TY  - JOUR
AB  - BACKGROUND: Severe cases of COVID-19 are characterized by an excessive presence of neutrophils. Neutrophil extracellular traps (NETs), released by activated neutrophils due to SARS-CoV-2 infection, contribute to lung epithelial cell death and are key drivers in COVID-19-associated immunothrombosis. However, the mechanism underlying NET formation in COVID-19 remain unclear. METHODS: Extracellular vesicles (EVs) were isolated from the serum of COVID-19 patients and healthy volunteers, while neutrophils were isolated from blood samples of healthy volunteers. Neutrophils were treated with EVs, and the formation of NETs was observed. To identify the components responsible for the COVID-19-EVs-induced NET formation, we analyzed the expression profiles of microRNA (miRNAs) in COVID-19-EVs. We identified eight highly expressed miRNAs in COVID-19-EVs and explored their potential roles in COVID-19-EVs-mediated NET formation. Additionally, we explored the role of miR-20b-5p in COVID-19-EVs-induced NET formation. RESULTS: In this study, we demonstrate that patients with COVID-19 have a higher concentration of serum EVs (COVID-19-EVs) than healthy controls (Normal-EVs). We also found that COVID-19-EVs are internalized by neutrophils to induced NET formation. Through comprehensive miRNA profiling of COVID-19-EVs versus Normal-EVs, we identified 78 differentially expressed miRNAs, with 27 of these being upregulated and 51 being downregulated. Subsequently, we discovered that COVID-19-EVs that were highly abundant with certain miRNAs promote NET formation. Specifically, miR-20b-5p was found to be the strongest inducer of NET formation of the identified miRNAs. Inhibition of miR-20b-5p resulted in a significant decrease in COVID-19-EVs-mediated induction of NET formation. CONCLUSION: Herein, we reveal a previously unknown role of COVID-19-EVs in NET formation, which contributes to COVID-19 progression. This study suggests that miR-20b-5p may serve as a potential therapeutic target for COVID-19 treatment.
AU  - Liao, Y.*
AU  - Liu, Y.*
AU  - Li, D.*
AU  - Luo, S.
AU  - Huang, Y.*
AU  - Wu, J.*
AU  - Su, J.*
AU  - Yang, Y.*
AU  - Zhu, Z.*
AU  - Yanglan, M.*
AU  - Deng, H.*
AU  - Wu, X.*
AU  - Xu, J.*
AU  - Cao, F.*
AU  - Cai, C.*
AU  - Li, Z.*
AU  - Yang, R.*
AU  - Deng, X.*
AU  - Wei, J.*
AU  - Wang, L.*
C1  - 73403
C2  - 57050
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - COVID-19 patient serum-derived extracellular vesicles deliver miR-20b-5p induces neutrophil extracellular traps.
JO  - Cell Commun. Signal.
VL  - 23
IS  - 1
PB  - Bmc
PY  - 2025
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - Background: Thrombospondin-1 (TSP-1), a Ca2+-binding trimeric glycoprotein secreted by multiple cell types, has been implicated in the pathophysiology of several clinical conditions. Signaling involving TSP-1, through its cognate receptor CD47, orchestrates a wide array of cellular functions including cytoskeletal organization, migration, cell-cell interaction, cell proliferation, autophagy, and apoptosis. In the present study, we investigated the impact of TSP-1/CD47 signaling on Ca2+ dynamics, survival, and deformability of human red blood cells (RBCs).Methods: Whole-cell patch-clamp was employed to examine transmembrane cation conductance. RBC intracellular Ca2+ levels and multiple indices of RBC cell death were determined using cytofluorometry analysis. RBC morphology and microvesiculation were examined using imaging flow cytometry. RBC deformability was measured using laser-assisted optical rotational cell analyzer.Results: Exposure of RBCs to recombinant human TSP-1 significantly increased RBC intracellular Ca2+ levels. As judged by electrophysiology experiments, TSP-1 treatment elicited an amiloride-sensitive inward current alluding to a possible Ca2+ influx via non-selective cation channels. Exogenous TSP-1 promoted microparticle shedding as well as enhancing Ca2+- and nitric oxide-mediated RBC cell death. Monoclonal (mouse IgG1) antibody-mediated CD47 ligation using 1F7 recapitulated the cell death-inducing effects of TSP-1. Furthermore, TSP-1 treatment altered RBC cell shape and stiffness (maximum elongation index).Conclusions: Taken together, our data unravel a new role for TSP-1/CD47 signaling in mediating Ca2+ influx into RBCs, a mechanism potentially contributing to their dysfunction in a variety of systemic diseases.
