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Berlin Brandenburg

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  • Signal Transduction
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  • 1
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(6), p.e0131506
    Description: Although inactivating frameshift mutations in the Transforming growth factor beta receptor type 2 (TGFBR2) gene are considered as drivers of microsatellite unstable (MSI) colorectal tumorigenesis, consequential alterations of the downstream target proteome are not resolved completely. Applying a click-it chemistry protein labeling approach combined with mass spectrometry in a MSI colorectal cancer model cell line, we identified 21 de novo synthesized proteins differentially expressed upon reconstituted TGFBR2 expression. One candidate gene, the TGF-ß family member Growth differentiation factor-15 (GDF-15), exhibited TGFBR2-dependent transcriptional upregulation causing increased intracellular and extracellular protein levels. As a new TGFBR2 target gene it may provide a link between the TGF-ß branch and the BMP/GDF branch of SMAD-mediated signaling.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 2
    In: Nature, 2011, Vol.471(7340), p.591
    Description: Members of the tumour necrosis factor (TNF) receptor superfamily have important functions in immunity and inflammation. Recently linear ubiquitin chains assembled by a complex containing HOIL-1 and HOIP (also known as RBCK1 and RNF31, respectively) were implicated in TNF signalling, yet their relevance in vivo remained uncertain. Here we identify SHARPIN as a third component of the linear ubiquitin chain assembly complex, recruited to the CD40 and TNF receptor signalling complexes together with its other constituents, HOIL-1 and HOIP. Mass spectrometry of TNF signalling complexes revealed RIP1 (also known as RIPK1) and NEMO (also known as IKKγ or IKBKG) to be linearly ubiquitinated. Mutation of the Sharpin gene (Sharpin^sup cpdm/cpdm^) causes chronic proliferative dermatitis (cpdm) characterized by inflammatory skin lesions and defective lymphoid organogenesis. Gene induction by TNF, CD40 ligand and interleukin-1β was attenuated in cpdm-derived cells which were rendered sensitive to TNF-induced death. Importantly, Tnf gene deficiency prevented skin lesions in cpdm mice. We conclude that by enabling linear ubiquitination in the TNF receptor signalling complex, SHARPIN interferes with TNF-induced cell death and, thereby, prevents inflammation. Our results provide evidence for the relevance of linear ubiquitination in vivo in preventing inflammation and regulating immune signalling. [PUBLICATION ]
    Keywords: Animals–Metabolism ; Cd40 Ligand–Chemistry ; Carrier Proteins–Metabolism ; Carrier Proteins–Metabolism ; Cell Line–Immunology ; Humans–Metabolism ; I-Kappa B Kinase–Pathology ; Immunity–Prevention & Control ; Inflammation–Metabolism ; Inflammation–Chemistry ; Inflammation–Metabolism ; Interleukin-1beta–Metabolism ; Mice–Chemistry ; Multiprotein Complexes–Genetics ; Multiprotein Complexes–Metabolism ; Nf-Kappa B–Metabolism ; Nerve Tissue Proteins–Deficiency ; Nerve Tissue Proteins–Genetics ; Nerve Tissue Proteins–Metabolism ; Phenotype–Cytology ; Receptor-Interacting Protein Serine-Threonine Kinases–Immunology ; Receptors, Tumor Necrosis Factor–Metabolism ; Receptors, Tumor Necrosis Factor–Pathology ; Receptors, Tumor Necrosis Factor–Deficiency ; Signal Transduction–Genetics ; Skin–Chemistry ; Skin–Metabolism ; Skin–Chemistry ; Skin–Metabolism ; Tumor Necrosis Factor-Alpha–Chemistry ; Tumor Necrosis Factor-Alpha–Metabolism ; Ubiquitin–Metabolism ; Ubiquitin–Metabolism ; Ubiquitin-Protein Ligase Complexes–Metabolism ; Ubiquitin-Protein Ligase Complexes–Metabolism ; Ubiquitin-Protein Ligases–Metabolism ; Ubiquitin-Protein Ligases–Metabolism ; Ubiquitination–Metabolism ; Mutation ; Apoptosis ; Proteins ; Recruitment ; Disease ; Carrier Proteins ; Ikbkg Protein, Human ; Interleukin-1beta ; Multiprotein Complexes ; Nf-Kappa B ; Nerve Tissue Proteins ; Rnf31 Protein, Human ; Receptors, Tumor Necrosis Factor ; Tumor Necrosis Factor-Alpha ; Ubiquitin ; Sharpin ; Cd40 Ligand ; Ripk1 Protein, Human ; Receptor-Interacting Protein Serine-Threonine Kinases ; I-Kappa B Kinase ; Hoil-1 Protein, Human ; Ubiquitin-Protein Ligase Complexes ; Ubiquitin-Protein Ligases;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 3
