TY  - JOUR
AB  - Ribosomal biosynthesis in nucleoli is an energy-demanding process driven by all RNA polymerases and hundreds of auxiliary proteins. We investigated how this process is regulated in activated T lymphocytes by T cell receptor (TCR) signals and the multiprotein complexes mTORC1 and mTORC2, both of which contain the kinase mTOR. Deficiency in mTORC1 slowed the proliferation of T cells, with further delays in each consecutive division, an effect not seen with deficiency in mTORC2. mTORC1 signaling was stimulated by components of conventional TCR signaling, and, reciprocally, TCR sensitivity was decreased by mTORC1 inhibition. The substantial increase in the amount of RNA per cell induced by TCR activation was reduced by 50% by deficiency in mTORC1, but not in mTORC2 or in S6 kinases 1 and 2, which are activated downstream of mTORC1. RNA-seq data showed that mTORC1 deficiency reduced the abundance of all RNA biotypes, although rRNA processing was largely intact in activated T cells. Imaging cytometry with FISH probes for nascent pre-rRNA revealed that deletion of mTORC1, but not that of mTORC2, reduced the number and expansion of nucleolar sites of active transcription. Protein translation was consequently decreased by 50% in the absence of mTORC1. Inhibiting RNA polymerase I blocked not only proliferation but also mTORC1 signaling. Our data show that TCR signaling, mTORC1 activity, and ribosomal biosynthesis in the nucleolus regulate each other during biomass production in clonally expanding T cells.
AU  - Rosenlehner, T.*
AU  - Pennavaria, S.*
AU  - Akçabozan, B.*
AU  - Jahani, S.*
AU  - O'Neill, T.J.
AU  - Krappmann, D.
AU  - Straub, T.*
AU  - Kranich, J.*
AU  - Obst, R.*
C1  - 72111
C2  - 56528
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Reciprocal regulation of mTORC1 signaling and ribosomal biosynthesis determines cell cycle progression in activated T cells.
JO  - Sci. Signal.
VL  - 17
IS  - 859
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - The stabilization of different active conformations of G protein-coupled receptors is thought to underlie the varying efficacies of biased and balanced agonists. Here, profiling the activation of signal transducers by angiotensin II type 1 receptor (AT1R) agonists revealed that the extent and kinetics of β-arrestin binding exhibited substantial ligand-dependent differences, which were lost when receptor internalization was inhibited. When AT1R endocytosis was prevented, even weak partial agonists of the β-arrestin pathway acted as full or near-full agonists, suggesting that receptor conformation did not exclusively determine β-arrestin recruitment. The ligand-dependent variance in β-arrestin translocation was much larger at endosomes than at the plasma membrane, showing that ligand efficacy in the β-arrestin pathway was spatiotemporally determined. Experimental investigations and mathematical modeling demonstrated how multiple factors concurrently shaped the effects of agonists on endosomal receptor-β-arrestin binding and thus determined the extent of functional selectivity. Ligand dissociation rate and G protein activity had particularly strong, internalization-dependent effects on the receptor-β-arrestin interaction. We also showed that endocytosis regulated the agonist efficacies of two other receptors with sustained β-arrestin binding: the V2 vasopressin receptor and a mutant β2-adrenergic receptor. In the absence of endocytosis, the agonist-dependent variance in β-arrestin2 binding was markedly diminished. Our results suggest that endocytosis determines the spatiotemporal bias in GPCR signaling and can aid in the development of more efficacious, functionally selective compounds.
AU  - Tóth, A.D.*
AU  - Szalai, B.*
AU  - Kovács, O.T.*
AU  - Garger, D.
AU  - Prokop, S.*
AU  - Soltész-Katona, E.*
AU  - Balla, A.*
AU  - Inoue, A.*
AU  - Várnai, P.*
AU  - Turu, G.*
AU  - Hunyady, L.*
C1  - 70898
C2  - 55965
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - G protein-coupled receptor endocytosis generates spatiotemporal bias in β-arrestin signaling.
