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Originally published In Press as doi:10.1074/jbc.M208495200 on September 25, 2002

J. Biol. Chem., Vol. 277, Issue 49, 46974-46979, December 6, 2002
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An Ephrin Mimetic Peptide That Selectively Targets the EphA2 Receptor*

Mitchell Koolpe, Monique Dail, and Elena B. PasqualeDagger

From the Burnham Institute, La Jolla, California 92037

Eph receptor tyrosine kinases represent promising disease targets because they are differentially expressed in pathologic versus normal tissues. The EphA2 receptor is up-regulated in transformed cells and tumor vasculature where it likely contributes to cancer pathogenesis. To exploit EphA2 as a therapeutic target, we used phage display to identify two related peptides that bind selectively to EphA2 with high affinity (submicromolar KD values). The peptides target the ligand-binding domain of EphA2 and compete with ephrin ligands for binding. Remarkably, one of the peptides has ephrin-like activity in that it stimulates EphA2 tyrosine phosphorylation and signaling. Furthermore, this peptide can deliver phage particles to endothelial and tumor cells expressing EphA2. In contrast, peptides corresponding to receptor-interacting portions of ephrin ligands bind weakly and promiscuously to many Eph receptors. Bioactive ephrin mimetic peptides could be used to selectively deliver agents to Eph receptor-expressing tissues and modify Eph signaling in therapies for cancer, pathological angiogenesis, and nerve regeneration.

* This work was supported by National Institutes of Health Grant CA82713 (to E. B. P.), Department of Defense postdoctoral fellowship DAMD17-01-1-0168 (to M. K.) awarded and administered by the United States Army Medical Research Acquisition Activity, and an American Heart Association predoctoral fellowship (to M. D.). We assert that the content of this manuscript does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: The Burnham Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-646-3131; Fax: 858-646-3199; E-mail: elenap@burnham.org.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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