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 invesfigations have focused on the role of this protein-protein interaction in axonal guidance, cell attachment and motility, there is now signiflcant evidence forthe 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 recognifion 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 descripfion and characterizafion 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 #
1P01CA138390-01A1
Application #
7799994
Study Section
Special Emphasis Panel (ZCA1-GRB-P (O1))
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2009-12-01
Budget End
2011-01-31
Support Year
1
Fiscal Year
2010
Total Cost
$394,043
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Singh, Deo R; Ahmed, Fozia; Paul, Michael D et al. (2017) The SAM domain inhibits EphA2 interactions in the plasma membrane. Biochim Biophys Acta 1864:31-38
Stammes, Marieke A; Prevoo, Hendrica A J M; Ter Horst, Meyke C et al. (2017) Evaluation of EphA2 and EphB4 as Targets for Image-Guided Colorectal Cancer Surgery. Int J Mol Sci 18:
Singec, Ilyas; Crain, Andrew M; Hou, Junjie et al. (2016) Quantitative Analysis of Human Pluripotency and Neural Specification by In-Depth (Phospho)Proteomic Profiling. Stem Cell Reports 7:527-542
Bhaskar, Archana; Tiwary, Bhupendra Nath (2016) Hypoxia inducible factor-1 alpha and multiple myeloma. Int J Adv Res (Indore) 4:706-715
Pasquale, Elena B (2016) Exosomes expand the sphere of influence of Eph receptors and ephrins. J Cell Biol 214:5-7
Barquilla, Antonio; Lamberto, Ilaria; Noberini, Roberta et al. (2016) Protein kinase A can block EphA2 receptor-mediated cell repulsion by increasing EphA2 S897 phosphorylation. Mol Biol Cell 27:2757-70
Singh, Deo R; Pasquale, Elena B; Hristova, Kalina (2016) A small peptide promotes EphA2 kinase-dependent signaling by stabilizing EphA2 dimers. Biochim Biophys Acta 1860:1922-8
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 22:876-887
Barquilla, Antonio; Pasquale, Elena B (2015) Eph receptors and ephrins: therapeutic opportunities. Annu Rev Pharmacol Toxicol 55:465-87

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