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Tanzer, M.C., Bludau, I., Stafford, C.A., Hornung, V., & Mann, M.

Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling


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 phosphorylationdependent
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/.

Read more at Nature Communications (2021)12:6053