defined. Stimulation of Tie2-expressing cells with Ang1 results in its ubiquitylation suggesting that this may provide the necessary signal fo...
Source: BJ Signal - August 17, 2009 Category: Biochemistry Authors: C Wherle, P Van Slyke, D J. Dumont Tags: BJ Signal Source Type: journals

Binding of cyclic nucleotides to phosphodiesterase 10A and 11A GAF domains does not stimulate catalytic activityEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
To date, 11 human cyclic nucleotide phosphodiesterase (PDE) families have been identified. Of these, five families contain non-catalytic tandem GAF domains (GAFa and GAFb) in the N-terminal part of the enzyme. For PDE2A, PDE5A and PDE6, the GAF domains have been shown to bind cyclic GMP with high affinity. For PDE2A and PDE5A, the ligand binding has been shown to stimulate the catalytic activity of the enzyme. For the most recently described PDEs, PDE10A and PDE11A, the GAF domains have previously been suggested to bind cAMP and cGMP, respectively. We have developed scintillation proximity based assays for cyclic nucleotid...
Source: BJ Signal - August 17, 2009 Category: Biochemistry Authors: K Matthiesen, J Nielsen Tags: BJ Signal Source Type: journals

Oxidative modifications of glyceraldehyde-3-phosphate dehydrogenase play a key role in its multiple cellular functionsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Knowledge of the cellular targets of reactive oxygen species (ROS) and their regulation is an essential prerequisite for understanding ROS-mediated signaling. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), is known as a major target protein in oxidative stresses and becomes thiolated in active site. However, the molecular and functional changes of oxidized GAPDH, inactive form, have not yet been characterized. To examine the modifications of GAPDH under oxidative stress, we separated the oxidation products by 2D-gel electrophoresis and identified them using nanoLC-ESI-q-TOF tandem MS. Intracellular GAPDH subjected to ox...
Source: BJ Signal - August 3, 2009 Category: Biochemistry Authors: N Hwang, S Yim, Y Kim, J Jeong, E Song, Y Lee, J Lee, S Choi, K Lee Tags: BJ Signal Source Type: journals

The C-terminal domain of Mnk1a plays a dual role in tightly regulating its activityEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The human family of MAP kinase signal-integrating kinases (Mnks) comprises four related proteins derived from two genes by alternative splicing. The Mnk1 gene gives rise to two proteins, Mnk1a and Mnk1b, which possess distinct C-termini and properties. Despite lacking the C-terminal MAP kinase-binding site, Mnk1b shows higher basal activity than Mnk1a. In contrast, the activity of Mnk1a is tightly regulated by signalling through ERK and p38 MAP kinase. We show that the short C-terminus of Mnk1b confers on it a ‘default’ behaviour of substantial, but unregulated, activity. In contrast, the longer C-terminu...
Source: BJ Signal - August 2, 2009 Category: Biochemistry Authors: S Goto, Z Yao, C G. Proud Tags: BJ Signal Source Type: journals

Glucocorticoids can activate the {alpha}-ENaC gene promoter independently of SGK1Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The role of SGK1 (serum and glucocorticoid-inducible kinase 1) in the glucocorticoid-induced of α-ENaC (epithelial Na+ channel α subunit) gene transcription was explored by monitoring the transcriptional activity of a luciferase-linked, α-ENaC reporter gene construct (pGL3-KR1) expressed in H441 airway epithelial cells. Dexamethasone evoked a concentration-dependent (EC50 ~ 4 µM) increase in transcriptional activity dependent upon a glucocorticoid response element in the α-ENac sequence. Although dexamethasone also activated endogenous SGK1, artificially increasing cellular SGK1 ac...
Source: BJ Signal - July 20, 2009 Category: Biochemistry Authors: N McTavish, J Getty, A Burchell, S M. Wilson Tags: BJ Signal Source Type: journals