JO  - Sci. Signal.
VL  - 17
IS  - 842
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - Mammalian macrophage migration inhibitory factor (MIF) and its paralog, D-dopachrome tautomerase, are multifunctional inflammatory cytokines. Plants have orthologous MIF and D-dopachrome tautomerase-like (MDL) proteins that mimic some of the effects of MIF on immune cells in vitro. We explored the structural and functional similarities between the three Arabidopsis thaliana MDLs and MIF. X-ray crystallography of the MDLs revealed high structural similarity between MDL and MIF homotrimers and suggested a potential explanation for the lack of tautomerase activity in the MDLs. MDL1 and MDL2 interacted with each other and with MIF in vitro, in yeast, and in plant leaves and formed hetero-oligomeric complexes with MIF in vitro. The MDLs stimulated signaling through the MIF receptors CXCR2 or CXCR4 and enhanced the responses to MIF in a yeast reporter system, in human neutrophils, and in human lung epithelial cells. Pharmacological inhibitors that disrupted MIF activity or prevented the formation of MIF-MDL hetero-oligomers blocked the observed synergism. These findings demonstrate that MDLs can enhance cellular responses to MIF, which may have functional implications in tissues exposed to MDLs from the diet or environment.
AU  - Spiller, L.*
AU  - Manjula, R.*
AU  - Leissing, F.*
AU  - Basquin, J.*
AU  - Bourilhon, P.*
AU  - Sinitski, D.*
AU  - Brandhofer, M.*
AU  - Levecque, S.*
AU  - Gerra, S.*
AU  - Sabelleck, B.*
AU  - Zhang, L.*
AU  - Feederle, R.
AU  - Flatley, A.
AU  - Hoffmann, A.*
AU  - Panstruga, R.*
AU  - Bernhagen, J.*
AU  - Lolis, E.*
C1  - 68869
C2  - 53679
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Plant MDL proteins synergize with the cytokine MIF at CXCR2 and CXCR4 receptors in human cells.
JO  - Sci. Signal.
VL  - 16
IS  - 812
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - CARD11 acts as a gatekeeper for adaptive immune responses after T cell or B cell antigen receptor (TCR/BCR) ligation on lymphocytes. PKCθ/β-catalyzed phosphorylation of CARD11 promotes the assembly of the CARD11-BCL10-MALT1 (CBM) complex and lymphocyte activation. Here, we demonstrated that PKCθ/β-dependent CARD11 phosphorylation also suppressed CARD11 functions in T or B cells. Through mass spectrometry-based proteomics analysis, we identified multiple constitutive and inducible CARD11 phosphorylation sites in T cells. We demonstrated that a single TCR- or BCR-inducible phosphorylation on Ser893 in the carboxyl terminus of CARD11 prevented the activation of the transcription factor NF-κB, the kinase JNK, and the protease MALT1. Moreover, CARD11 Ser893 phosphorylation sensitized BCR-addicted lymphoma cells to toxicity induced by Bruton's tyrosine kinase (BTK) inhibitors. Phosphorylation of Ser893 in CARD11 by PKCθ controlled the strength of CARD11 scaffolding by impairing the formation of the CBM complex. Thus, PKCθ simultaneously catalyzes both stimulatory and inhibitory CARD11 phosphorylation events, which shape the strength of CARD11 signaling in lymphocytes.
AU  - Kutzner, K.
AU  - Woods, S.
AU  - Karayel, O.*
AU  - Gehring, T.
AU  - Yin, H.
AU  - Flatley, A.
AU  - Grass, C.
AU  - Wimberger, N.
AU  - Tofaute, M.J.
AU  - Seeholzer, T.
AU  - Feederle, R.
AU  - Mann, M.*
AU  - Krappmann, D.
C1  - 64531
C2  - 52257
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Phosphorylation of serine-893 in CARD11 suppresses the formation and activity of the CARD11-BCL10-MALT1 complex in T and B cells.
