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- Title
The phosphoproteome of toll-like receptor-activated macrophages.
- Authors
Weintz, Gabriele; Olsen, Jesper V; Frühauf, Katja; Niedzielska, Magdalena; Amit, Ido; Jantsch, Jonathan; Mages, Jörg; Frech, Cornelie; Dölken, Lars; Mann, Matthias; Lang, Roland
- Abstract
Recognition of microbial danger signals by toll-like receptors (TLR) causes re-programming of macrophages. To investigate kinase cascades triggered by the TLR4 ligand lipopolysaccharide (LPS) on systems level, we performed a global, quantitative and kinetic analysis of the phosphoproteome of primary macrophages using stable isotope labelling with amino acids in cell culture, phosphopeptide enrichment and high-resolution mass spectrometry. In parallel, nascent RNA was profiled to link transcription factor (TF) phosphorylation to TLR4-induced transcriptional activation. We reproducibly identified 1850 phosphoproteins with 6956 phosphorylation sites, two thirds of which were not reported earlier. LPS caused major dynamic changes in the phosphoproteome (24% up-regulation and 9% down-regulation). Functional bioinformatic analyses confirmed canonical players of the TLR pathway and highlighted other signalling modules (e.g. mTOR, ATM/ATR kinases) and the cytoskeleton as hotspots of LPS-regulated phosphorylation. Finally, weaving together phosphoproteome and nascent transcriptome data by in silico promoter analysis, we implicated several phosphorylated TFs in primary LPS-controlled gene expression.
- Publication
Molecular Systems Biology, 2010, Vol 6, Issue 1, p1
- ISSN
1744-4292
- Publication type
Article
- DOI
10.1038/msb.2010.29