AU  - Bissinger, R.*
AU  - Petkova-Kirova, P.*
AU  - Mykhailova, O.*
AU  - Oldenborg, P.A.*
AU  - Novikova, E.*
AU  - Donkor, D.A.*
AU  - Dietz, T.*
AU  - Bhuyan, A.A.M.*
AU  - Sheffield, W.P.*
AU  - Grau, M.*
AU  - Artunc, F.
AU  - Kaestner, L.*
AU  - Acker, J.P.*
AU  - Qadri, S.M.*
C1  - 60151
C2  - 49278
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Thrombospondin-1/CD47 signaling modulates transmembrane cation conductance, survival, and deformability of human red blood cells.
JO  - Cell Commun. Signal.
VL  - 18
IS  - 1
PB  - Bmc
PY  - 2020
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - The Drosophila melanogaster Germ cell-expressed protein (GCE) is a paralog of the juvenile hormone (JH) receptor - Methoprene tolerant protein (MET). Both proteins mediate JH function, preventing precocious differentiation during D. melanogaster development. Despite that GCE and MET are often referred to as equivalent JH receptors, their functions are not fully redundant and show tissue specificity. Both proteins belong to the family of bHLH-PAS transcription factors. The similarity of their primary structure is limited to defined bHLH and PAS domains, while their long C-terminal fragments (GCEC, METC) show significant differences and are expected to determine differences in GCE and MET protein activities. In this paper we present the structural characterization of GCEC as a coil-like intrinsically disordered protein (IDP) with highly elongated and asymmetric conformation. In comparison to previously characterized METC, GCEC is less compacted, contains more molecular recognition elements (MoREs) and exhibits a higher propensity for induced folding. The NMR shifts perturbation experiment and pull-down assay clearly demonstrated that the GCEC fragment is sufficient to form an interaction interface with the ligand binding domain (LBD) of the nuclear receptor Fushi Tarazu factor-1 (FTZ-F1). Significantly, these interactions can force GCEC to adopt more fixed structure that can modulate the activity, structure and functions of the full-length receptor. The discussed relation of protein functionality with the structural data of inherently disordered GCEC fragment is a novel look at this protein and contributes to a better understanding of the molecular basis of the functions of the C-terminal fragments of the bHLH-PAS family. [MediaObject not available: see fulltext.]
AU  - Kolonko, M.*
AU  - Bystranowska, D.*
AU  - Taube, M.*
AU  - Kozak, M.*
AU  - Bostock, M.J.
AU  - Popowicz, G.M.
AU  - Ożyhar, A.*
AU  - Greb-Markiewicz, B.*
C1  - 60489
C2  - 49311
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - The intrinsically disordered region of GCE protein adopts a more fixed structure by interacting with the LBD of the nuclear receptor FTZ-F1.
JO  - Cell Commun. Signal.
VL  - 18
IS  - 1
PB  - Bmc
PY  - 2020
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - BackgroundThe understanding of lysosomes has been expanded in recent research way beyond their view as cellular trash can. Lysosomes are pivotal in regulating metabolism, endocytosis and autophagy and are implicated in cancer. Recently it was discovered that the lysosomal V-ATPase, which is known to induce apoptosis, interferes with lipid metabolism in cancer, yet the interplay between these organelles is poorly understood.MethodsLC-MS/MS analysis was performed to investigate lipid distribution in cells. Cell survival and signaling pathways were analyzed by means of cell biological methods (qPCR, Western Blot, flow cytometry, CellTiter-Blue). Mitochondrial structure was analyzed by confocal imaging and electron microscopy, their function was determined by flow cytometry and seahorse measurements.ResultsOur data reveal that interfering with lysosomal function changes composition and subcellular localization of triacylglycerids accompanied by an upregulation of PGC1 alpha and PPAR alpha expression, master regulators of energy and lipid metabolism. Furthermore, cardiolipin content is reduced driving mitochondria into fission, accompanied by a loss of membrane potential and reduction in oxidative capacity, which leads to a deregulation in cellular ROS and induction of mitochondria-driven apoptosis. Additionally, cells undergo a metabolic shift to glutamine dependency, correlated with the fission phenotype and sensitivity to lysosomal inhibition, most prominent in Ras mutated cells.ConclusionThis study sheds mechanistic light on a largely uninvestigated triangle between lysosomes, lipid metabolism and mitochondrial function. Insight into this organelle crosstalk increases our understanding of mitochondria-driven cell death. Our findings furthermore provide a first hint on a connection of Ras pathway mutations and sensitivity towards lysosomal inhibitors.
