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Eph receptors are negatively controlled by protein tyrosine phosphatase receptor type O

Nature Neuroscience volume 9, pages 761–769 (2006)Cite this article

Abstract

Eph receptors are activated by the autophosphorylation of tyrosine residues upon the binding of their ligands, the ephrins; however, the protein tyrosine phosphatases (PTPs) responsible for the negative regulation of Eph receptors have not been elucidated. Here, we identified protein tyrosine phosphatase receptor type O (Ptpro) as a specific PTP that efficiently dephosphorylates both EphA and EphB receptors as substrates. Biochemical analyses revealed that Ptpro dephosphorylates a phosphotyrosine residue conserved in the juxtamembrane region, which is required for the activation and signal transmission of Eph receptors. Ptpro thus seems to moderate the amount of maximal activation of Eph receptors. Using the chick retinotectal projection system, we show that Ptpro controls the sensitivity of retinal axons to ephrins and thereby has a crucial role in the establishment of topographic projections. Our findings explain the molecular mechanism that determines the threshold of the response of Eph receptors to ephrins in vivo.

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Figure 1: Specific interaction between a substrate-trapping mutant of Ptpro and Eph receptors.
Figure 2: Dephosphorylation of Eph receptors by Ptpro.
Figure 3: Ptpro preferentially dephosphorylates the second tyrosine residue in the juxtamembrane regions of Eph receptors.
Figure 4: Ptpro regulates the sensitivity of chick retinal axons to ephrin-A2-Fc.
Figure 5: Ptpro regulates the ephrin-A2–induced growth cone collapse of retinal axons.
Figure 6: Retinotectal projection in chick embryos overexpressing Ptpro in the retina.
Figure 7: Retinotectal projection in chick embryos with suppressed Ptpro expression in the retina.

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Acknowledgements

We thank C.L. Cepko (Harvard Medical School, Boston) for providing the RIAS vector and F. Bonhoeffer (Max-Planck-Institute for Developmental Biology, Tübingen) for the silicon matrix used to produce the ephrin-A2-Fc stripe. We also thank Y. Ayabe and M. Gotoh for technical assistance and A. Kodama for secretarial assistance. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Core Research for Evolutional Science and Technology (CREST) program of the Japan Science and Technology Agency (JST).

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Author notes

  1. Takafumi Shintani and Masaru Ihara: These authors equally contributed to this study.

Authors and Affiliations

  1. Division of Molecular Neurobiology, National Institute for Basic Biology, 5-1 Higashiyama, Myodaiji-cho, Okazaki, 444-8787, Japan

    Takafumi Shintani, Masaru Ihara, Hiraki Sakuta, Hiroo Takahashi, Ikuko Watakabe & Masaharu Noda

  2. School of Life Science, Graduate University for Advanced Studies, Okazaki, 444-8787, Japan

    Takafumi Shintani, Masaru Ihara, Hiraki Sakuta, Hiroo Takahashi & Masaharu Noda

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Correspondence to Masaharu Noda.

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Supplementary information

Supplementary Fig. 1

Expression analysis of Ptpro in the developing chick retina. (PDF 58 kb)

Supplementary Fig. 2

Specific dephosphorylation of Eph receptors by Ptpro. (PDF 33 kb)

Supplementary Fig. 3

Inhibition of ephrin-induced tyrosine phosphorylation of Eph receptors by Ptpro in PC-3 prostrate epithelial cells expressing EphA2 endogenously. (PDF 28 kb)

Supplementary Fig. 4

Ptprz exerts no effect on the sensitivity of chick retinal axons to ephrin-A2-Fc. (PDF 32 kb)

Supplementary Fig. 5

Improvement of transfection and expression of the transgene of the RIAS vector on simultaneous electroporation of the RCAS vector. (PDF 28 kb)

Supplementary Fig. 6

Retinotectal projection at E19 in embryos electroporated with RCAS/PtproδN(DA). (PDF 57 kb)

Supplementary Methods (PDF 137 kb)

Supplementary Note (PDF 64 kb)

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Shintani, T., Ihara, M., Sakuta, H. et al. Eph receptors are negatively controlled by protein tyrosine phosphatase receptor type O. Nat Neurosci 9, 761–769 (2006). https://doi.org/10.1038/nn1697

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