Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI

Nature Neuroscience volume 6, pages 461–467 (2003)Cite this article

Abstract

The neurotrophin receptor p75NTR is involved in the regulation of axonal elongation by neurotrophins as well as several myelin components, including Nogo, myelin-associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (OMgp). Neurotrophins stimulate neurite outgrowth by inhibiting Rho activity, whereas myelin-derived proteins activate RhoA and thereby inhibit growth. Here we show that direct interaction of the Rho GDP dissociation inhibitor (Rho-GDI) with p75NTR initiates the activation of RhoA, and this interaction between p75NTR and Rho-GDI is strengthened by MAG or Nogo. We also found that p75NTR facilitates the release of prenylated RhoA from Rho-GDI. The peptide ligand that is associated with the fifth α helix of p75NTR inhibits the interaction between Rho-GDI and p75NTR, thus silencing the action mediated by p75NTR. This peptide has potential as a therapeutic agent against the inhibitory cues that block regeneration in the central nervous system.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Co-immunoprecipitation of p75NTR with Rho-GDI.
Figure 2: p75NTR directly associates with Rho-GDI.
Figure 3: p75NTR reduces the Rho-GDI activity.
Figure 4: Pep5 inhibits interaction of Rho-GDI with p75NTR.
Figure 5: Pep5 silences the inhibitory action of p75NTR.

Similar content being viewed by others

References

  1. Dechant, G. & Barde, Y.A. The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nat. Neurosci. 5, 1131–1136 (2002).

    Article  CAS  Google Scholar 

  2. Yamashita, T., Tucker, K.L. & Barde, Y.A. Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 24, 585–593 (1999).

    Article  CAS  Google Scholar 

  3. Davies, A.M. Neurotrophins: neurotrophic modulation of neurite growth. Curr. Biol. 10, 198–200 (2000).

    Article  Google Scholar 

  4. Schmidt, A. & Hall, A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev. 16, 1587–1609 (2002).

    Article  CAS  Google Scholar 

  5. Yamashita, T., Higuchi, H. & Tohyama, M. The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J. Cell Biol. 157, 565–570 (2002).

    Article  CAS  Google Scholar 

  6. Wang, K.C., Kim, J.A., Sivasankaran, R., Segal, R. & He, Z. p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74–78 (2002).

    Article  CAS  Google Scholar 

  7. Wong, S.T. et al. p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat. Neurosci. 5, 1302–1308 (2002).

    Article  CAS  Google Scholar 

  8. Sasaki, T. & Takai, Y. The Rho small G protein family–Rho GDI system as a temporal and spatial determinant for cytoskeletal control. Biochem. Biophys. Res. Commun. 245, 641–645 (1998).

    Article  CAS  Google Scholar 

  9. Fournier, A.E., GrandPre, T. & Strittmatter, S.M. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409, 341–346 (2001).

    Article  CAS  Google Scholar 

  10. Masuda, T. et al. Molecular cloning and characterization of yeast rho GDP dissociation inhibitor. J. Biol. Chem. 269, 19713–19718 (1994).

    CAS  PubMed  Google Scholar 

  11. Feinstein, D.L. & Larhammar, D. Identification of a conserved protein motif in a group of growth factor receptors. FEBS Lett. 272, 7–11 (1990).

    Article  CAS  Google Scholar 

  12. Koch, G., Haberman, B., Mohr, C., Just, I. & Aktories, K. Interaction of mastoparan with the low molecular mass GTP-binding proteins rho/rac. FEBS Lett. 291, 336–340 (1991).

    Article  CAS  Google Scholar 

  13. Takahashi, K. et al. Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein. J. Biol. Chem. 272, 23371–23375 (1997).

    Article  CAS  Google Scholar 

  14. Yaku, H., Sasaki, T. & Takai, Y. The Dbl oncogene product as a GDP/GTP exchange protein for the Rho family: its properties in comparison with those of Smg GDS. Biochem. Biophys. Res. Commun. 198, 811–817 (1994).

    Article  CAS  Google Scholar 

  15. Ilag, L.L. et al. Selection of a peptide ligand to the p75 neurotrophin receptor death domain and determination of its binding sites by NMR. Biochem. Biophys. Res. Commun. 255, 104–109 (1999).

    Article  CAS  Google Scholar 

  16. Schwarze, S.R., Ho, A., Vocero-Akbani, A. & Dowdy, S.F. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285, 1569–1572 (1999).

    Article  CAS  Google Scholar 

  17. Bentley, C.A. & Lee, K.F. p75 is important for axon growth and Schwann cell migration during development. J. Neurosci. 20, 7706–7715 (2000).

