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Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling

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. We reasoned that a systems-level proteomic analysis of TNF signaling could dissect its diverse functions and offer a base for developing more targeted therapies. Combining phosphoproteomics time course experiments with spatial and kinase inhibitor analysis clusters phosphorylations into functional modules. The majority of regulated phosphorylations could be assigned to an upstream kinase by inhibiting master kinases and spatial proteomics revealed phosphorylation-dependent translocations of hundreds of proteins upon TNF stimulation. Phosphoproteome analysis of TNF-induced apoptosis and necroptosis revealed a key role for transcriptional cyclin-dependent kinase (CDK) activity to promote cytokine production and prevent excessive cell death downstream of the TNF signaling receptor. Our comprehensive interrogation of TNF induced pathways and sites can be explored at http://tnfviewer.biochem.mpg.de/.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Myeloid Cell Line

SUBMITTER: Mario Oroshi

LAB HEAD: Matthias Mann

PROVIDER: PXD021366 | Pride | 2021-10-11

REPOSITORIES: Pride

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			Action	DRS
	20170819_QX6_MaTa_SA_mock_1_DMSO_180min_1.raw	Raw
	20170819_QX6_MaTa_SA_mock_1_DMSO_180min_4.raw	Raw
	20170819_QX6_MaTa_SA_mock_1_TSI_180min_1.raw	Raw
	20170819_QX6_MaTa_SA_mock_1_TSI_180min_2.raw	Raw
	20170819_QX6_MaTa_SA_mock_1_TSI_180min_4.raw	Raw

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