Feedback regulation in EGFR signaling involves IRF2BP proteins and temporal control by (de)SUMOylation

Molecular switches are essential modules in signaling networks by enabling a quick response to environmental changes. Here, we describe a role for small ubiquitin-like-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 repressors, including IRF2BP1, IRF2BP2 and IRF2BPL as novel players in EGFR signaling, which lost SUMO transiently within 15 min of EGF treatment. We found 38 genes whose expression within the first hour of EGF treatment was altered in cells expressing SUMOylation deficient IRF2BP1, including Dual specific phosphatase 1 (DUSP1), an important feedback regulator of EGFR signalling. We show that IRF2BP1 binds to the proximal promoter of DUSP1, whose activation requires IRF2BP1 deSUMOylation. Thus, the SUMO-dependent molecular switch of IRF2BP1 activity is important to finely tune EGFR signaling