    In: Protein Science, October 2015, Vol.24(10), pp.1686-1694
    Description: Protein‐linked glycans play key roles in cell differentiation, cell–cell interactions, cell growth, adhesion and immune response. Aberrant glycosylation is a characteristic feature of tumor cells and is involved in tumor growth, escape from apoptosis, metastasis formation, and resistance to therapy. It can serve as cancer biomarker and treatment target. To enable comprehensive screening for the impact of tumor driving mutations in colorectal cancer cells we present a method for specific analysis of tumor driver‐induced glycome changes. The strategy is based on a combination of three technologies, that is recombinase‐mediated cassette exchange (RMCE), Click‐It chemistry and mass spectrometry. The new method is exemplified by the analysis of the impact of inactivating mutations of the TGF‐ß‐receptor type II (TGFBR2) on sialic acid incorporation into protein‐linked glycans of the colon cancer cell line HCT116. Overall, 70 proteins were found to show sialic acid incorporation exclusively upon TGFBR2 expression whereas 7 proteins lost sialylation upon TGFBR2 reconstitution. Validation of detected candidate glycoproteins is demonstrated with the cell surface glycoprotein nectin‐3 known to be involved in metastasis, invasion and prognosis of various cancers. Altogether, our new approach can help to systematically puzzle out the influence of tumor‐specific mutations in a major signaling pathway, as exemplified by the TGFBR2 tumor suppressor, on the tumor glycome. It facilitates the identification of glycan‐based tumor markers that could be used for diagnostic and therapeutic applications. In principle the outlined strategy can be adapted to any cancer cell line, tumor driver mutation and several glycan‐building blocks.
    Keywords: Colorectal Cancer ; Microsatellite Instability ; Sialylation ; Tgfbr2 ; Nectin‐3
    ISSN: 0961-8368
    E-ISSN: 1469-896X
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  • 4
    Language: English
    In: Molecular & cellular proteomics : MCP, December 2014, Vol.13(12), pp.3446-56
    Description: Activin receptor type II (ACVR2) is a member of the transforming growth factor type II receptor family and controls cell growth and differentiation, thereby acting as a tumor suppressor. ACVR2 inactivation is known to drive colorectal tumorigenesis. We used an ACVR2-deficient microsatellite unstable colon cancer cell line (HCT116) to set up a novel experimental design for comprehensive analysis of proteomic changes associated with such functional loss of a tumor suppressor. To this end we combined two existing technologies. First, the ACVR2 gene was reconstituted in an ACVR2-deficient colorectal cancer (CRC) cell line by means of recombinase-mediated cassette exchange, resulting in the generation of an inducible expression system that allowed the regulation of ACVR2 gene expression in a doxycycline-dependent manner. Functional expression in the induced cells was explicitly proven. Second, we used the methionine analog azidohomoalanine for metabolic labeling of newly synthesized proteins in our cell line model. Labeled proteins were tagged with biotin via a Click-iT chemistry approach enabling specific extraction of labeled proteins by streptavidin-coated beads. Tryptic on-bead digestion of captured proteins and subsequent ultra-high-performance LC coupled to LTQ Orbitrap XL mass spectrometry identified 513 proteins, with 25 of them differentially expressed between ACVR2-deficient and -proficient cells. Among these, several candidates that had already been linked to colorectal cancer or were known to play a key role in cell growth or apoptosis control were identified, proving the utility of the presented experimental approach. In principle, this strategy can be adapted to analyze any gene of interest and its effect on the cellular de novo proteome.