JO  - Sci. Signal.
VL  - 15
IS  - 723
PB  - Amer Assoc Advancement Science
PY  - 2022
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - Members of the RAF family of serine-threonine kinases are intermediates in the mitogen-activated protein kinase and extracellular signal-regulated kinase (MAPK-ERK) signaling pathway, which controls key differentiation processes in B cells. By analyzing mice with B cell-specific deletion of Raf1, Braf, or both, we showed that Raf-1 and B-Raf acted together in mediating the positive selection of pre-B and transitional B cells as well as in initiating plasma cell differentiation. However, genetic or chemical inactivation of RAFs led to increased ERK phosphorylation in mature B cells. ERK activation in the absence of Raf-1 and B-Raf was mediated by multiple RAF-independent pathways, with phosphoinositide 3-kinase (PI3K) playing an important role. Furthermore, we found that ERK phosphorylation strongly increased during the transition from activated B cells to pre-plasmablasts. This increase in ERK phosphorylation did not occur in B cells lacking both Raf-1 and B-Raf, which most likely explains the partial block of plasma cell differentiation in mice lacking both RAFs. Collectively, our data indicate that B-Raf and Raf-1 are not necessary to mediate ERK phosphorylation in naïve or activated B cells but are essential for mediating the marked increase in ERK phosphorylation during the transition from activated B cells to pre-plasmablasts.
AU  - Scheffler, L.
AU  - Feicht, S.
AU  - Babushku, T.
AU  - Kuhn, L.
AU  - Ehrenberg, S.
AU  - Frankenberger, S.
AU  - Lehmann, F.M.
AU  - Hobeika, E.*
AU  - Jungnickel, B.
AU  - Baccarini, M.*
AU  - Bornkamm, G.W.
AU  - Strobl, L.J.
AU  - Zimber-Strobl, U.
C1  - 62037
C2  - 50629
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - ERK phosphorylation is RAF independent in naïve and activated B cells but RAF dependent in plasma cell differentiation.
JO  - Sci. Signal.
VL  - 14
IS  - 682
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - Although brain-derived neurotrophic factor (BDNF) is implicated in the nociceptive signaling of peripheral sensory neurons, the underlying mechanisms remain largely unknown. Here, we elucidated the effects of BDNF on the neuronal excitability of trigeminal ganglion (TG) neurons and the pain sensitivity of rats mediated by T-type Ca2+ channels. BDNF reversibly and dose-dependently enhanced T-type channel currents through the activation of tropomyosin receptor kinase B (TrkB). Antagonism of phosphatidylinositol 3-kinase (PI3K) but not of its downstream target, the kinase AKT, abolished the BDNF-induced T-type channel response. BDNF application activated p38 mitogen-activated protein kinase (MAPK), and this effect was prevented by inhibition of PI3K but not of protein kinase A (PKA). Antagonism of either PI3K or p38 MAPK prevented the BDNF-induced stimulation of PKA activity, whereas PKA inhibition blocked the BDNF-mediated increase in T-type currents. BDNF increased the rate of action potential firing in TG neurons and enhanced the pain sensitivity of rats to mechanical stimuli. Moreover, inhibition of TrkB signaling abolished the increased mechanical sensitivity in a rat model of chronic inflammatory pain, and this effect was attenuated by either T-type channel blockade or knockdown of the channel Ca(v)3.2. Together, our findings indicate that BDNF enhances T-type currents through the stimulation of TrkB coupled to PI3K-p38-PKA signaling, thereby inducing neuronal hyperexcitability of TG neurons and pain hypersensitivity in rats.
AU  - Wang, H.*
AU  - Wei, Y.*
AU  - Pu, Y.*
AU  - Jiang, D.
AU  - Jiang, X.*
AU  - Zhang, Y.*
AU  - Tao, J.*
C1  - 56970
C2  - 47376
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Brain-derived neurotrophic factor stimulation of T-type Ca2+ channels in sensory neurons contributes to increased peripheral pain sensitivity.
