Phosphorylation of ETS1 by Src Family Kinases Prevents Its Recognition by the COP1 Tumor Suppressor

• ETS1 and ETS2 are substrates of the COP1 tumor suppressor ubiquitin ligase complex
• Phosphorylation of specific Ser/Thr residues in ETS1 and ETS2 enables COP1 binding
• Tyr phosphorylation of ETS1 by Src family kinases prevents COP1 binding
• Src-induced accumulation of ETS1 promotes breast cancer growth in vitro and in vivo

SummaryOncoproteins and tumor suppressors antagonistically converge on critical nodes governing neoplastic growth, invasion, and metastasis. We discovered that phosphorylation of the ETS1 and ETS2 transcriptional oncoproteins at specific serine or threonine residues creates binding sites for the COP1 tumor suppressor protein, which is an ubiquitin ligase component, leading to their destruction. In the case of ETS1, however, phosphorylation of a neighboring tyrosine residue by Src family kinases disrupts COP1 binding, thereby stabilizing ETS1. Src-dependent accumulation of ETS1 in breast cancer cells promotes anchorage-independent growth in vitro and tumor growth in vivo. These findings expand the list of potential COP1 substrates to include proteins whose COP1-binding sites are subject to regulatory phosphorylation and provide insights into transformation by Src family kinases.