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Molecular 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 compare the endogenous SUMO proteomes of HeLa cells before and after EGF stimulation. Thereby, we identify a small group of transcriptional coregulators including IRF2BP1, IRF2BP2, and IRF2BPL as novel players in EGFR signaling. Comparison of cells expressing wild type or SUMOylation‐deficient IRF2BP1 indicates that transient deSUMOylation of IRF2BP proteins is important for appropriate expression of immediate early genes including dual specificity phosphatase 1 (DUSP1, MKP‐1) and the transcription factor ATF3. We find that IRF2BP1 is a repressor, whose transient deSUMOylation on the DUSP1 promoter allows—and whose timely reSUMOylation restricts—DUSP1 transcription. Our work thus provides a paradigm how comparative SUMO proteome analyses serve to reveal novel regulators in signal transduction and transcription. SYNOPSIS: Transcriptional repressors of the IRF2BP family and SUMO play a critical role in EGFR signaling. Transient de‐SUMOylation of IRF2BP proteins in response to EGF contributes to immediate early gene transcription. EGF induces rapid and transient deSUMOylation of five transcriptional regulators.DeSUMOylation of IRF2BP proteins upon EGF treatment enhances the transcriptional response of immediate early genes.Loss of IRF2BP1/2 leads to elevated EGFR expression and enhanced cell proliferation. [ABSTRACT FROM AUTHOR]