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Science 326 (5959): 1502-1509

Copyright © 2009 by the American Association for the Advancement of Science

Cell-Specific Information Processing in Segregating Populations of Eph Receptor Ephrin–Expressing Cells

Claus Jørgensen,1 Andrew Sherman,1,2 Ginny I. Chen,1,2 Adrian Pasculescu,1 Alexei Poliakov,3 Marilyn Hsiung,1 Brett Larsen,1 David G. Wilkinson,3 Rune Linding,4,* Tony Pawson1,2,*

Abstract: Cells have self-organizing properties that control their behavior in complex tissues. Contact between cells expressing either B-type Eph receptors or their transmembrane ephrin ligands initiates bidirectional signals that regulate cell positioning. However, simultaneously investigating how information is processed in two interacting cell types remains a challenge. We implemented a proteomic strategy to systematically determine cell-specific signaling networks underlying EphB2- and ephrin-B1–controlled cell sorting. Quantitative mass spectrometric analysis of mixed populations of EphB2- and ephrin-B1–expressing cells that were labeled with different isotopes revealed cell-specific tyrosine phosphorylation events. Functional associations between these phosphotyrosine signaling networks and cell sorting were established with small interfering RNA screening. Data-driven network modeling revealed that signaling between mixed EphB2- and ephrin-B1–expressing cells is asymmetric and that the distinct cell types use different tyrosine kinases and targets to process signals induced by cell-cell contact. We provide systems- and cell-specific network models of contact-initiated signaling between two distinct cell types.

1 Samuel Lunenfeld Research Institute (SLRI), Mount Sinai Hospital, Toronto M5G 1X5, Canada.
2 Department of Molecular Genetics, University of Toronto, Toronto M5S 1A8, Canada.
3 Division of Developmental Neurobiology, Medical Research Council (MRC) National Institute for Medical Research (NIMR), London NW7 1AA, UK.
4 Cellular & Molecular Logic Team, Section of Cell and Molecular Biology, Institute of Cancer Research (ICR), London SW3 6JB, UK.

* To whom correspondence should be addressed. E-mail: linding{at}icr.ac.uk (R.L.); pawson{at}lunenfeld.ca (T.P.)

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