AU  - Bartel, K.*
AU  - Pein, H.*
AU  - Popper, B.*
AU  - Schmitt, S.*
AU  - Janaki-Raman, S.*
AU  - Schulze, A.*
AU  - Lengauer, F.*
AU  - Koeberle, A.*
AU  - Werz, O.*
AU  - Zischka, H.
AU  - Müller, R.*
AU  - Vollmar, A.M.*
AU  - von Schwarzenberg, K.*
C1  - 56679
C2  - 47243
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Connecting lysosomes and mitochondria - a novel role for lipid metabolism in cancer cell death.
JO  - Cell Commun. Signal.
VL  - 17
IS  - 1
PB  - Bmc
PY  - 2019
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - Escape from immune control must be important in the natural course of B-cell lymphomas, especially for those with activation of NF-kappa B. The pre-clinical LMP1/CD40-expressing transgenic mouse model is characterized by B-cell specific CD40 signaling responsible for NF-kappa B continuous activation with a spleen monoclonal B-cell tumor after 1 year in 60% of cases. LMP1/CD40 tumors B-cells expressed high levels of PD-L1. This expression was dependent on activation of either NF-kappa B, JAK1/JAK2 or BTK pathways since these pathways were activated in tumor B-cells and ex vivo treatment with the inhibitory molecules PHA-408, ruxolitinib and ibrutinib led to decrease of its expression. Treatment of LMP1/CD40-expressing lymphomatous mice with an anti-PD-L1 monoclonal antibody induced tumor regression with decreased spleen content, activation and proliferation rate of B-cells as well as a marked increase in T-cell activation, as assessed by CD62L and CD44 expression. These results highlight the interest of therapies targeting the PD-1/PD-L1 axis in activated lymphomas with PD-L1 expression, with possible synergies with tyrosine kinase inhibitors.
AU  - Vincent-Fabert, C.*
AU  - Roland, L.*
AU  - Zimber-Strobl, U.
AU  - Feuillard, J.*
AU  - Faumont, N.*
C1  - 56742
C2  - 47276
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Pre-clinical blocking of PD-L1 molecule, which expression is down regulated by NF-κB, JAK1/JAK2 and BTK inhibitors, induces regression of activated B-cell lymphoma.
JO  - Cell Commun. Signal.
VL  - 17
IS  - 1
PB  - Bmc
PY  - 2019
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - BackgroundCholecystokinin (CCK) is implicated in the regulation of nociceptive sensitivity of primary afferent neurons. Nevertheless, the underlying cellular and molecular mechanisms remain unknown.MethodsUsing patch clamp recording, western blot analysis, immunofluorescent labelling, enzyme-linked immunosorbent assays, adenovirus-mediated shRNA knockdown and animal behaviour tests, we studied the effects of CCK-8 on the sensory neuronal excitability and peripheral pain sensitivity mediated by A-type K+ channels.ResultsCCK-8 reversibly and concentration-dependently decreased A-type K+ channel (I-A) in small-sized dorsal root ganglion (DRG) neurons through the activation of CCK type B receptor (CCK-BR), while the sustained delayed rectifier K+ current was unaffected. The intracellular subunit of CCK-BR coimmunoprecipitated with G(o). Blocking G-protein signaling with pertussis toxin or by the intracellular application of anti-G antibody reversed the inhibitory effects of CCK-8. Antagonism of phosphatidylinositol 3-kinase (PI3K) but not of its common downstream target Akts abolished the CCK-BR-mediated I-A response. CCK-8 application significantly activated JNK mitogen-activated protein kinase. Antagonism of either JNK or c-Src prevented the CCK-BR-mediated I-A decrease, whereas c-Src inhibition attenuated the CCK-8-induced p-JNK activation. Application of CCK-8 enhanced the action potential firing rate of DRG neurons and elicited mechanical and thermal pain hypersensitivity in mice. These effects were mediated by CCK-BR and were occluded by I-A blockade.ConclusionOur findings indicate that CCK-8 attenuated I-A through CCK-BR that is coupled to the G-dependent PI3K and c-Src-mediated JNK pathways, thereby enhancing the sensory neuronal excitability in DRG neurons and peripheral pain sensitivity in mice.
