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EphrinB1 controls cell–cell junctions through the Par polarity complex

Nature Cell Biology volume 10, pages 979–986 (2008)Cite this article

Abstract

A body of evidence is emerging that shows a requirement for ephrin ligands in the proper migration of cells, and the formation of cell and tissue boundaries. These processes are dependent on the cell–cell adhesion system, which plays a crucial role in normal morphogenetic processes during development, as well as in invasion and metastasis1,2,3,4,5,6,7,8,9. Although ephrinB ligands are bi-directional signalling molecules, the precise mechanism by which ephrinB1 signals through its intracellular domain to regulate cell–cell adhesion in epithelial cells remains unclear. Here, we present evidence that ephrinB1 associates with the Par polarity complex protein Par-6 (a scaffold protein required for establishing tight junctions) and can compete with the small GTPase Cdc42 for association with Par-6. This competition causes inactivation of the Par complex, resulting in the loss of tight junctions. Moreover, the interaction between ephrinB1 and Par-6 is disrupted by tyrosine phosphorylation of the intracellular domain of ephrinB1. Thus, we have identified a mechanism by which ephrinB1 signalling regulates cell–cell junctions in epithelial cells, and this may influence how we devise therapeutic interventions regarding these molecules in metastatic disease.

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Figure 1: EphrinB1 binds Par-6 in vivo and in vitro.
Figure 2: Inhibition and overexpression of ephrinB1 causes disruption of tight junction formation.
Figure 3: EphrinB1 and active Cdc42 (CA Cdc42) compete for Par-6 binding.
Figure 4: FGF signalling blocks the interaction between ephrinB1 and Par-6 through tyrosine phosphorylation of the intracellular domain of ephrinB1.
Figure 5: Phosphorylation on Tyr 310 regulates tight junction formation by dissociating ephrinB1 from Par-6.

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Acknowledgements

We thank S.Y. Sokol, O. Ossipova and K. Itoh for the Lgl2 antibody, helpful suggestions and critical reading of this manuscript; K. Nagashima and A. Kamata for TEM; A. Traweger for the GST–Par-3 construct; S. Shyam and J. Archaya for critical reading of this manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute.

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  1. Yong-Sik Bong

    Present address: Current address: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA.,

Authors and Affiliations

  1. Laboratory of Cell and Developmental Signaling, National Cancer Institute-Frederick, Frederick, 21702, Maryland, USA

    Hyun-Shik Lee, Tagvor G. Nishanian, Kathleen Mood, Yong-Sik Bong & Ira O. Daar

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Contributions

H.L. and I.D. designed the experiments, analysed the data and wrote the manuscript; H.L., T.N., K.M. and Y.B. performed the experiments.

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Correspondence to Ira O. Daar.

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The authors declare no competing financial interests.

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Supplementary Figures S1, S2, S3, S4, S5, S6, S7, S8, S9 and S10 (PDF 1907 kb)

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Lee, HS., Nishanian, T., Mood, K. et al. EphrinB1 controls cell–cell junctions through the Par polarity complex. Nat Cell Biol 10, 979–986 (2008). https://doi.org/10.1038/ncb1758

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