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PNAS 104 (44): 17305-17310

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

ephrinB1 signals from the cell surface to the nucleus by recruitment of STAT3

Yong-Sik Bong*, Hyun-Shik Lee*, Laura Carim-Todd{dagger}, Kathleen Mood*, Tagvor G. Nishanian*, Lino Tessarollo{dagger}, and Ira O. Daar*,{ddagger}

*Laboratory of Cell and Developmental Signaling and {dagger}Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702

Edited by Anthony J. Pawson, University of Toronto, ON, Toronto, Canada, and approved June 26, 2007

Received for publication March 13, 2007.

Abstract: The Eph (erythropoietin-producing hepatoma) family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. The transmembrane ephrinB (Eph receptor interactor B) protein is a bidirectional signaling molecule that sends a forward signal through the activation of its cognate receptor tyrosine kinase, residing on another cell. A reverse signal can be transduced into the ephrinB-expressing cell via tyrosine phosphorylation of its conserved C-terminal cytoplasmic domain. Although some insight has been gained regarding how ephrinB may send signals affecting cytoskeletal components, little is known about how ephrinB1 reverse signaling affects transcriptional processes. Here we report that signal transducer and activator of transcription 3 (STAT3) can interact with ephrinB1 in a phosphorylation-dependent manner that leads to enhanced activation of STAT3 transcriptional activity. This activity depends on the tyrosine kinase Jak2, and two tyrosines within the intracellular domain of ephrinB1 are critical for the association with STAT3 and its activation. The recruitment of STAT3 to ephrinB1, and its resulting Jak2-dependent activation and transcription of reporter targets, reveals a signaling pathway from ephrinB1 to the nucleus.

Key Words: FGF receptor • Eph receptor • neuroepithelial cells • tyrosine phosphorylation • Jak2

Author contributions: Y.-S.B., L.T., and I.O.D. designed research; Y.-S.B., H.-S.L., L.C.-T., K.M., and T.G.N. performed research; Y.-S.B., L.C.-T., and I.O.D. analyzed data; and Y.-S.B., H.-S.L., L.C.-T., L.T., and I.O.D. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0702337104/DC1.

{ddagger}To whom correspondence should be addressed at: Laboratory of Cell and Developmental Signaling, Building 560, National Cancer Institute, Frederick, MD 21702. E-mail: daar{at}ncifcrf.gov

© 2007 by The National Academy of Sciences of the USA

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