AU  - Yu, S.*
AU  - Zhang, Y.*
AU  - Zhao, X.*
AU  - Chang, Z.*
AU  - Wei, Y.*
AU  - Sun, Y.*
AU  - Jiang, D.
AU  - Jiang, X.*
AU  - Tao, J.*
C1  - 56356
C2  - 47029
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Cholecystokinin type B receptor-mediated inhibition of A-type K+ channels enhances sensory neuronal excitability through the phosphatidylinositol 3-kinase and c-Src-dependent JNK pathway.
JO  - Cell Commun. Signal.
VL  - 17
IS  - 1
PB  - Bmc
PY  - 2019
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - Background: The actin-bundling protein Fascin (FSCN1) is a tumor marker that is highly expressed in numerous types of cancer including lymphomas and is important for migration and metastasis of tumor cells. Fascin has also been detected in B lymphocytes that are freshly-infected with Epstein-Barr virus (EBV), however, both the inducers and the mechanisms of Fascin upregulation are still unclear. Results: Here we show that the EBV-encoded oncoprotein latent membrane protein 1 (LMP1), a potent regulator of cellular signaling and transformation, is sufficient to induce both Fascin mRNA and protein in lymphocytes. Fascin expression is mainly regulated by LMP1 via the C-terminal activation region 2 (CTAR2). Block of canonical NF-κB signaling using a chemical inhibitor of IκB kinase β (IKKβ) or cotransfection of a dominant-negative inhibitor of IκB (NFKBIA) reduced not only expression of p100, a classical target of the canonical NF-κB-pathway, but also LMP1-induced Fascin expression. Furthermore, chemical inhibition of IKKβ reduced both Fascin mRNA and protein levels in EBV-transformed lymphoblastoid cell lines, indicating that canonical NF-κB signaling is required for LMP1-mediated regulation of Fascin both in transfected and transformed lymphocytes. Beyond that, chemical inhibition of IKKβ significantly reduced invasive migration of EBV-transformed lymphoblastoid cells through extracellular matrix. Transient transfection experiments revealed that Fascin contributed to LMP1-mediated enhancement of invasive migration through extracellular matrix. While LMP1 enhanced the number of invaded cells, functional knockdown of Fascin by two different small hairpin RNAs resulted in significant reduction of invaded, non-attached cells. Conclusions: Thus, our data show that LMP1-mediated upregulation of Fascin depends on NF-κB and both NF-κB and Fascin contribute to invasive migration of LMP1-expressing lymphocytes.
AU  - Mohr, C.F.*
AU  - Kalmer, M.A.*
AU  - Gross, C.*
AU  - Mann, M.C.*
AU  - Sterz, K.
AU  - Kieser, A.
AU  - Fleckenstein, B.W.*
AU  - Kress, A.K.*
C1  - 31910
C2  - 34869
CY  - London
TI  - The tumor marker Fascin is induced by the Epstein-Barr virus-encoded oncoprotein LMP1 via NF-κB in lymphocytes and contributes to their invasive migration.
JO  - Cell Commun. Signal.
VL  - 12
IS  - 1
PB  - Biomed Central Ltd
PY  - 2014
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - Background: The CARMA1-BCL10-MALT1 (CBM) complex bridges T cell receptor (TCR) signaling to the canonical I kappa B kinase (IKK)/NF-kappa B pathway. The CBM complex constitutes a signaling cluster of more than 1 Mio Dalton. Little is known about factors that facilitate the rapid assembly and maintenance of this dynamic higher order complex. Findings: Here, we report the novel interaction of the aryl hydrocarbon receptor (AHR) interacting protein (AIP) and the molecular scaffold protein CARMA1. In T cells, transient binding of CARMA1 and AIP enhanced formation of the CBM complex. Thereby, AIP promoted optimal IKK/NF-kappa B signaling and IL-2 production in response to TCR/CD28 co-stimulation. Conclusions: Our data demonstrate that AIP acts as a positive regulator of NF-kappa B signaling upon T cell activation.
