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Cancer Cell. 2014 Aug 11;26(2):222-34. doi: 10.1016/j.ccr.2014.06.026.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
2
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
7
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8
Rodent Histopathology Core, Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02115, USA.
9
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Cell Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
11
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: william_kaelin@dfci.harvard.edu.

Abstract

Oncoproteins 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.

PMID:
25117710
PMCID:
PMC4169234
DOI:
10.1016/j.ccr.2014.06.026
[Indexed for MEDLINE]
Free PMC Article

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