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Multiple signaling interactions of Abl and Arg kinases with the EphB2 receptor

Oncogene volume 20, pages 3995–4006 (2001)Cite this article

Abstract

The Eph family of receptor tyrosine kinases and the Abl family of non-receptor tyrosine kinases have both been implicated in tissue morphogenesis. They regulate the organization of the actin cytoskeleton in the developing nervous system and participate in signaling pathways involved in axon growth. Both Eph receptors and Abl are localized in the neuronal growth cone, suggesting that they play a role in axon pathfinding. Two-hybrid screens identified regions of Abl and Arg that bind to the EphB2 and EphA4 receptors, suggesting a novel signaling connection involving the two kinase families. The association of full-length Abl and Arg with EphB2 was confirmed by co-immunoprecipitation and found to involve several distinct protein interactions. The SH2 domains of Abl and Arg bind to tyrosine-phosphorylated motifs in the juxtamembrane region of EphB2. A second, phosphorylation-independent interaction with EphB2 involves non-conserved sequences in the C-terminal tails of Abl and Arg. A third interaction between Abl and EphB2 is probably mediated by an intermediary protein because it requires tyrosine phosphorylation of EphB2, but not the binding sites for the Abl SH2 domain. The connection between EphB2 and Abl/Arg appears to be reciprocal. Activated EphB2 causes tyrosine phosphorylation of Abl and Arg, and vice versa. Interestingly, treatment of COS cells and B35 neuronal-like cells with ephrin-B1 to activate endogenous EphB2 decreased the kinase activity of endogenous Abl. These data are consistent with the opposite effects that Eph receptors and Abl have on neurite ougrowth and suggest that Eph receptors and Abl family kinases have shared signaling activities.

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Acknowledgements

The authors thank Pam Woodring and Jean Wang for antibodies, constructs, and helpful discussions; Gary Kruh for the Arg cDNA; Yama Abassi and Kristiina Vuori for the GST–Crk construct; William Stallcup for the B35 cells; and Keith Murai for helpful comments on the manuscript. This work was supported by NIH grants HD26351 and HD25938 (EB Pasquale), postdoctoral support from FWF Austria and the Swiss National Science Foundation (AH Zisch), and a postdoctoral fellowship from the National Sciences and Engineering Research Council of Canada (VC Dodelet).

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  1. Andreas H Zisch

    Present address: Department of Materials, Institute for Biomedical Engineering, ETH-Zurich, University of Zurich, CH-8044, Switzerland

  2. Hai-Hui Yu: H-H Yu and AH Zisch contributed equally

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  1. The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, 92037, California, CA, USA

    Hai-Hui Yu, Andreas H Zisch, Vincent C Dodelet & Elena B Pasquale

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Correspondence to Elena B Pasquale.

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Yu, HH., Zisch, A., Dodelet, V. et al. Multiple signaling interactions of Abl and Arg kinases with the EphB2 receptor. Oncogene 20, 3995–4006 (2001). https://doi.org/10.1038/sj.onc.1204524

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