Potentiation of flagellin responses in gut epithelial cells by interferon gamma is associated with STAT-independent regulation of MyD88 expressionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study has investigated regulation of flagellin /TLR5 signalling in human colonocytes (HT29-19A) by interferon-gamma (IFNγ), a cytokine released early in the inflammatory process which has multiple effects on gut epithelial function that may facilitate abnormal responses to enteric bacteria. Flagellin induced a dose-dependent secretion of chemokines CXCL8 and CCL2 in the human colonocyte line, HT29-19A. Exposure to IFNγ did not induce chemokine secretion but markedly potentiated responses to flagellin increasing CXL8 gene expression and protein secretion by ~4 fold. Potentiation by IFNγ was indepen...
Source: BJ Signal - July 20, 2009 Category: Biochemistry Authors: C Bannon, P Davies, A Collett, G Warhurst Tags: BJ Cell Source Type: journals

Inositol pyrophosphates modulate hydrogen peroxide signalingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study we use Saccharomyces cerevisiae mutants to examine the potential roles of inositol pyrophosphates in responding to cell damage caused by reactive oxygen species (ROS). Yeast lacking kcs1 (the S. cerevisiae IP6K) have greatly reduced IP7 and IP8 levels, and display increased resistance to cell death caused by hydrogen peroxide (H2O2) consistent with a sustained activation of DNA repair mechanisms controlled by the Rad53 pathway. Other Rad53 controlled functions such actin polymerization appear unaffected by inositol pyrophosphates. Yeast lacking vip1 (S. cerevisiae PP-IP5K) accumulate large amounts of the inos...
Source: BJ Signal - July 16, 2009 Category: Biochemistry Authors: S Maria Nancy Onnebo, A Saiardi Tags: BJ Signal Source Type: journals

Specific role of phosphoinositide 3-kinase p110{alpha} in the regulation of phagocytosis and pinocytosis in macrophagesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Phosphoinositide 3-kinase (PI3K) has been implicated in phagocytosis and fluid-phase pinocytosis in macrophages. The subtype-specific role of PI3K in these processes is poorly understood. To elucidate this issue, we made Raw 264.7 cells deficient in each of the class-I PI3K catalytic subunits: p110α, p110β, p110δ and p110γ. Among these cells, only the p110α-deficient cells exhibited lower phagocytosis of opsonized and non-opsonized zymosan. The p110α-deficient cells also showed the impaired phagocytosis of IgG-opsonized erythrocytes and the impaired fluid-phase pinocytosis of dextr...
Source: BJ Signal - July 14, 2009 Category: Biochemistry Authors: N Tamura, K Hazeki, N Okazaki, Y Kametani, H Murakami, Y Takaba, Y Ishikawa, K Nigorikawa, O Hazeki Tags: BJ Signal Source Type: journals

A mechanism for the supperssion of IL-1-induced NF-{kappa}B activation by the protein phosphatase 2C{eta}-2Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Interleukin-1 (IL-1) is a pro-inflammatory cytokine that has a variety of effects during the process of inflammation. Stimulating cells with IL-1 initiates a signaling cascade, which includes the activation of the nuclear transcription factor-κB (NF-κB), and subsequently induces a variety of inflammatory genes. Although the molecular mechanism for the IL-1-induced activation of NF-κB has been well documented, much less is known about the mechanism by which protein phosphatases downregulate this pathway. Here we show that mouse protein phosphatase 2Cη-2 (PP2Cη-2), a novel member of the pro...
Source: BJ Signal - July 13, 2009 Category: Biochemistry Authors: T Henmi, K Amano, Y Nagaura, K Matsumoto, S Echigo, S Tamura, T Kobayashi Tags: BJ Signal Source Type: journals