JO  - Sci. Signal.
VL  - 12
IS  - 600
PB  - Amer Assoc Advancement Science
PY  - 2019
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - Purpose of Review Advances in technology have expanded telemedicine opportunities covering medical practice, research, and education. This is of particular importance in movement disorders (MDs), where the combination of disease progression, mobility limitations, and the sparse distribution of MD specialists increase the difficulty to access. In this review, we discuss the prospects, challenges, and strategies for telemedicine in MDs.Recent Findings Telemedicine for MDs has been mainly evaluated in Parkinson's disease (PD) and compared to in-office care is cost-effective with similar clinical care, despite the barriers to engagement. However, particular groups including pediatric patients, rare MDs, and the use of telemedicine in underserved areas need further research.Summary Interdisciplinary telemedicine and tele-education for MDs are feasible, provide similar care, and reduce travel costs and travel time compared to in-person visits. These benefits have been mainly demonstrated for PD but serve as a model for further validation in other movement disorders.
AU  - Babaei, R.*
AU  - Schuster, M.*
AU  - Meln, I.*
AU  - Lerch, S.*
AU  - Ghandour, R.A.*
AU  - Pisani, D.F.*
AU  - Bayindir-Buchhalter, I.*
AU  - Marx, J.*
AU  - Wu, S.*
AU  - Schoiswohl, G.*
AU  - Billeter, A.T.*
AU  - Krunic, D.*
AU  - Mauer, J.*
AU  - Lee, Y.H.*
AU  - Granneman, J.G.*
AU  - Fischer, L.*
AU  - Müller-Stich, B.P.*
AU  - Amri, E.Z.*
AU  - Kershaw, E.E.*
AU  - Heikenwälder, M.*
AU  - Herzig, S.
AU  - Vegiopoulos, A.*
C1  - 53452
C2  - 44872
CY  - 233 Spring St, New York, Ny 10013 Usa
TI  - Jak-TGF beta cross-talk links transient adipose tissue inflammation to beige adipogenesis.
JO  - Sci. Signal.
VL  - 11
IS  - 527
PB  - Springer
PY  - 2018
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - The evolution of cancer is characterized by the appearance of specific mutations, but these mutations are translated into proteins that must cooperate to induce malignant transformation. Using a systemic approach with the multiepitope ligand cartography (MELC) technology, we analyzed protein expression profiles (PEPs) in nevi and BRAF(V600E)-positive superficial spreading melanomas (SSMs) from patient tissues to identify key transformation events. The PEPs in nevi and SSMs differed predominantly in the abundance of specific antigens, but the PEPs of nevi- and melanoma-associated keratinocytes gradually changed during the transformation process. A stepwise change in PEP with similar properties occurred in keratinocytes cocultured with melanoma cells. Analysis of the individual steps indicated that activation of the metalloproteinase ADAM10 by signal peptide peptidase-like 3 (SPPL3) triggered by mutant BRAF(V600E) was a critical transformation event. SPPL3-mediated ADAM10 activation involved the translocation of SPPL3 and ADAM10 into Rab4- or Rab27-positive endosomal compartments. This endosomal translocation, and hence ADAM10 activation, was inhibited by the presence of the tumor suppressor PTEN. Our findings suggest that systematic tissue antigen analysis could complement whole-genome approaches to provide more insight into cancer development.
AU  - Ostalecki, C.*
AU  - Lee, J.H.*
AU  - Dindorf, J.*
AU  - Collenburg, L.*
AU  - Schierer, S.*
AU  - Simon, B.*
AU  - Schliep, S.*
AU  - Kremmer, E.
AU  - Schuler, G.*
AU  - Baur, A.S.*
C1  - 50718
C2  - 42867
TI  - Multiepitope tissue analysis reveals SPPL3-mediated ADAM10 activation as a key step in the transformation of melanocytes.
