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Vol. 15, Issue 4, 1647-1655, April 2004

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Ectopic EphA4 Receptor Induces Posterior Protrusions via FGF Signaling in Xenopus Embryos

Eui Kyun Park ^*  , Neil Warner   ^¶, Yong-Sik Bong ^*, David Stapleton  ^||, Ryu Maeda ^* #, Tony Pawson  ^¶, and Ira O. Daar ^* **

^* Regulation of Cell Growth Laboratory, National Cancer Institute–Frederick, Frederick, Maryland 21702; Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada; and ^¶ Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5G 1A8, Canada

Submitted September 17, 2003; Revised January 7, 2004; Accepted January 8, 2004
Monitoring Editor: Carl-Henrik Heldin

The Eph family of receptor tyrosine kinases regulates numerous biological processes. To examine the biochemical and developmental contributions of specific structural motifs within Eph receptors, wild-type or mutant forms of the EphA4 receptor were ectopically expressed in developing Xenopus embryos. Wild-type EphA4 and a mutant lacking both the SAM domain and PDZ binding motif were constitutively tyrosine phosphorylated in vivo and catalytically active in vitro. EphA4 induced loss of cell adhesion, ventro-lateral protrusions, and severely expanded posterior structures in Xenopus embryos. Moreover, mutation of a conserved SAM domain tyrosine to phenylalanine (Y928F) enhanced the ability of EphA4 to induce these phenotypes, suggesting that the SAM domain may negatively regulate some aspects of EphA4 activity in Xenopus. Analysis of double mutants revealed that the Y928F EphA4 phenotypes were dependent on kinase activity; juxtamembrane sites of tyrosine phosphorylation and SH2 domain-binding were required for cell dissociation, but not for posterior protrusions. The induction of protrusions and expansion of posterior structures is similar to phenotypic effects observed in Xenopus embryos expressing activated FGFR1. Furthermore, the budding ectopic protrusions induced by EphA4 express FGF-8, FGFR1, and FGFR4a. In addition, antisense morpholino oligonucleotide-mediated loss of FGF-8 expression in vivo substantially reduced the phenotypic effects in EphA4Y928F expressing embryos, suggesting a connection between Eph and FGF signaling.

These authors contributed equally to this work.

Present address: Kyungpook National University Hospital, Biomedical Research Institute, Jung-gu, Daegu, Korea

^|| Present address: St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy 3065, Victoria, Australia

^# Present address: Laboratory for Developmental Gene Regulation, RIKEN, Brain Science Institute, Saitama, Japan.

^** Corresponding author. E-mail address: daar{at}ncifcrf.gov.

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