Interaction of mitochondrial thioredoxin with glucocorticoid receptor and NF-{kappa}{Beta} modulates glucocorticoid receptor and NF-{kappa}B signaling in HEK 293 cellsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Mitochondrial thioredoxin (Trx2) is an antioxidant, antiapoptotic factor, essential for cell viability. The cytoplasmic thioredoxin (Trx1) is a cofactor and regulator of redox sensitive transcription factors such as the glucocorticoid receptor (GR) and NF-κB. Both transcription factors have been detected in mitochondria and a role in mitochondrial transcription regulation and apoptosis has been proposed. Here, we show using surface plasmon resonance and immunoprecepitation that GR and the p65 subunit of NF-κΒ are Trx2 interacting proteins. The interaction of Trx2 with GR is independent of the presence ...
Source: BJ Signal - July 1, 2009 Category: Biochemistry Authors: A G Psarra, S Hermann, G Panayotou, G Spyrou Tags: BJ Signal Source Type: journals

DNA damage signalling recruits RREB-1 to the p53 tumor suppressor promoterEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Transcriptional regulation of the p53 tumor suppressor gene plays an important role in expression control of various target genes involved in the DNA damage response. However, the molecular basis for this regulation remains obscure. Here we demonstrate that RAS-responsive element-binding protein-1 (RREB-1) efficiently binds to the p53 promoter via the p53 core promoter element and transactivates p53 expression. Silencing of RREB-1 significantly reduces p53 expression at both the mRNA and the protein levels. Notably, disruption of RREB-1-mediated p53 transcription suppresses the expression of the p53 target genes. We also s...
Source: BJ Signal - June 25, 2009 Category: Biochemistry Authors: H Liu, H Hew, Z Lu, T Yamaguchi, Y Miki, K Yoshida Tags: BJ Signal Source Type: journals

Sodium nitrite therapy attenuates hypertensive effects of HBOC-201 via nitrite reductionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hypertension secondary to scavenging of nitric oxide (NO) remains a limitation in the use hemoglobin based oxygen carriers (HBOCs). Recent studies suggest that nitrite reduction to NO by deoxyhemoglobin supports NO-signaling. Herein, we tested whether nitrite would attenuate HBOC-mediated hypertension using HBOC-201 (Biopure), a bovine cross-linked, low oxygen affinity hemoglobin. Similar to unmodified hemoglobin, deoxygenated HBOC-201 reduced nitrite to NO with rates directly proportional to the extent of deoxygenation. The functional importance of HBOC-201 dependent nitrite reduction was demonstrated using isolated aorti...
Source: BJ Signal - June 24, 2009 Category: Biochemistry Authors: C Rodriguez, D A. Vitturi, J He, M Vandromme, A Brandon, A Hutchings, L W. Rue III, J D. Kerby, R P. Patel Tags: BJ Energy Source Type: journals

Recruitment of NAADP-sensitive acidic Ca2{+} stores by glutamateEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
NAADP is a novel second messenger thought to mobilize acidic Ca2+ stores that are functionally coupled to the endoplasmic reticulum. Although NAADP-sensitive Ca2+ stores have been described in neurons, the physiological cues that recruit them are not known. Here we show that in both hippocampal neurons and glia, extracellular application of glutamate in the absence of external Ca2+ evoked cytosolic Ca2+ signals that were inhibited by blockade of V-type ATPases or following osmotic bursting of lysosomes. The sensitivity of both cell types to glutamate correlated well with lysosomal Ca2+ co...
Source: BJ Signal - June 22, 2009 Category: Biochemistry Authors: V Pandey, C Chuang, A M Lewis, P Aley, E Brailoiu, N Dun, G C Churchill, S Patel Tags: BJ Signal Source Type: journals

Two novel phosphatidylinositol 4-phosphate, 5-kinase type I gamma splice variants expressed in human cells display distinctive cellular targetingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The generation of various phosphoinositide messenger molecules at distinct locations within the cell is mediated via the specific targeting of different isoforms and splice variants of phosphoinositide kinases. The lipid messenger phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) is generated by several of these enzymes when targeted to distinct cellular compartments. Several splice variants of the type Iγ isoform of phosphatidylinositol 4-phosphate, 5-kinase (PIPKIγ) which generate PtdIns(4,5)P2 have been identified, and each splice variant is thought to serve a unique functional role within cells. Here,...
Source: BJ Signal - June 22, 2009 Category: Biochemistry Authors: N J Schill, R A Anderson Tags: BJ Signal Source Type: journals

