SummaryMolecular switches are essential modules in signaling networks and transcriptional reprogramming. Here, we describe a role for small ubiquitin-related-modifier SUMO as a molecular switch in epidermal growth factor receptor (EGFR) signaling. Using quantitative mass spectrometry, we compared the endogenous SUMO-proteomes of Hela cells before and after EGF-stimulation. Thereby, we identified a small group of transcriptional co-regulators including IRF2BP1, IRF2BP2 and IRF2BPL as novel players in EGFR signaling. Comparison of cells expressing wildtype or SUMOylation deficient IRF2BP1 indicated that transient deSUMOylation of IRF2BP1 is important for appropriate expression of immediate early genes including Dual specificity phosphatase 1 (DUSP1, MKP-1), an important feedback regulator of EGFR signaling. We find that IRF2BP1 is a SUMO-dependent repressor, whose transient deSUMOylation on the DUSP1 promotor allows - and whose timely reSUMOylation restricts - DUSP1 expression. Our work thus provides a paradigm how comparative SUMO proteome analyses serve to reveal novel regulators in signal transduction and transcription.
