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ephrinB1 signals from the cell surface to the nucleus by recruitment of STAT3
Tagvor G. Nishanian*,
Lino Tessarollo, and
Ira O. Daar*,
*Laboratory of Cell and Developmental Signaling and 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.
The Eph (erythropoietin-producing hepatoma) family of receptortyrosine kinases and their membrane-bound ligands, the ephrins,have been implicated in regulating cell adhesion and migrationduring development by mediating cell-to-cell signaling events.The transmembrane ephrinB (Eph receptor interactor B) proteinis a bidirectional signaling molecule that sends a forward signalthrough the activation of its cognate receptor tyrosine kinase,residing on another cell. A reverse signal can be transducedinto the ephrinB-expressing cell via tyrosine phosphorylationof its conserved C-terminal cytoplasmic domain. Although someinsight has been gained regarding how ephrinB may send signalsaffecting cytoskeletal components, little is known about howephrinB1 reverse signaling affects transcriptional processes.Here we report that signal transducer and activator of transcription3 (STAT3) can interact with ephrinB1 in a phosphorylation-dependentmanner that leads to enhanced activation of STAT3 transcriptionalactivity. This activity depends on the tyrosine kinase Jak2,and two tyrosines within the intracellular domain of ephrinB1are critical for the association with STAT3 and its activation.The recruitment of STAT3 to ephrinB1, and its resulting Jak2-dependentactivation and transcription of reporter targets, reveals asignaling pathway from ephrinB1 to the nucleus.
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.