The signaling cascades of the Eph receptor tyrosine kinase family and the ephrin ligands have been implicated in pathological forms of angiogenesis and tumorigenesis. While initial investigations have focused on the role of this protein-protein interaction in axonal guidance, cell attachment and motility, there is now significant evidence for the overexpression and dysregulation of this interaction in numerous cancerous tissues. The key research hypothesis of this proposal is that a limited set of structural determinants are responsible for the promiscuity and selectivity of ligand recognition exhibited by the Eph receptor family, and that these structural determinants can be exploited for small molecule modulators of this interaction. The proposed research will result in a demonstrated description and characterization of the mode of binding across this large family of receptor-ligand interactions. The outcome will be translated in a discovery approach to the development of small molecule compounds that exploit these structural determinants.
Aim 1 : Evaluate structural determinants of specificity versus promiscuity in Eph receptor-ligand binding by using X-ray crystallography.
Aim 2 : Develop strategies to stabilize the flexible Eph receptor J-K loop in the ephrin-binding cleft to facilitate receptor crystallization in complex with small molecular weight chemical compounds.
Aim 3 : Characterize and improve small molecular weight chemical compounds identified in high throughput screens and virtual ligand screens for inhibitors of EphB2 and EphB4 receptor ligand binding.

Public Health Relevance

The Eph receptor tyrosine kinases and their ephrin ligands are involved in tumor growth and represent an important asset of cancer targets. Defining the structural features responsible for Eph receptor ligand specificity and affinity will enable the development of new peptide and small molecules as potenfial cancer. therapeufic starting points.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA138390-04
Application #
8448018
Study Section
Special Emphasis Panel (ZCA1-GRB-P)
Project Start
Project End
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$346,987
Indirect Cost
$104,285
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Singh, Deo R; Ahmed, Fozia; King, Christopher et al. (2015) EphA2 Receptor Unliganded Dimers Suppress EphA2 Pro-tumorigenic Signaling. J Biol Chem 290:27271-9
Bhatia, Shilpa; Hirsch, Kellen; Baig, Nimrah A et al. (2015) Effects of altered ephrin-A5 and EphA4/EphA7 expression on tumor growth in a medulloblastoma mouse model. J Hematol Oncol 8:105
Singh, Deo R; Cao, QingQing; King, Christopher et al. (2015) Unliganded EphA3 dimerization promoted by the SAM domain. Biochem J 471:101-9
Wu, Bainan; Wang, Si; De, Surya K et al. (2015) Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells. Chem Biol 22:876-87
Forse, Garry Jason; Uson, Maria Loressa; Nasertorabi, Fariborz et al. (2015) Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5. PLoS One 10:e0127081

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