Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling.
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Cited by: 30


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 .


Spatial Proteomics

MeSH terms

A549 Cells
Cell Death
Cell Line
Cyclin-Dependent Kinases
Signal Transduction
Tumor Necrosis Factor-alpha
U937 Cells


Tanzer, Maria C
Bludau, Isabell
Stafford, Che A
Hornung, Veit
Mann, Matthias

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