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Many of the pathways involved in organ development are conserved between species and organ types. An example of such a conserved regulatory cascade is the PAX-SIX-EYA-DACH pathway. It is often referred to as the Retinal Determination pathway since it was first described in the context of fly eye development. However it is now recognized to be critical for the embryonic development of multiple organs, including the kidney, ear and muscle. Mutations in the genes that comprise this pathway are associated with severe birth defects. The long-term goal of our research program is to understand the structural and mechanistic details of proteins that form part of this important cascade. Our studies are leading to fundamental new insights regarding developmental processes, as well as identifying new opportunities for targeted drug development.
The EYA proteins are found at elevated levels in breast and ovarian cancers and this is associated with a poor prognosis. We have previously shown that the EYA proteins are tyrosine phosphatases that utilize a non-conventional reaction mechanism. More recently we have demonstrated that this enzymatic activity confers cells with the ability to be more motile and invasive. In animal studies we show that the tyrosine phosphatase activity of the EYAs is linked to the metastatic capability of breast cancer cells. In ongoing studies we are developing inhibitors for the EYA tyrosine phosphatase activity. Such compounds can serve as lead compounds in the development of EYA-targeted therapeutic agents for breast cancer as well as be used as research tools.
We welcome interested students and postdocs to join us in these projects. To get more information, contact Rashmi Hegde.
click to enlarge
Overview of the research process in the Hegde Lab
A breast epithelial cell over-expressing a mutationally-altered EYA protein (red phalloidin, blue DAPI)
Schematic representation of the active site of the EYA3 tyrosine phosphatase
An inhibitor docked in the active site of Eya3
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