AU  - Schimmack, G.
AU  - Eitelhuber, A.C.
AU  - Vincendeau, M.
AU  - Demski, K.
AU  - Shinohara, H.*
AU  - Kurosaki, T.*
AU  - Krappmann, D.
C1  - 32057
C2  - 34947
CY  - London
TI  - AIP augments CARMA1-BCL10-MALT1 complex formation to facilitate NF-kappa B signaling upon T cell activation.
JO  - Cell Commun. Signal.
VL  - 12
IS  - 1
PB  - Biomed Central Ltd
PY  - 2014
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - Background: Although ADP-ribosylation has been described five decades ago, only recently a distinction has been made between eukaryotic intracellular poly- and mono-ADP-ribosylating enzymes. Poly-ADP-ribosylation by ARTD1 (formerly PARP1) is best known for its role in DNA damage repair. Other polymer forming enzymes are ARTD2 (formerly PARP2), ARTD3 (formerly PARP3) and ARTD5/6 (formerly Tankyrase 1/2), the latter being involved in Wnt signaling and regulation of 3BP2. Thus several different functions of poly-ADP-ribosylation have been well described whereas intracellular mono-ADP-ribosylation is currently largely undefined. It is for example not known which proteins function as substrate for the different mono-ARTDs. This is partially due to lack of suitable reagents to study mono-ADP- ribosylation, which limits the current understanding of this post-translational modification. Results: We have optimized a novel screening method employing protein microarrays, ProtoArrays (R), applied here for the identification of substrates of ARTD10 (formerly PARP10) and ARTD8 (formerly PARP14). The results of this substrate screen were validated using in vitro ADP-ribosylation assays with recombinant proteins. Further analysis of the novel ARTD10 substrate GSK3 beta revealed mono-ADP- ribosylation as a regulatory mechanism of kinase activity by non-competitive inhibition in vitro. Additionally, manipulation of the ARTD10 levels in cells accordingly influenced GSK3 beta activity. Together these data provide the first evidence for a role of endogenous mono-ADP- ribosylation in intracellular signaling. Conclusions: Our findings indicate that substrates of ADP-ribosyltransferases can be identified using protein microarrays. The discovered substrates of ARTD10 and ARTD8 provide the first sets of proteins that are modified by mono-ADP-ribosyltransferases in vitro. By studying one of the ARTD10 substrates more closely, the kinase GSK3 beta, we identified mono-ADP- ribosylation as a negative regulator of kinase activity.
AU  - Feijs, K.L.H.*
AU  - Kleine, H.*
AU  - Braczynski, A.*
AU  - Forst, A.H.*
AU  - Herzog, N.*
AU  - Verheugd, P.*
AU  - Linzen, U.*
AU  - Kremmer, E.
AU  - Lüscher, B.*
C1  - 24463
C2  - 31550
TI  - ARTD10 substrate identification on protein microarrays: Regulation of GSK3β by mono-ADP-ribosylation.
JO  - Cell Commun. Signal.
VL  - 11
IS  - 1
PB  - Biomed Central
PY  - 2013
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - Background: The p53 protein is the best studied target in human cancer. For decades, p53 has been believed to act mainly as a tumor suppressor and by transcriptional regulation. Only recently, the complex and diverse function of p53 has attracted more attention. Using several molecular approaches, we studied the impact of different p53 variants on extrinsic and intrinsic apoptosis signaling. Results: We reproduced the previously published results within intrinsic apoptosis induction: while wild-type p53 promoted cell death, different p53 mutations reduced apoptosis sensitivity. The prediction of the impact of the p53 status on the extrinsic cell death induction was much more complex. The presence of p53 in tumor cell lines and primary xenograft tumor cells resulted in either augmented, unchanged or reduced cell death. The substitution of wild-type p53 by mutant p53 did not affect the extrinsic apoptosis inducing capacity. Conclusions: In summary, we have identified a non-expected impact of p53 on extrinsic cell death induction. We suggest that the impact of the p53 status of tumor cells on extrinsic apoptosis signaling should be studied in detail especially in the context of therapeutic approaches that aim to restore p53 function to facilitate cell death via the extrinsic apoptosis pathway.