    Keywords: Gene Expression Regulation, Neoplastic ; Activin Receptors, Type II -- Genetics ; Proteome -- Genetics ; Staining and Labeling -- Methods
    ISSN: 15359476
    E-ISSN: 1535-9484
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  • 5
    Language: English
    In: Molecular Cell, 27 July 2012, Vol.47(2), pp.306-319
    Description: The CD95 (Fas/APO-1) death-inducing signaling complex (DISC) is essential for the initiation of CD95-mediated apoptotic and nonapoptotic responses. The CD95 DISC comprises CD95, FADD, procaspase-8, procaspase-10, and c-FLIP proteins. Procaspase-8 and procaspase-10 are activated at the DISC, leading to the formation of active caspases and apoptosis initiation. In this study we analyzed the stoichiometry of the CD95 DISC. Using quantitative western blots, mass spectrometry, and mathematical modeling, we reveal that the amount of DED proteins procaspase-8/procaspase-10 and c-FLIP at the DISC exceeds that of FADD by several-fold. Furthermore, our findings imply that procaspase-8, procaspase-10, and c-FLIP could form DED chains at the DISC, enabling the formation of dimers and efficient activation of caspase-8. Taken together, our findings provide an enhanced understanding of caspase-8 activation and initiation of apoptosis at the DISC. ► The amount of procaspase-8/procaspase-10 and c-FLIP at the DISC exceeds that of FADD ► Procaspase-8, procaspase-10, and c-FLIP could form DED chains/platforms at the DISC, ► The length of the DED chains is variable and depends on the stimulation strength ► Mathematical model supported by quantitative mass spectrometry and western blot
    Keywords: Biology
    ISSN: 1097-2765
    E-ISSN: 1097-4164
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  • 6
    Language: English
    In: Neurogenetics, December 2018, Vol.19(4), pp.237-255
    Description: Autosomal recessive ataxia telangiectasia (A-T) is characterized by radiosensitivity, immunodeficiency, and cerebellar neurodegeneration. A-T is caused by inactivating mutations in the ataxia telangiectasiamutated (ATM) gene, a serine-threonine protein kinase involved in DNA damage response and excitatory neurotransmission. The selective vulnerability of cerebellar Purkinje neurons (PN) to A-T is not well understood. Employing global proteomic profiling of cerebrospinal fluid from patients at ages around 15 years, we detected reduced calbindin, reelin, cerebellin-1, cerebellin-3, protocadherin fat 2, sempahorin 7A, and increased apolipoprotein B and J peptides. Bioinformatic enrichment was observed for pathways of lipoproteins, endocytosis, extracellular matrix receptor interaction, peptidase activity, adhesion, calcium binding, and complement immunity. This seemed important since secretion of reelin from glutamatergic afferent axons is crucial for PN lipoprotein receptor endocytosis and lipid signaling. Reelin expression is downregulated by irradiation and reelin/ApoB mutations are known causes of ataxia. Validation efforts in 2-month-old Atm-/- mice before onset of motor deficits confirmed cerebellar transcript reductions for reelin receptors Apoer2/Vldlr with increases for their ligands Apoe/Apoh and cholesterol 24-hydroxylase Cyp46a1. Concomitant dysregulations were found for Vglut2/Sema7a as climbing fiber markers, glutamate receptors like Grin2b, and calcium homeostasis factors (Atp2b2, Calb1, Itpr1), while factors involved in DNA damage, oxidative stress, neuroinflammation, and cell adhesion were normal at this stage. Quantitative immunoblots confirmed ApoB and ApoJ increases and VLDLR reduction in cerebellar tissue at the age of 2 months. These findings show that ApoB excess and reelin signaling deficits reflect the neurodegeneration in A-T in a sensitive and specific way. As extracellular factors, apolipoproteins and their cargo such as vitamin E may be useful for neuroprotective interventions.
