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Phosphorylation of ETS1 by Src family kinases prevents its recognition by the COP1 tumor suppressor

Gang Lu1, Qing Zhang1, Ying Huang2

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Cancer Cell
|August 14, 2014
PubMed

Insights

The COP1 tumor suppressor targets ETS1 and ETS2 oncoproteins for destruction via phosphorylation. However, Src kinases stabilize ETS1, promoting breast cancer growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Oncoproteins and tumor suppressors regulate cancer progression.
  • COP1 is a tumor suppressor and ubiquitin ligase component that targets proteins for destruction.

Purpose of the Study:

  • To investigate the role of phosphorylation in regulating ETS1 and ETS2 oncoprotein stability.
  • To elucidate the mechanism by which COP1 interacts with ETS1 and ETS2.
  • To understand the impact of Src family kinases on ETS1 stability and cancer growth.

Main Methods:

  • Phosphorylation site analysis of ETS1 and ETS2.
  • Co-immunoprecipitation assays to study protein-protein interactions.
  • Ubiquitin ligase assays to assess protein degradation.
  • In vitro and in vivo cancer cell growth assays.

Main Results:

  • Phosphorylation of ETS1 and ETS2 creates binding sites for COP1, leading to their degradation.
  • Src family kinase-mediated phosphorylation of a tyrosine residue on ETS1 disrupts COP1 binding, stabilizing ETS1.
  • Stabilized ETS1 promotes anchorage-independent growth in vitro and tumor growth in vivo in breast cancer cells.

Conclusions:

  • Regulatory phosphorylation controls the interaction between COP1 and its substrates, including ETS1 and ETS2.
  • Src family kinase activity contributes to cancer progression by stabilizing ETS1.
  • These findings offer insights into the mechanisms of neoplastic growth and potential therapeutic targets.

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