AU  - Wachter, F.
AU  - Grunert, M.
AU  - Blaj, C.
AU  - Weinstock, D.M.*
AU  - Jeremias, I.
AU  - Ehrhardt, H.
C1  - 24727
C2  - 31652
TI  - Impact of the p53 status of tumor cells on extrinsic and intrinsic apoptosis signaling.
JO  - Cell Commun. Signal.
VL  - 11
IS  - 1
PB  - BioMed Central
PY  - 2013
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - Background: Signaling studies in cell lines are hampered by non-physiological alterations obtained in vitro. Physiologic primary tumor cells from patients with leukemia require passaging through immune-compromised mice for amplification. The aim was to enable molecular work in patients' ALL cells by establishing siRNA transfection into cells amplified in mice. Results: We established delivering siRNA into these cells without affecting cell viability. Knockdown of single or multiple genes reduced constitutive or induced protein expression accompanied by marked signaling alterations. Conclusion: Our novel technique allows using patient-derived tumor cells instead of cell lines for signaling studies in leukemia.
AU  - Höfig, I.
AU  - Ehrhardt, H.
AU  - Jeremias, I.
C1  - 7967
C2  - 29954
TI  - Efficient RNA interference in patients' acute lymphoblastic leukemia cells amplified as xenografts in mice.
JO  - Cell Commun. Signal.
VL  - 10
IS  - 1
PB  - Biomed Central Ltd.
PY  - 2012
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - Background: ADP-ribosylation is a posttranslational modification catalyzed in cells by ADP-ribosyltransferases (ARTD or PARP enzymes). The ARTD family consists of 17 members. Some ARTDs modify their substrates by adding ADP-ribose in an iterative process, thereby synthesizing ADP-ribose polymers, the best-studied example being ARTD1/PARP1. Other ARTDs appear to mono-ADP-ribosylate their substrates and are unable to form polymers. The founding member of this latter subclass is ARTD10/PARP10, which we identified as an interaction partner of the nuclear oncoprotein MYC. Biochemically ARTD10 uses substrate-assisted catalysis to modify its substrates. Our previous studies indicated that ARTD10 may shuttle between the nuclear and cytoplasmic compartments. We have now addressed this in more detail. Results: We have characterized the subcellular localization of ARTD10 using live-cell imaging techniques. ARTD10 shuttles between the cytoplasmic and nuclear compartments. When nuclear, ARTD10 can interact with MYC as measured by bimolecular fluorescence complementation. The shuttling is controlled by a Crm1-dependent nuclear export sequence and a central ARTD10 region that promotes nuclear localization. The latter lacks a classical nuclear localization sequence and does not promote full nuclear localization. Rather this non-conventional nuclear localization sequence results in an equal distribution of ARTD10 between the cytoplasmic and the nuclear compartments. ARTD10 forms discrete and dynamic bodies primarily in the cytoplasm but also in the nucleus. These contain poly-ubiquitin and co-localize in part with structures containing the poly-ubiquitin receptor p62/SQSTM1. The co-localization depends on the ubiquitin-associated domain of p62, which mediates interaction with poly-ubiquitin. Conclusions: Our findings demonstrate that ARTD10 is a highly dynamic protein. It shuttles between the nuclear and cytosolic compartments dependent on a classical nuclear export sequence and a domain that mediates nuclear uptake. Moreover ARTD10 forms discrete bodies that exchange subunits rapidly. These bodies associate at least in part with the poly-ubiquitin receptor p62. Because this protein is involved in the uptake of cargo into autophagosomes, our results suggest a link between the formation of ARTD10 bodies and autophagy. Lay abstract Post-translational modifications refer to changes in the chemical appearance of proteins and occur, as the name implies, after proteins have been synthesized. These modifications frequently affect the behavior of proteins, including alterations in their activity or their subcellular localization. One of these modifications is the addition of ADP-ribose to a substrate from the cofactor NAD+. The enzymes responsible for this reaction are ADP-ribosyltransferases (ARTDs or previously named PARPs). Presently we know very little about the role of mono-ADP-ribosylation of proteins that occurs in cells. We identified ARTD10, a mono-ADP-ribosyltransferase, as an interaction partner of the oncoprotein MYC. In this study we have analyzed how ARTD10 moves within a cell. By using different live-cell imaging technologies that allow us to follow the position of ARTD10 molecules over time, we found that ARTD10 shuttles constantly in and out of the nucleus. In the cytosol ARTD10 forms distinct structures or bodies that themselves are moving within the cell and that exchange ARTD10 subunits rapidly. We have identified the regions within ARTD10 that are required for these movements. Moreover we defined these bodies as structures that interact with p62. This protein is known to play a role in bringing other proteins to a structure referred to as the autophagosome, which is involved in eliminating debris in cells. Thus our work suggests that ARTD10 might be involved in and is regulated by ADP-riboslyation autophagosomal processes.
