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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Branchio-Oto-Renal Syndrome / genetics
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Branchio-Oto-Renal Syndrome / physiopathology*
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Homeodomain Proteins / chemistry
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Homeodomain Proteins / physiology*
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Humans
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / physiology*
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MCF-7 Cells
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Mice
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Mice, Nude
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Models, Molecular
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Mutation, Missense
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Neoplasm Metastasis / physiopathology*
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Nuclear Proteins / chemistry
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Nuclear Proteins / physiology*
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Protein Tyrosine Phosphatases / chemistry
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Protein Tyrosine Phosphatases / physiology*
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Structure-Activity Relationship
Substances
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Homeodomain Proteins
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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SIX1 protein, human
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EYA2 protein, human
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Protein Tyrosine Phosphatases