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Regulation of EphB2 activation and cell repulsion by feedback control of the MAPK pathway

Division of Developmental Neurobiology, Medical Research Council National Institute for Medical Research, London NW7 1AA, England, UK

Correspondence to David G. Wilkinson: dwilkin{at}nimr.mrc.ac.uk

In this study, we investigated whether the ability of Eph receptor signaling to mediate cell repulsion is antagonized by fibroblast growth factor receptor (FGFR) activation that can promote cell invasion. We find that activation of FGFR1 in EphB2-expressing cells prevents segregation, repulsion, and collapse responses to ephrinB1 ligand. FGFR1 activation leads to increased phosphorylation of unstimulated EphB2, which we show is caused by down-regulation of the leukocyte common antigen–related tyrosine phosphatase receptor that dephosphorylates EphB2. In addition, FGFR1 signaling inhibits further phosphorylation of EphB2 upon stimulation with ephrinB1, and we show that this involves a requirement for the mitogen-activated protein kinase (MAPK) pathway. In the absence of activated FGFR1, EphB2 activates the MAPK pathway, which in turn promotes EphB2 activation in a positive feedback loop. However, after FGFR1 activation, the induction of Sprouty genes inhibits the MAPK pathway downstream of EphB2 and decreases cell repulsion and segregation. These findings reveal a novel feedback loop that promotes EphB2 activation and cell repulsion that is blocked by transcriptional targets of FGFR1.

A. Pasini's present address is Laboratoire de Genetique et Physiologie du Developpement, Institute de Biologie du Developpement de Marseille, F-13288 Marseille, Cedex 09, France.

Abbreviations used in this paper: ERK, extracellular signal-regulated kinase; FGFR, FGF receptor; GAP, GTPase-activating protein; iFGFR, inducible FGFR; LAR, leukocyte common antigen related; MEK, MAPK/ERK kinase; PTP, protein tyrosine phosphatase.

© 2008 Poliakov et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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