Human heme oxygenase-1 induction by nitro-linoleic acid is mediated by cyclic AMP, AP-1, and E-box response element interactionsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Nitro-fatty acid products of oxidative inflammatory reactions mediate anti-inflammatory cell signaling responses. Nitro-linoleic acid (LNO2) induces expression of heme oxygenase-1 (HO-1), an enzyme that catabolizes heme into products exhibiting potent anti-inflammatory properties. Here the molecular mechanisms underlying HO-1 induction by LNO2 were examined in human aortic endothelial cells (HAEC), human embryonic kidney (HEK) 293 cells, and in transcription factor-deficient mouse embryonic fibroblasts (MEF). LNO2 induced HO-1 expression in Nrf2 deficient MEF and in HEK 293 cells transfected with Nrf2 specific shRNA, suppo...
Source: BJ Signal - June 17, 2009 Category: Biochemistry Authors: M M. Wright, J Kim, T D Hock, N Leitinger, B A Freeman, A Agarwal Tags: BJ Signal Source Type: journals

Generation and functional characterization of a BCL10 inhibitory peptide that represses NF-{kappa}B activationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The molecular complex containing BCL10 and CARMA proteins has been recently identified as key component in the signalling transduction pathways that regulate activation of NF-κB transcription factor in lymphoid and non-lymphoid cells. Assembly of the molecular complexes containing BCL10 and CARMA proteins relies on homophylic interactions established between the CARD domains of these proteins. In order to identify BCL10 inhibitory peptides, we have established a method of assaying peptides derived from the CARD of BCL10 in a binding competition assays of CARD-CARD self-association. By this procedure, a short peptide...
Source: BJ Signal - June 17, 2009 Category: Biochemistry Authors: D Marasco, R Stilo, A Sandomenico, S Maria Monti, B Tizzano, A De Capua, E Varricchio, D Liguoro, T Zotti, S Formisano, M Ruvo, P Vito Tags: BJ Signal Source Type: journals

The insert region of the Rac GTPases is dispensable for activation of superoxide-producing NADPH oxidasesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Rac1 and Rac2, which belong to the Rho subfamily of Ras-related GTPases, play an essential role in activation of gp91phox (also known as Nox2), the catalytic core of the superoxide-producing NADPH oxidase in phagocytes; and Rac1 also contributes to activation of the non-phagocytic oxidases Nox1 and Nox3, each related closely to gp91phox/Nox2. It has remained controversial whether the insert region of Rac (amino acids 123–135), unique to the Rho subfamily proteins, is involved in gp91phox/Nox2 activation. Here we show that removal of the insert region from Rac1 neither affects activation of gp91phox/Nox2, which is re...
Source: BJ Signal - June 16, 2009 Category: Biochemistry Authors: K Miyano, H Koga, R Minakami, H Sumimoto Tags: BJ Signal Source Type: journals

Coupling oxidative signals to protein phosphorylation via methionine oxidation in ArabidopsisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The mechanisms involved in sensing oxidative signaling molecules such as H2O2 in plant and animal cells are not completely understood. In the present study, we tested the postulate that oxidation of methionine (Met) to Met sulfoxide (MetSO) can couple oxidative signals to changes in protein phosphorylation. We demonstrate that when a Met residue functions as a hydrophobic recognition element within a phosphorylation motif, its oxidation can strongly inhibit peptide phosphorylation in vitro. This is shown to occur with recombinant soybean calcium dependent protein kinases (CDPKs) and human AMP-dependent protein kinase (AMPK...
Source: BJ Signal - June 15, 2009 Category: Biochemistry Authors: S C. Hardin, C T. Larue, M Oh, V Jain, S C Huber Tags: BJ Plant Source Type: journals