    Article  CAS  Google Scholar 

  18. Walsh, G.S., Krol, K.M., Crutcher, K.A. & Kawaja, M.D. Enhanced neurotrophin-induced axon growth in myelinated portions of the CNS in mice lacking the p75 neurotrophin receptor. J. Neurosci. 19, 4155–4168 (1999).

    Article  CAS  Google Scholar 

  19. Lee, K.F., Bachman, K., Landis, S. & Jaenisch, R. Dependence on p75 for innervation of some sympathetic targets. Science 263, 1447–1449 (1994).

    Article  CAS  Google Scholar 

  20. McQuillen, P.S., DeFreitas, M.F., Zada, G. & Shatz, C.J. A novel role for p75NTR in subplate growth cone complexity and visual thalamocortical innervation. J. Neurosci. 22, 3580–3593 (2000).

    Article  Google Scholar 

  21. Del Pozo, M.A. et al. Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI. Nat. Cell Biol. 4, 232–239 (2002).

    Article  CAS  Google Scholar 

  22. von Schack, D. et al. Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system. Nat. Neurosci. 4, 977–978 (2001).

    Article  CAS  Google Scholar 

  23. Lee, K.F. et al. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69, 737–749 (1992).

    Article  CAS  Google Scholar 

  24. Liepinsh, E., Ilag, L.L., Otting, G. & Ibanez, C.F. NMR structure of the death domain of the p75 neurotrophin receptor. EMBO J. 16, 4999–5005 (1997).

    Article  CAS  Google Scholar 

  25. Ren, X.D., Kiosses, W.B. & Schwartz, M.A. Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskelton. EMBO J. 18, 578–585 (1999).

    Article  CAS  Google Scholar 

  26. Forget, M.A., Desrosiers, R.R., Gingras, D. & Beliveau, R. Phosphorylation states of Cdc42 and RhoA regulate their interactions with Rho GDP dissociation inhibitor and their extraction from biological membranes. Biochem. J. 361, 243–254 (2002).

    Article  CAS  Google Scholar 

  27. Hart, M.J., Eva, A., Evans, T., Aaronson, S.A. & Cerione, R.A. Catalysis of guanine nucleotide exchange on the CDC42Hs protein by the dbl oncogene product. Nature 354, 311–314 (1991).

    Article  CAS  Google Scholar 

  28. Cai, D., Shen, Y., De Bellard, M., Tang, S. & Filbin, M.T. Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism. Neuron 22, 89–101 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Y. Takai for gifts of pGEX–GST–Rho-GDI, pEF–BOS–myc–Rho-GDI and pRSET-Dbl, R. Beliveau for yeast expressing GST-RhoA, Y. Nagai for the control TAT-fused peptide and Y. Hara for technical assistance. This work was supported by a Grant-in-Aid from the Japan Brain Foundation.

Author information

Authors and Affiliations

  1. Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Toshihide Yamashita & Masaya Tohyama

  2. Core Research for Evolutional Science and Technology (CREST), Kawaguchi, 332-0012, Japan

    Toshihide Yamashita & Masaya Tohyama

Authors
  1. Toshihide Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masaya Tohyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshihide Yamashita.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1.

Pep5 does not inhibit the biological effects mediated by neurotrophin binding to p75NTR. (a) Pep5 does not inhibit the NGF-induced promotion of the neurite outgrowth from the hippocampal neurons (E18 rats). NGF (50 ng/ml) was added to the cultures of dissociated hippocampal neurons with or without 100 nM TAT-Pep5. After 18 hr, cells were fixed and stained for TuJ1. Length of the longest neurite per neuron was measured. Data are mean ± s.e.m. for 30 individual neurons that have neurites longer than 30 μm. Asterisks indicate statistical significance (*P < 0.01, Student's t test). Pep5, TAT-Pep5. (b) Pep5 does not inhibit the cell death of superior cervical ganglion neurons induced by BDNF. Cultured neurons were treated with BDNF at 100 ng/ml in the presence or absence of 100 nM Tat-Pep5. After 18 hr, cells were fixed and stained with Hoechst dye to label nuclei. Apoptotic cells were counted on the basis of cellular morphology (as viewed by phase-contrast microscopy) and by the presence of condensed chromatin (detected with Hoechst dye). The results are mean ± S.E. from three experiments. Asterisks indicate statistical significance (*P < 0.01, Student's t test). Pep5, TAT-Pep5. (GIF 16 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamashita, T., Tohyama, M. The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nat Neurosci 6, 461–467 (2003). https://doi.org/10.1038/nn1045

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1045

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing