Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome

Nat Struct Mol Biol. 2013 Apr;20(4):447-53. doi: 10.1038/nsmb.2505. Epub 2013 Feb 24.


SIX1 interacts with EYA to form a bipartite transcription factor essential for mammalian development. Loss of function of this complex causes branchio-oto-renal (BOR) syndrome, whereas re-expression of SIX1 or EYA promotes metastasis. Here we describe the 2.0-Å structure of SIX1 bound to EYA2, which suggests a new DNA-binding mechanism for SIX1 and provides a rationale for the effect of BOR syndrome mutations. The structure also reveals that SIX1 uses predominantly a single helix to interact with EYA. Substitution of a single amino acid in this helix is sufficient to disrupt SIX1-EYA interaction, SIX1-mediated epithelial-mesenchymal transition and metastasis in mouse models. Given that SIX1 and EYA are overexpressed in many tumor types, our data indicate that targeting the SIX1-EYA complex may be a potent approach to inhibit tumor progression in multiple cancer types.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Branchio-Oto-Renal Syndrome / genetics
  • Branchio-Oto-Renal Syndrome / physiopathology*
  • Homeodomain Proteins / chemistry
  • Homeodomain Proteins / physiology*
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / physiology*
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Mutation, Missense
  • Neoplasm Metastasis / physiopathology*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / physiology*
  • Protein Tyrosine Phosphatases / chemistry
  • Protein Tyrosine Phosphatases / physiology*
  • Structure-Activity Relationship


  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • SIX1 protein, human
  • EYA2 protein, human
  • Protein Tyrosine Phosphatases

Associated data

  • PDB/4EGC