AU  - Kleine, H.*
AU  - Herrmann, A.*
AU  - Lamark, T.*
AU  - Forst, A.H.*
AU  - Verheugd, P.*
AU  - Luscher-Firzlaff, J.*
AU  - Lippok, B.*
AU  - Feijs, K.L.H.*
AU  - Herzog, N.*
AU  - Kremmer, E.
AU  - Johansen, T.*
AU  - Müller-Newen, G.*
AU  - Lüscher, B.*
C1  - 11525
C2  - 30704
TI  - Dynamic subcellular localization of the mono-ADP-ribosyltransferase ARTD10 and interaction with the ubiquitin receptor p62.
JO  - Cell Commun. Signal.
VL  - 10
PB  - Biomed Central Ltd.
PY  - 2012
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - BACKGROUND: Aggressive Non-Hodgkin lymphomas (NHL) are a group of lymphomas derived from germinal centre B cells which display a heterogeneous pattern of oncogenic pathway activation. We postulate that specific immune response associated signalling, affecting gene transcription networks, may be associated with the activation of different oncogenic pathways in aggressive Non-Hodgkin lymphomas (NHL).Methodology: The B cell receptor (BCR), CD40, B-cell activating factor (BAFF)-receptors and Interleukin (IL) 21 receptor and Toll like receptor 4 (TLR4) were stimulated in human transformed germinal centre B cells by treatment with anti IgM F(ab)2-fragments, CD40L, BAFF, IL21 and LPS respectively. The changes in gene expression following the activation of Jak/STAT, NF-[cyrillic small letter ka with descender]B, MAPK, Ca2+ and PI3K signalling triggered by these stimuli was assessed using microarray analysis. The expression of top 100 genes which had a change in gene expression following stimulation was investigated in gene expression profiles of patients with Aggressive non-Hodgkin Lymphoma (NHL). RESULTS: alphaIgM stimulation led to the largest number of changes in gene expression, affecting overall 6596 genes. While CD40L stimulation changed the expression of 1194 genes and IL21 stimulation affected 902 genes, only 283 and 129 genes were modulated by lipopolysaccharide or BAFF receptor stimulation, respectively. Interestingly, genes associated with a Burkitt-like phenotype, such as MYC, BCL6 or LEF1, were affected by alphaIgM. Unique and shared gene expression was delineated. NHL-patients were sorted according to their similarity in the expression of TOP100 affected genes to stimulated transformed germinal centre B cells The alphaIgM gene module discriminated individual DLBCL in a similar manner to CD40L or IL21 gene modules. DLBCLs with low module activation often carry chromosomal MYC aberrations. DLBCLs with high module activation show strong expression of genes involved in cell-cell communication, immune responses or negative feedback loops. Using chemical inhibitors for selected kinases we show that mitogen activated protein kinase- and phosphoinositide 3 kinase-signalling are dominantly involved in regulating genes included in the alphaIgM gene module. CONCLUSION: We provide an in vitro model system to investigate pathway activation in lymphomas. We defined the extent to which different immune response associated pathways are responsible for differences in gene expression which distinguish individual DLBCL cases. Our results support the view that tonic or constitutively active MAPK/ERK pathways are an important part of oncogenic signalling in NHL. The experimental model can now be applied to study the therapeutic potential of deregulated oncogenic pathways and to develop individual treatment strategies for lymphoma patients.
AU  - Schrader, A.*
AU  - Meyer, K.*
AU  - von Bonin, F.*
AU  - Vockerodt, M.*
AU  - Walther, N.*
AU  - Hand, E.*
AU  - Ulrich, A.*
AU  - Matulewicz, K.*
AU  - Lenze, D.*
AU  - Hummel, M.*
AU  - Kieser, A.
AU  - Engelke, M.*
AU  - Trümper, L.*
AU  - Kube, D.*
C1  - 11684
C2  - 30756
TI  - Global gene expression changes of in vitro stimulated human transformed germinal centre B cells as surrogate for oncogenic pathway activation in individual aggressive B cell lymphomas.
JO  - Cell Commun. Signal.
VL  - 10
IS  - 1
PB  - Biomed Central Ltd.
PY  - 2012
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - ABSTRACT: The 13th meeting of the Signal Transduction Society was held in Weimar, from October 28 to 30, 2009. Special focus of the 2009 conference was "Aging and Senescence", which was co-organized by the SFB 728 "Environmentally-Induced Aging Processes" of the University of Düsseldorf and the study group 'Signal Transduction' of the German Society for Cell Biology (DGZ). In addition, several other areas of signal transduction research were covered and supported by different consortia associated with the Signal Transduction Society including the long-term associated study groups of the German Society for Immunology and the Society for Biochemistry and Molecular Biology, and for instance the SFB/Transregio 52 "Transcriptional Programming of Individual T Cell Subsets" located in Würzburg, Mainz and Berlin. The different research areas that were introduced by outstanding keynote speakers attracted more than 250 scientists, showing the timeliness and relevance of the interdisciplinary concept and exchange of knowledge during the three days of the scientific program. This report gives an overview of the presentations of the conference.
AU  - Entschladen, F.*
AU  - Altschmied, J.*
AU  - Baumgrass, R.*
AU  - Behrmann, I.*
AU  - Giehl, K.*
AU  - Hermanns, H.*
AU  - Kieser, A.
AU  - Klotz, L.O.*
AU  - Kubatzky, K.F.*
AU  - Hass, R.*
AU  - Janssen, O.*
AU  - Friedrich, K.*
C1  - 1143
C2  - 27242
TI  - Signal transduction, receptors, mediators and genes: Younger than ever - the 13th meeting of the Signal Transduction Society focused on aging and immunology.
JO  - Cell Commun. Signal.
VL  - 8
PB  - BioMed Central Ltd.
PY  - 2010
SN  - 1478-811X
ER  - 

TY  - JOUR
AB  - ABSTRACT: The historical town of Weimar in Thuringia, the "green heart of Germany" was the sphere of Goethe and Schiller, the two most famous representatives of German literature's classic era. Not yet entirely as influential as those two cultural icons, the Signal Transduction Society (STS) has nevertheless in the last decade established within the walls of Weimar an annual interdisciplinary Meeting on "Signal Transduction - Receptors, Mediators and Genes", which is well recognized as a most attractive opportunity to exchange results and ideas in the field.The 12th STS Meeting was held from October 28 to 31 and provided a state-of-the-art overview of various areas of signal transduction research in which progress is fast and discussion lively. This report is intended to share with the readers of CCS some highlights of the Meeting Workshops devoted to specific aspects of signal transduction.
AU  - Friedrich, K.*
AU  - Lindquist, J.A.*
AU  - Entschladen, F.*
AU  - Serfling, E.
AU  - Thiel, G.*
AU  - Kieser, A.*
AU  - Gieh, K.*
AU  - Ehrhardt, C.*
AU  - Feller, S.M.*
AU  - Ullrich, O.*
AU  - Schaper, F.*
AU  - Janssen, O.*
AU  - Hass, R.*
C1  - 1144
C2  - 27243
TI  - Signal transduction in the footsteps of Goethe and Schiller.
JO  - Cell Commun. Signal.
VL  - 7
PB  - BioMed Central Ltd.
PY  - 2009
SN  - 1478-811X
ER  -