JO  - Sci. Signal.
VL  - 10
IS  - 470
PY  - 2017
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - Mapping the in vivo distribution of endogenous oxidants in animal tissues is of substantial biomedical interest. Numerous health-related factors, including diet, physical activity, infection, aging, toxins, or pharmacological intervention, may cause redox changes. Tools are needed to pinpoint redox state changes to particular organs, tissues, cell types, and subcellular organelles. We describe a procedure that preserves the in vivo redox state of genetically encoded redox biosensors within histological tissue sections, thus providing "redox maps" for any tissue and comparison of interest. We demonstrate the utility of the technique by visualizing endogenous redox differences and changes in the context of tumor growth, inflammation, embryonic development, and nutrient starvation.
AU  - Fujikawa, Y.*
AU  - Roma, L.P.*
AU  - Sobotta, M.C.*
AU  - Rose, A.J.*
AU  - Berriel Diaz, M.
AU  - Locatelli, G.*
AU  - Breckwoldt, M.O.*
AU  - Misgeld, T.*
AU  - Kerschensteiner, M.*
AU  - Herzig, S.
AU  - Müller-Decker, K.*
AU  - Dick, T.P.*
C1  - 48133
C2  - 39928
CY  - Washington
TI  - Mouse redox histology using genetically encoded probes.
JO  - Sci. Signal.
VL  - 9
IS  - 419
PB  - Amer Assoc Advancement Science
PY  - 2016
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - PEN is an abundant peptide in the brain that has been implicated in the regulation of feeding. We identified a receptor for PEN in mouse hypothalamus and Neuro2A cells. PEN bound to and activated GPR83, a G protein (heterotrimeric guanine nucleotide)-binding protein)-coupled receptor (GPCR). Reduction of GPR83 expression in mouse brain and Neuro2A cells reduced PEN binding and signaling, consistent with GPR83 functioning as the major receptor for PEN. In some brain regions, GPR83 colocalized with GPR171, a GPCR that binds the neuropeptide bigLEN, another neuropeptide that is involved in feeding and is generated from the same precursor protein as is PEN. Coexpression of these two receptors in cell lines altered the signaling properties of each receptor, suggesting a functional interaction. Our data established PEN as a neuropeptide that binds GPR83 and suggested that these two ligand-receptor systems-PEN-GPR83 and bigLEN-GPR171-may be functionally coupled in the regulation of feeding.
AU  - Gomes, I.*
AU  - Bobeck, E.N.*
AU  - Margolis, E.B.*
AU  - Gupta, A.*
AU  - Sierra, S.*
AU  - Fakira, A.K.*
AU  - Fujita, W.*
AU  - Müller, T.D.
AU  - Müller, A.*
AU  - Tschöp, M.H.
AU  - Kleinau, G.*
AU  - Fricker, L.D.*
AU  - Devi, L.A.*
C1  - 48492
C2  - 41126
CY  - Washington
TI  - Identification of GPR83 as the receptor for the neuroendocrine peptide PEN.
JO  - Sci. Signal.
VL  - 9
IS  - 425
PB  - Amer Assoc Advancement Science
PY  - 2016
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - Members of the nuclear factor B (NF-B) family of transcription factors regulate many cellular functions. Activation of NF-B signaling is commonly classified as occurring through canonical or noncanonical pathways. Most NF-B–inducing stimuli, including the viral oncoprotein Tio, lead to a concerted activation of both NF-B pathways; however, extensive crosstalk at multiple levels between these signaling cascades restricts the ability to discriminate between the canonical and the noncanonical effects. We showed that noncanonical NF-B activation by Tio depends on a distinct sequence motif that directly recruits tumor necrosis factor receptor–associated factor 3 (TRAF3). Through its TRAF3-binding motif, Tio triggered a ubiquitin-independent depletion of TRAF3 from the cytosol, which prevented TRAF3 from inhibiting signaling through the noncanonical NF-B cascade. Furthermore, the Tio-TRAF3 interaction did not affect components of the canonical NF-B signaling pathway or the expression of target genes; thus, Tio induced noncanonical NF-B independently of crosstalk with the canonical pathway. Together, these data identify a distinct molecular mechanism of noncanonical NF-B activation that should enable studies into the particular functions of this pathway.
