title: Regulation of EphB2 activation and cell repulsion by feedback control of the MAPK pathway.
abstract: 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.
authors.affiliation: Division of Developmental Neurobiology, Medical Research Council National Institute for Medical Research, London NW7 1AA, England, UK.
authors.forename: Alexei
authors.initials: A
authors.lastname: Poliakov
authors.forename: Maria L
authors.initials: ML
authors.lastname: Cotrina
authors.forename: Andrea
authors.initials: A
authors.lastname: Pasini
authors.forename: David G
authors.initials: DG
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004705:Endocytosis; D036387:Ephrin-B1 / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D036183:Receptor, EphB2 / Q000235:genetics / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: C092571:Efnb1 protein, mouse; D036387:Ephrin-B1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C485561:SPRY2 protein, human; C499038:SPRY4 protein, human; D036183:Receptor, EphB2; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020928:Mitogen-Activated Protein Kinases