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Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling

Author

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  • Maria C. Tanzer

    (Max Planck Institute of Biochemistry)

  • Isabell Bludau

    (Max Planck Institute of Biochemistry)

  • Che A. Stafford

    (Ludwig-Maximilians-Universität)

  • Veit Hornung

    (Ludwig-Maximilians-Universität)

  • Matthias Mann

    (Max Planck Institute of Biochemistry)

Abstract

Tumor necrosis factor (TNF) is one of the few cytokines successfully targeted by therapies against inflammatory diseases. However, blocking this well studied and pleiotropic ligand can cause dramatic side-effects. Here, we reason that a systems-level proteomic analysis of TNF signaling could dissect its diverse functions and offer a base for developing more targeted therapies. Therefore, we combine phosphoproteomics time course experiments with subcellular localization and kinase inhibitor analysis to identify functional modules of protein phosphorylation. The majority of regulated phosphorylation events can be assigned to an upstream kinase by inhibiting master kinases. Spatial proteomics reveals phosphorylation-dependent translocations of hundreds of proteins upon TNF stimulation. Phosphoproteome analysis of TNF-induced apoptosis and necroptosis uncovers a key role for transcriptional cyclin-dependent kinase activity to promote cytokine production and prevent excessive cell death downstream of the TNF signaling receptor. This resource of TNF-induced pathways and sites can be explored at http://tnfviewer.biochem.mpg.de/ .

Suggested Citation

  • Maria C. Tanzer & Isabell Bludau & Che A. Stafford & Veit Hornung & Matthias Mann, 2021. "Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26289-6
    DOI: 10.1038/s41467-021-26289-6
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    1. Jonathan J. Swietlik & Stefanie Bärthel & Chiara Falcomatà & Diana Fink & Ankit Sinha & Jingyuan Cheng & Stefan Ebner & Peter Landgraf & Daniela C. Dieterich & Henrik Daub & Dieter Saur & Felix Meissn, 2023. "Cell-selective proteomics segregates pancreatic cancer subtypes by extracellular proteins in tumors and circulation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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