AU  - de Jong, S.J.*
AU  - Albrecht, J.-C.*
AU  - Giehler, F.
AU  - Kieser, A.
AU  - Sticht, H.*
AU  - Biesinger, B.*
C1  - 24090
C2  - 31322
TI  - Noncanonical NF-κB activation by the oncoprotein Tio occurs through a nonconserved TRAF3-binding motif.
JO  - Sci. Signal.
VL  - 6
IS  - 272
PB  - Amer. Assoc. of Advancement in Science
PY  - 2013
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - In response to genotoxic stress induced by DNA double-stranded breaks (DSBs), the inhibitor of κB kinase (IKK) to nuclear factor κB (NF-κB) pathway is activated, which can promote cancer progression and increase the resistance of cancer cells to ionizing radiation or chemotherapeutic drugs. The kinase ataxia telangiectasia mutated (ATM) has a critical role in the activation of NF-κB in response to genotoxic stress. Two reports reveal key cytoplasmic functions of ATM in triggering IKK activation upon DNA damage. After induction of DSBs, ATM is exported from the nucleus and stimulates the ubiquitin ligase activity of tumor necrosis factor receptor-associated factor 6 (TRAF6) or X-linked inhibitor of apoptosis protein, which catalyze the auto-polyubiquitylation of TRAF6 and the polyubiquitylation of the IKK adaptor ELKS, respectively. Ubiquitylation promotes the assembly of signalosomes containing the kinase TAK1 (transforming growth factor b-activated kinase 1). These signalosomes are the site of activation of the cytosolic IKK complex, which stimulates NF-κB-dependent induction of a proliferative and antiapoptotic gene program. These studies show that ATM executes essential functions outside the nucleus in response to DSBs.
AU  - Hadian, K.
AU  - Krappmann, D.
C1  - 5269
C2  - 28641
TI  - Signals from the nucleus: Activation of NF-κB by cytosolic ATM in the DNA damage response.
JO  - Sci. Signal.
VL  - 4
IS  - 156
PB  - Amer Assoc Advancement Science
PY  - 2011
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - Sperm of the sea urchin Arbacia punctulata can respond to a single molecule of chemoattractant released by an egg. The mechanism underlying this extreme sensitivity is unknown. Crucial signaling events in the response of A. punctulata sperm to chemoattractant include the rapid synthesis of the intracellular messenger guanosine 3',5'-monophosphate (cGMP) and the ensuing membrane hyperpolarization that results from the opening of potassium-selective cyclic nucleotide-gated (CNGK) channels. Here, we use calibrated photolysis of caged cGMP to show that approximately 45 cGMP molecules are generated during the response to a single molecule of chemoattractant. The CNGK channel can respond to such small cGMP changes because it is exquisitely sensitive to cGMP and activated in a noncooperative fashion. Like voltage-activated Ca(v) and Na(v) channels, the CNGK polypeptide consists of four homologous repeat sequences. Disabling each of the four cyclic nucleotide-binding sites through mutagenesis revealed that binding of a single cGMP molecule to repeat 3 is necessary and sufficient to activate the CNGK channel. Thus, CNGK has developed a mechanism of activation that is different from the activation of other CNG channels, which requires the cooperative binding of several ligands and operates in the micromolar rather than the nanomolar range.
AU  - Bonigk, W.*
AU  - Loogen, A.*
AU  - Seifert, R.*
AU  - Kashikar, N.*
AU  - Klemm, C.*
AU  - Krause, E.*
AU  - Hagen, V.*
AU  - Kremmer, E.*
AU  - Strünker, T.*
AU  - Kaupp, U.B.*
C1  - 5421
C2  - 27490
SP  - ra68
TI  - An atypical CNG channel activated by a single cGMP molecule controls sperm chemotaxis.