    Keywords: Apob ; Ataxia Telangiectasia ; Diagnostic Biomarkers ; Label-Free Mass Spectrometry ; Reelin ; Apolipoproteins B ; Cell Adhesion Molecules, Neuronal ; Extracellular Matrix Proteins ; Nerve Tissue Proteins ; Serine Endopeptidases ; Ataxia Telangiectasia -- Genetics
    ISSN: 13646745
    E-ISSN: 1364-6753
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  • 7
    Language: English
    In: PROTEOMICS, January 2009, Vol.9(2), pp.322-334
    Description: Olfactory sensory neurons expose to the inhaled air chemosensory cilia which bind odorants and operate as transduction organelles. Odorant receptors in the ciliary membrane activate a transduction cascade which uses cAMP and Ca for sensory signaling in the ciliary lumen. Although the canonical transduction pathway is well established, molecular components for more complex aspects of sensory transduction, like adaptation, regulation, and termination of the receptor response have not been systematically identified. Moreover, open questions in olfactory physiology include how the cilia exchange solutes with the surrounding mucus, assemble their highly polarized set of proteins, and cope with noxious substances in the ambient air. A specific ciliary proteome would promote research efforts in all of these fields. We have improved a method to detach cilia from rat olfactory sensory neurons and have isolated a preparation specifically enriched in ciliary membrane proteins. Using LC‐ESI‐MS/MS analysis, we identified 377 proteins which constitute the olfactory cilia proteome. These proteins represent a comprehensive data set for olfactory research since more than 80% can be attributed to the characteristic functions of olfactory sensory neurons and their cilia: signal processing, protein targeting, neurogenesis, solute transport, and cytoprotection. Organellar proteomics thus yielded decisive information about the diverse physiological functions of a sensory organelle.
    Keywords: Mass Spectrometry ; Olfactory Receptor Neurons ; Proteomic Analysis ; Sensory Cilia ; Signal Transduction
    ISSN: 1615-9853
    E-ISSN: 1615-9861
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  • 8
    In: Chemical Senses, 2008, 2007, Vol. 33(2), pp.145-162
    Description: The cilia of mammalian olfactory receptor neurons (ORNs) represent the sensory interface that is exposed to the air within the nasal cavity. The cilia are the site where odorants bind to specific receptors and initiate olfactory transduction that leads to excitation of the neuron. This process involves a multitude of ciliary proteins that mediate chemoelectrical transduction, amplification, and adaptation of the primary sensory signal. Many of these proteins were initially identified by their enzymatic activities using a membrane protein preparation from olfactory cilia. This so-called “calcium-shock” preparation is a versatile tool for the exploration of protein expression, enzyme kinetics, regulatory mechanisms, and ciliary development. To support such studies, we present a first proteomic analysis of this membrane preparation. We subjected the cilia preparation to liquid chromatography-electrospray ionisation (LC-ESI-MS/MS) tandem mass spectrometry and identified 268 proteins, of which 49% are membrane proteins. A detailed analysis of their cellular and subcellular localization showed that the cilia preparation obtained by calcium shock not only is highly enriched in ORN proteins but also contains a significant amount of nonciliary material. Although our proteomic study does not identify the entire set of ciliary and nonciliary proteins, it provides the first estimate of the purity of the calcium-shock preparation and provides valuable biochemical information for further research.
    Keywords: Olfactory Receptor Neurons ; Proteomic Analysis ; Signal Transduction ; Sensory Cilia
    ISSN: 0379-864X
    E-ISSN: 1464-3553
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  • 9
    Language: English
    In: Molecular Cell, 11 December 2009, Vol.36(5), pp.831-844
    Description: TNF is a key inflammatory cytokine. Using a modified tandem affinity purification approach, we identified HOIL-1 and HOIP as functional components of the native TNF-R1 signaling complex (TNF-RSC). Together, they were shown to form a linear ubiquitin chain assembly complex (LUBAC) and to ubiquitylate NEMO. We show that LUBAC binds to ubiquitin chains of different linkage types and that its recruitment to the TNF-RSC is impaired in TRADD-, TRAF2-, and cIAP1/2- but not in RIP1- or NEMO-deficient MEFs. Furthermore, the E3 ligase activity of cIAPs, but not TRAF2, is required for HOIL-1 recruitment to the TNF-RSC. LUBAC enhances NEMO interaction with the TNF-RSC, stabilizes this protein complex, and is required for efficient TNF-induced activation of NF-κB and JNK, resulting in apoptosis inhibition. Finally, we demonstrate that sustained stability of the TNF-RSC requires LUBAC's enzymatic activity, thereby adding a third form of ubiquitin linkage to the triggering of TNF signaling by the TNF-RSC.
    Keywords: Proteins ; Signaling ; Molimmuno ; Biology
    ISSN: 1097-2765
    E-ISSN: 1097-4164
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