Characterization of a Peptide that Specifically Blocks the Ras Binding Domain of p75

  • Silvia Egert
  • Heike Piechura
  • Nina Hambruch
  • Martin Feigel
  • Andrea BlöchlEmail author


The neurotrophin receptor p75 interacts with the GTPase Ras. Unstimulated it inactivates Ras while ligand binding induces Ras activation. We developed an inhibitory peptide (ip75RBD) which interferes with the binding domain of Ras of the intracellular domain of p75. ip75RBD inhibits the binding of Ras to the receptor in vitro. It is membrane-permeable and inhibits ligand-induced Ras activation via p75 in vivo but does not influence Ras activation by the stimulated receptor tyrosine kinases Trk and the epidermal growth factor receptor EGFR. The activation of the neutral sphingomyelinase by stimulated p75 is slightly delayed but not inhibited by the peptide. p75-mediated neuronal death induced by NGF or aggregated beta-amyloid1–42 is reduced. We conclude that ip75RBD specifically blocks the Ras binding site of p75 and can be used to analyze p75-induced Ras signaling.


p75 Ras inhibition 


  1. Blöchl A., Blumenstein L., Ahmadian M. R. (2004) Europ. J. Neurosci. 20:2321–2335CrossRefGoogle Scholar
  2. Blankemeyer-Menge B., Frank R. (1988) Tetrahedron 44:6031–6040CrossRefGoogle Scholar
  3. Brewer G. J., Torricelli J. R., Evege E. K., Price P. J. (1993) J. Neurosci. Res. 35:567–576PubMedCrossRefGoogle Scholar
  4. Bronfman F. C., Fainzilber M. (2004) EMBO Rep. 5:867–871PubMedCrossRefGoogle Scholar
  5. Brownbridge G. G., Lowe P. N., Moore K. J., Skinner R. H., Webb M. R. (1993) J. Biol. Chem. 268:10914–10919PubMedGoogle Scholar
  6. Chapman B. S. (1995) FEBS Lett. 374:216–220PubMedCrossRefGoogle Scholar
  7. Daniel S., Noda M., Cerione R. A., Sharp G. W. (2002) Biochemistry 41:9663–9671PubMedCrossRefGoogle Scholar
  8. Dostaler S. M., Ross G. M., Myers S. M., Weaver D. F., Ananthanarayanan V., Riopelle R. J. (1998) Eur. J. Neurosci. 8:870–879CrossRefGoogle Scholar
  9. Eichler J., Beyermann M., Bienert M. (1989) Collect. Czech. Chem. Commun. 54:1746–1752CrossRefGoogle Scholar
  10. Fabian J. R., Vojtek A. B., Cooper J. A., Morrison D. K. (1994) Proc. Natl. Acad. Sci. USA 91:5982–5986PubMedCrossRefGoogle Scholar
  11. Feinstein D. L., Larhammar D. (1990) FEBS Lett. 272:7–11PubMedCrossRefGoogle Scholar
  12. Frank R. (1992) Tetrahedron 48:9217–9232CrossRefGoogle Scholar
  13. Gentry J. J., Barker P. A., Carter B. D. (2004) Prog. Brain Res. 146:25–39PubMedCrossRefGoogle Scholar
  14. Hanke J. H., Gardner J. P., Dow R. L. et al. (1996) J. Biol.Chem 271:695–701PubMedCrossRefGoogle Scholar
  15. Huang E. J., Reichardt L. F. (2003) Annu. Rev. Biochem. 72:609–642PubMedCrossRefGoogle Scholar
  16. Ilag L. L., Rottenberger C., Liepinsh E., Wellnhofer G., Rudert F., Otting G. (1999) Biochem. Biophys. Res. Commun. 255:104–109PubMedCrossRefGoogle Scholar
  17. Koch G., Haberman B., Mohr C., Just I., Aktories K. (1991) FEBS Lett. 291:336–340PubMedCrossRefGoogle Scholar
  18. Klinker J. F., Laugwitz K. L., Hageluken A., Seifert R. (1996) Biochem. Pharmacol. 51:217–223PubMedCrossRefGoogle Scholar
  19. Kusunoki H., Wakamatsu K., Sato K., Miyazawa T., Kohno T. (1998) Biochem. 37:4782–4790CrossRefGoogle Scholar
  20. Liepinsh E., Ilag L. L., Otting G., Ibanez C. F. (1997) EMBO J. 16:4999–5005PubMedCrossRefGoogle Scholar
  21. De Rooij J., Bos J. L. (1997) Oncogene 14:623–625PubMedCrossRefGoogle Scholar
  22. Rudert F., Woltering C., Frisch C., Rottenberger C., Ilag L. L. (1998) FEBS Lett. 440:135–140PubMedCrossRefGoogle Scholar
  23. Scheffzek K., Ahmadian M. R., Kabsch W. et al. (1997) Science 277:333–338PubMedCrossRefGoogle Scholar
  24. Schor N. F. (2005) Prog. Neurobiol. 77:201–214PubMedCrossRefGoogle Scholar
  25. Susen K., Heumann R., Blöchl A. (1999) FEBS Lett. 463:231–234PubMedCrossRefGoogle Scholar
  26. Susen K., Blöchl A. (2005) J. Mol. Med. 83:720–735PubMedCrossRefGoogle Scholar
  27. Tanaka T., Kohno T., Kinoshita S. et al. (1998) J. Biol. Chem. 273:3247–3252PubMedCrossRefGoogle Scholar
  28. Teng K. K., Hempstead B. L. (2004) Cell. Mol. Life Sci. 61:35–48PubMedCrossRefGoogle Scholar
  29. Weingarten R., Ransnas L., Mueller H., Sklar L. A., Bokoch G. M. (1990) J. Biol. Chem. 265:11044–11049PubMedGoogle Scholar
  30. Yamashita T., Tohyama M. (2003) Nat. Neurosci. 6:461–467PubMedGoogle Scholar
  31. Yamashita T., Fujitani M., Hata K., Mimura F., Yamagishi S. (2005) Anat. Sci. Int. 80:37–41PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2007

Authors and Affiliations

  • Silvia Egert
    • 1
    • 2
  • Heike Piechura
    • 1
  • Nina Hambruch
    • 1
  • Martin Feigel
    • 2
  • Andrea Blöchl
    • 1
    Email author
  1. 1.Faculty of Chemistry, Biochemistry IIRuhr-University BochumBochumGermany
  2. 2.NaturstoffchemieRuhr-University BochumBochumGermany

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