title: Phosphorylation of ETS1 by Src family kinases prevents its recognition by the COP1 tumor suppressor.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Tomaino
authors.affiliation: Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ehrenberger
authors.affiliation: 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.
authors.forename: Elgene
authors.initials: E
authors.lastname: Lim
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Rodent Histopathology Core, Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Michaela
authors.initials: M
authors.lastname: Bowden
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Brock
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Dillon
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: 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.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: 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.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yaffe
authors.affiliation: 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.
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011485:Protein Binding; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D050787:Proto-Oncogene Protein c-ets-2 / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D047368:Tumor Burden; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C494041:ETS1 protein, human; C494069:ETS2 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D050787:Proto-Oncogene Protein c-ets-2; C471981:COP1 protein, human; D044767:Ubiquitin-Protein Ligases; D019061:src-Family Kinases