Abstract |
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.
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Authors | Aaron N Patrick, Joshua H Cabrera, Anna L Smith, Xiaojiang S Chen, Heide L Ford, Rui Zhao |
Journal | Nature structural & molecular biology
(Nat Struct Mol Biol)
Vol. 20
Issue 4
Pg. 447-53
(Apr 2013)
ISSN: 1545-9985 [Electronic] United States |
PMID | 23435380
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Homeodomain Proteins
- Intracellular Signaling Peptides and Proteins
- Nuclear Proteins
- SIX1 protein, human
- EYA2 protein, human
- Protein Tyrosine Phosphatases
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Topics |
- Animals
- Branchio-Oto-Renal Syndrome
(genetics, physiopathology)
- Homeodomain Proteins
(chemistry, physiology)
- Humans
- Intracellular Signaling Peptides and Proteins
(chemistry, physiology)
- MCF-7 Cells
- Mice
- Mice, Nude
- Models, Molecular
- Mutation, Missense
- Neoplasm Metastasis
(physiopathology)
- Nuclear Proteins
(chemistry, physiology)
- Protein Tyrosine Phosphatases
(chemistry, physiology)
- Structure-Activity Relationship
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