Immunocytochemical techniques reveal multiple, distinct cellular pools of PtdIns4P and PtdIns(4,5)P2Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report distinct pools of this lipid in both Golgi and plasma membranes, which are synthesised by different PI 4-kinase activities, and also the presence of PtdIns4P in cytoplasmic vesicles which are not readily identifiable as PI 4-kinase containing trafficking intermediates. In addition, we present evidence that the majority of PtdIns4P resides in the plasma membrane, where it is metabolically distinct from the steady-state plasma membrane pool of PtdIns(4,5)P2. (Source: BJ Signal)
Source: BJ Signal - June 9, 2009 Category: Biochemistry Authors: G R V Hammond, G Schiavo, R Francis Irvine Tags: BJ Cell Source Type: journals

Epidermal growth factor stimulates translocation of the class II phosphoinositide 3-kinase PI3K-C2{beta} to the nucleusEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study we test the hypothesis that PI3K-C2β translocates to nuclei in response to growth factor stimulation. Fractionating homogenates of quiescent cells revealed that less than 5% of total PI3K-C2β resides in nuclei. Stimulation with epidermal growth factor sequentially increased levels of this enzyme in the cytosol and then in nuclei. Using detergent treated nuclei, PI3K-C2β co-localized with lamin A/C in the nuclear matrix. This was confirmed biochemically and phosphoinositide kinase assay showed a statistically significant increase in nuclear PI3K-C2β levels and lipid kinase activity ...
Source: BJ Signal - June 4, 2009 Category: Biochemistry Authors: H Banfic, D Visnjic, N Mise, S Balakrishnan, S Deplano, Y E. Korchev, J Domin Tags: BJ Signal Source Type: journals

8-Bromo-cyclic inosine diphosphoribose: towards a selective cyclic ADP-ribose agonistEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cyclic ADP-ribose (cADPR) is a universal Ca2+ mobilizing second messenger. In T cells cADPR is involved in sustained Ca2+ release and also in Ca2+ entry. Potential mechanisms for the latter include either capacitative Ca2+ entry secondary to store depletion by cADPR or direct activation of the non-selective cation channel transient receptor potential – melastatin type 2 (TRPM2). Here we characterize the molecular target of the newly-described membrane-permeant cADPR agonist 8-bromo-cyclic inosine diphosphoribose (8-Br-N1-cIDPR). 8-Br-N1-cIDPR evoked Ca2+ signalling in the human T-...
Source: BJ Signal - June 3, 2009 Category: Biochemistry Authors: T Kirchberger, C Moreau, G K. Wagner, R Fliegert, C C. Siebrands, M Nebel, F Schmid, A Harneit, F Odoardi, A Flügel, B V.L. Potter, A H. Guse Tags: BJ Signal Source Type: journals

Cul3-mediated Nrf2 ubiquitination and ARE activation are dependent on the partial molar volume at position 151 of Keap1Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Nrf2 is a transcription factor that activates transcription of a battery of cytoprotective genes by binding to the antioxidant response element (ARE). Nrf2 is repressed by the cysteine-rich Keap1 protein, which targets Nrf2 for ubiquitination and subsequent degradation by a Cul3-mediated ubiquitination complex. We find that modification of C151 of human Keap1 by mutation to a tryptophan relieves the repression by Keap1 and allows activation of the ARE by Nrf2. Keap1 C151W has a decreased affinity for Cul3, and can no longer serve to target Nrf2 for ubiquitination, though it retains its affinity for Nrf2. A series of 12 mut...
Source: BJ Signal - June 2, 2009 Category: Biochemistry Authors: A L. Eggler, E Small, M Hannink, A D. Mesecar Tags: BJ Gene Source Type: journals

Isolation and characterization of a secreted, cell-surface glycoprotein SCUBE2 from humansEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we isolated the full-length cDNA and studied the role of human SCUBE2 in the HH signaling cascade. When overexpressed, recombinant human SCUBE2 manifests as a secreted, surface-anchored glycoprotein. Deletion mapping analysis defines the critical role of the spacer region and/or cystein-rich repeats for membrane association. Further biochemical analyses and functional reporter assays demonstrated that human SCUBE2 can specifically interact with Sonic HH (SHH) and SHH receptor Patched-1 (PTCH1), and enhance the SHH signaling activity within the cholesterol-rich raft microdomains of the plasma membranes. Toget...
Source: BJ Signal - June 1, 2009 Category: Biochemistry Authors: M Tsai, C Cheng, Y Lin, C Chen, A Wu, M Wu, C Hsu, R Yang Tags: BJ Signal Source Type: journals

AMPK{alpha}1 regulates the antioxidant status of vascular endothelial cellsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
AMP-activated protein kinase (AMPK) is a key regulator of cellular energy because of its capacity to detect changes in the concentration of AMP. Recent evidence, however, indicates the existence of alternative mechanisms of activation of this protein. Mitochondrial reactive oxygen species (ROS), generated as a result of the interaction between nitric oxide and mitochondrial cytochrome c oxidase, activate AMPKα1 in human umbilical vein endothelial cells (HUVECs) at a low oxygen concentration (i.e. 3%). This activation is independent of changes in AMP. We now show, using HUVECs in which AMPKα1 has been silence...
Source: BJ Signal - May 14, 2009 Category: Biochemistry Authors: S L Colombo, S Moncada Tags: BJ BJ Signal Source Type: journals

Glycyrrhizin, the main active compound in licorice, attenuates pro-inflammatory responses by interfering with membrane-dependent receptor signalingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we aimed to elucidate the molecular mechanism of GL in attenuating inflammatory responses in macrophages. Using microarray analysis, we found that GL caused a broad block in the induction of pro-inflammatory mediators induced by the toll-like receptor 9 (TLR9) agonist CpG-DNA in RAW 264.7 cells. Furthermore, we found that GL also strongly attenuated inflammatory responses induced by TLR3 and TLR4 ligands. The inhibition was accompanied by reduced activation not only of the NF-κB pathway but also of the parallel MAPKs signaling cascade upon stimulation with TLR9 and TLR4 agonists. Further analysis of u...
Source: BJ Signal - May 14, 2009 Category: Biochemistry Authors: B Schröfelbauer, J Raffetseder, M Hauner, A Wolkerstorfer, W Ernst, O H. J. Szolar Tags: BJ BJ Signal Source Type: journals

PKC epsilon has an alcohol binding site in its second cysteine rich regulatory domainEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Alcohols regulate expressions and functions of Protein kinase C (PKC) and it has been proposed that an alcohol-binding site is present in the PKCα in its C1 domain consisting of two cysteine rich subdomains C1A and C1B. Knockout mouse of PKCε showed significant decrease in alcohol consumption compared to the wild type. Here we show ethanol inhibited PKCε activity in a concentration dependent manner with an EC50 of 43 mM. Ethanol, butanol and octanol increased the binding affinity of a fluorescent phorbol ester Sapintoxin-D (SAPD) to PKCεC1B in a concentration dependent manner with EC50s of 78 mM...
Source: BJ Signal - May 11, 2009 Category: Biochemistry Authors: J Das, S Pany, G M. Rahman, S J. Slater Tags: BJ BJ Signal Source Type: journals

NF-{kappa}B activation primes cells to a pro-inflammatory polarized response to a TLR7 agonistEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Toll-like receptor 7 (TLR7) mediates anti-viral immunity by recognizing ssRNA viruses. Small molecular weight TLR7 agonists have been approved, or are being evaluated, for treatment of cancers or infectious diseases. Although TLR7 is predominantly expressed in a restricted set of immune cell types including plasmacytoid dendritic cells (pDCs), it is also expressed in non-native expressing cells (e.g., hepatocytes) under certain circumstances. To elucidate the molecular basis of TLR7 induction by pro-inflammatory stimulation and the subsequent cellular responses in these non-native TLR7-expressing cell types, we firstly clo...
Source: BJ Signal - May 8, 2009 Category: Biochemistry Authors: J Lee, M Hayashi, J Lo, C Fearns, W Chu, Y Luo, R Xiang, T Chuang Tags: BJ BJ Signal Source Type: journals

Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
mTOR stimulates cell growth by phosphorylating and promoting activation of AGC family kinases such as Akt, S6K and SGK. mTOR complex-1 (mTORC1) phosphorylates the hydrophobic motif of S6K, whereas mTORC2 phosphorylates the hydrophobic motif of Akt and SGK. Here we describe the small molecule Ku-0063794, which inhibits both mTORC1 and mTORC2 with an IC50 of ~10 nM, but does not suppress the activity of 76 other protein kinases or 7 lipid kinases including Class 1 PI 3-kinases at 1000-fold higher concentrations. Ku-0063794 is cell permeant, suppresses activation and hydrophobic motif phosphorylation of Akt, S6K and SGK, but ...
Source: BJ Signal - April 29, 2009 Category: Biochemistry Authors: J M. García-Martínez, J Moran, R G. Clarke, A Gray, S C. Cosulich, C M. Chresta, D R. Alessi Tags: BJ Signal Source Type: journals

The RhoU/Wrch1 Rho GTPase gene is a common transcriptional target of both the gp130/Stat3 and Wnt-1 pathwaysEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Stat3 is a transcription factor activated by cytokines, growth factors and oncogenes, whose activity is required for cell survival/proliferation of a wide variety of primary tumors and tumor cell lines. Prominent among its multiple effects on tumor cells is the stimulation of cell migration and metastasis, whose functional mechanisms are however not completely characterized. RhoU/Wrch1 (Wnt-responsive Cdc42 homolog) is an atypical Rho GTPase thought to be constitutively bound to GTP. RhoU was first identified as a Wnt-1-inducible mRNA and subsequently shown to act on the actin cytoskeleton by stimulating filopodia formatio...
Source: BJ Signal - April 28, 2009 Category: Biochemistry Authors: D Schiavone, S Dewilde, F Vallania, J Turkson, F Di Cunto, V Poli Tags: BJ Gene Source Type: journals

Characterization of SENP7, a SUMO-2/-3 specific isopeptidaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Modification of proteins by SUMO (Small Ubiqutin-like Modifer) plays important roles in regulating the activity, stability and cellular localization of target proteins. Like ubiquitination, SUMO modification is a dynamic process that can be reversed by SUMO-specific proteases (SENPs). So far, six SENPs have been discovered in humans although knowledge of their regulation, specificity and biological functions is limited. Here, we report that SENP7 has a restricted substrate specificity being unable to process SUMO precursors and displaying paralogue specific isopeptidase activity. The C-terminal catalytic domain of SENP7 ef...
Source: BJ Signal - April 24, 2009 Category: Biochemistry Authors: L Shen, M Geoffroy, E G Jaffray, R T. Hay Tags: BJ Signal Source Type: journals

Group III secreted phospholipase A2 transgenic mice spontaneously develop inflammationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Phospholipase A2 (PLA2) group III is an atypical secreted PLA2 (sPLA2) that is homologous to bee venom PLA2 rather than to other mammalian sPLA2s. Here, we show that endogenous group III sPLA2 (PLA2G3) is expressed in mouse skin and that transgenic (Tg) mice overexpressing human PLA2G3 spontaneously develop skin inflammation. PLA2G3 Tg mice over 9 months of age frequently developed dermatitis with hyperkeratosis, acanthosis, parakeratosis, erosion, ulcer and sebaceous gland hyperplasia. The dermatitis was accompanied by infiltration of neutrophils and macrophages and by elevated levels of proinflammatory cytokines, chemoki...
Source: BJ Signal - April 17, 2009 Category: Biochemistry Authors: H Sato, Y Taketomi, Y Isogai, S Masuda, T Kobayashi, K Yamamoto, M Murakami Tags: BJ Disease Source Type: journals

Mycobacterium tuberculosis PtkA is a novel protein tyrosine kinase whose substrate is PtpAEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In Mycobacterium tuberculosis, signal transduction is mediated by 11 serine/threonine kinases, but no tyrosine kinases have been identified thus far. The protein encoded by the ORF Rv2232 has been annotated as a member of the HAD superfamily, which includes phosphatases, phosphomanno- and phosphogluco-mutases, and haloacid dehydrogenases. Here we report, based on biochemical and mutational analyses, that the Rv2232-encoded protein named Protein tyrosine kinase A (PtkA) is a bona fide protein tyrosine kinase. The cognate substrate of PtkA is the secreted protein tyrosine phosphatase A (PtpA). (Source: BJ Signal)
Source: BJ Signal - April 15, 2009 Category: Biochemistry Authors: H Bach, D Wong, Y Av-Gay Tags: BJ Signal Source Type: journals

The extracellular domain of the TGF{beta} type II receptor regulates membrane raft partitioningEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study we investigated the determinant in the TGFβ type II receptor (TβRII) that is necessary for membrane raft/caveolar targeting. Using subcellular fractionation and immunofluorescence microscopy techniques we demonstrate that the extracellular domain of TβRII mediates receptor partitioning into raft and caveolin-positive membrane domains. Pharmacological perturbation of glycosylation using tunicamycin or the mutation of Mgat5 activity interfered with the raft partitioning of TβRII. However, this was not due to the glycosylation state of TβRII, as a non-glycosylated TβRII ...
Source: BJ Signal - April 8, 2009 Category: Biochemistry Authors: V Luga, S McLean, C Le Roy, M O'Connor-McCourt, J L Wrana, G M Di Guglielmo Tags: BJ Cell Source Type: journals

Protein phosphatase 2A plays a role in hydrogen peroxide-induced disruption of tight junctions in Caco-2 cell monolayersEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study shows that hydrogen peroxide increases the association of PP2A with the occludin by a Src kinase-dependent mechanism, and that PP2A activity is involved in hydrogen peroxide-induced disruption of tight junction in Caco-2 cell monolayers. (Source: BJ Signal)
Source: BJ Signal - April 8, 2009 Category: Biochemistry Authors: P Sheth, G Samak, J Shull, A Seth, R Rao Tags: BJ Cell Source Type: journals

Biochemical characterization of GSK1070916, a potent and selective inhibitor of Aurora B and Aurora C Kinases with an extremely long residence timeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The Aurora kinases (Aurora A, B and C) are serine/threonine protein kinases that play essential roles in mitosis and cytokinesis. Among them, AurB is required for maintaining proper chromosome alignment, separation and segregation during mitosis, and regulating a number of critical processes involved in cytokinesis. AurB overexpression has been observed in a variety of cancer cell lines and inhibition of AurB has been shown to induce tumor regression in mouse xenograft models. Here we report the enzymatic characterization of a potent and selective AurB/AurC inhibitor. GSK1070916 is a reversible and ATP-competitive inhibito...
Source: BJ Signal - March 11, 2009 Category: Biochemistry Authors: K Anderson, Z Lai, O B McDonald, J Darren Stuart, E N Nartey, M Hardwicke, K Newlander, D Dhanak, J Adams, D Patrick, R A Copeland, P J Tummino, J Yang Tags: BJ Disease Source Type: journals

Nuclear translocation and signaling of L1-CAM in human carcinoma cells requires ADAM10 and presenilin/{gamma}-secretase activityEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We reported before that L1 is cleaved by ADAM metalloprotease and that the cytoplasmic part is essential for L1 function. Here we analyzed closer the role of proteolytic cleavage for L1-mediated nuclear signaling. Using OVMz carcinoma cells and L1-transfected cells as model, we find that ADAM10-mediated cleavage of L1 proceeds in lipid rafts and non-raft domains. The cleavage product L1-32 is further processed by presenilin/γ-secretase to release an intracellular domain of 28 kDa (L1-ICD). Overexpression of dominant negative presenilin-1 or use of a specific γ-secretase inhibitor leads to an accumulation of L...
Source: BJ Signal - March 5, 2009 Category: Biochemistry Authors: S Riedle, H Kiefel, D Gast, S Bondong, S Wolterink, P Gutwein, P Altevogt Tags: BJ Disease Source Type: journals