JO  - Sci. Signal.
VL  - 2
IS  - 94
PB  - American Assoc. for the Advancement of Science
PY  - 2010
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - The 2008 annual meeting of the Signal Transduction Society covered a broad spectrum of topics, with signaling in immune cells as the special focus of the meeting. Many of the immune signaling talks concerned B and T lymphocytes in particular; the role of inflammatory cytokines in cancer progression was also addressed. Neoplastic development was also discussed with regard to aspects of cell cycle control, aging, and transformation. Topics extended to signaling pathways induced by bacteria, viruses, and environmental toxins, as well as those involved in differentiation, morphogenesis, and cell death. This international and interdisciplinary scientific gathering induced lively discussions and close interactions between participants.
AU  - Entschladen, F.*
AU  - Lindquist, J.A.*
AU  - Serfling, E.*
AU  - Thiel, G.*
AU  - Kieser, A.
AU  - Giehl, K.*
AU  - Ehrhardt, C.*
AU  - Feller, S.M.*
AU  - Ullrich, O.*
AU  - Schaper, F.*
AU  - Janssen, O.*
AU  - Hass, R.*
AU  - Friedrich, K.*
C1  - 5973
C2  - 27684
SP  - mr3
TI  - Signal transduction - receptors, mediators, and genes.
JO  - Sci. Signal.
VL  - 2
IS  - 63
PB  - Amer Assoc Advancement Science
PY  - 2009
SN  - 1945-0877
ER  - 

TY  - JOUR
AB  - Cytokines, pathogens, and antigens signal through NF-{kappa}B (nuclear factor {kappa}B) transcription factors to regulate the expression of genes that mediate the inflammatory response. Stimulation of G protein–coupled receptors (GPCRs) has also been shown to trigger inflammatory responses by activating the canonical NF-{kappa}B pathway, which involves the phosphorylation and degradation of cytosolic NF-{kappa}B inhibitors (I{kappa}Bs) that depend on the I{kappa}B kinase (IKK). However, genetic data about the molecular links between GPCR-proximal events and activation of IKK and, thereby, of NF-{kappa}B have remained elusive. Recent studies by Klemm et al., McAllister-Lucas et al., and Wang et al. now present compelling evidence that signaling complexes containing the adaptor proteins Bcl10 (B cell chronic lymphocytic leukemia and/or lymphoma 10) and Malt1 [mucosa-associated lymphoid tissue (MALT) lymphoma translocation gene 1], constitute the missing link between GPCRs and IKK and NF-{kappa}B activation (1–3). A separate study by Gross et al. reports an intriguing finding, that Dectin-1–mediated antifungal immunity in dendritic cells is also regulated by the Bcl10-Malt1 module (4). GPCR- and Dectin-1–induced NF-{kappa}B activation depends on the interaction of the Bcl10-Malt1 module with specific Bcl10-binding CARD (caspase recruitment domain)–containing scaffold proteins (2, 4). Together with previous data establishing a crucial role for CARD11 [also known as CARMA1, for CARD-MAGUK (membrane-associated guanylate kinase)] association with Bcl10-Malt1 in lymphocytes, these results suggest that diverse receptor systems use distinct CARD scaffolds and conserved Bcl10-Malt1 modules to stimulate IKK and NF-{kappa}B signaling (Fig. 1).
AU  - Wegener, E.
AU  - Krappmann, D.
C1  - 3934
C2  - 24466
SP  - p21.
TI  - CARD-Bcl10-Malt1 Signalosomes: Missing Link to NF-B.
JO  - Sci. Signal.
VL  - 384
IS  - 384
PB  - AAAS
PY  - 2007
SN  - 1945-0877
ER  -