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Neurotrophin dependence domain

A domain required for the mediation of apoptosis by the p75 neurotrophin receptor

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Abstract

The mechanisms underlying neurotrophin dependence, and cellular dependent states in general, are unknown. We show that a 29 amino acid region in the intracellular domain of the common neurotrophin receptor, p75NTR, is required for the mediation of apoptosis by p75NTR. Furthermore, contrary to results obtained with Fas, monomeric p75NTR is required for apoptosis induction, whereas multimerization inhibits the pro-apoptotic effect. Within the 29-residue domain required for apoptosis induction by p75NTR, a 14-residue region is sufficient as a peptide inducer of apoptosis. This 14-residue peptide requires the positively charged carboxyterminal residues for its effect on cell death, and these same residues are required by the full-length p75NTR. These studies define a novel type of domain that mediates neurotrophin dependence, and suggest that other cellular dependent states may be mediated by proteins displaying similar domains.

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References

  • Baldwin A. N., Bitler C. M., Welcher A. A., and Shooter E. M. (1992) Studies of the structure and binding properties of the cysteine-rich domain of rat low affinity nerve growth factor receptor (p75NGFR). J. Immunol. 267, 8352–8359.

    CAS  Google Scholar 

  • Barrett G. L. and Bartlett P. (1994) The p75 nerve growth factor receptor mediates survival or death depending on the stage of sensory neuron development. Proc. Natl. Acad. Sci. USA 91, 6501–6505.

    Article  PubMed  CAS  Google Scholar 

  • Bredesen D. E. and Rabizadeh S. (1997) p75NTR and apoptosis: Trk-dependent and Trk-independent effects. Trends Neurosci. 20, 287–290.

    Article  PubMed  CAS  Google Scholar 

  • Bredesen D. E., Ye X., Tasinato A., Sperandio S., Wang J. J., Assa-Munt N., and Rabidazeh S. (1998) p75NTR and the concept of cellular dependence: seeing how the other half die. Cell Death Differ. 5, 365–371.

    Article  PubMed  CAS  Google Scholar 

  • Bunone G., Mariotti A., Compagni A., Morandi E., and Valle G. D. (1997) Induction of apoptosis by p75 neurotrophin receptor in human neuroblastoma cells. Oncogene 14, 1463–1470.

    Article  PubMed  CAS  Google Scholar 

  • Casaccia-Bonnefil P., Carter B. D., Dobrowsky R. T., and Chao M. V. (1996) Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 383, 716–719.

    Article  PubMed  CAS  Google Scholar 

  • Chapman B. S. (1995) A region of the 75 kDa neurotrophin receptor homologous to the death domains of TNFR-I and Fas. FEBS Lett. 374, 216–220.

    Article  PubMed  CAS  Google Scholar 

  • Ellerby H. M., Martin S. J., Ellerby L. M., Naiem S. S., Rabizadeh S., Salvesen G. S., et al. (1997) Establishment of a cell-free system for neuronal apoptosis: comparison of pre-mitochondrial, mitochondrial, and post-mitochondrial phases. J. Neurosci. 17, 6165–6178.

    PubMed  CAS  Google Scholar 

  • Fawell S., Seery J., Daikh Y., Moore C., Chen L. L., Pepinsky B., and Barsoum J. (1994) Tat-mediated delivery of heterologous proteins into cells. Proc. Natl. Acad. Sci. USA 91, 664–668.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Feinstein E. Kimchi A., Wallach D., Boldin M., and Varfolomeev E. (1995) The death domain: a module shared by proteins with diverse cellular functions. Trends Biochem. Sci. 20, 342–344.

    Article  PubMed  CAS  Google Scholar 

  • Frade J. M., Rodriguez-Tebar A., and Barde Y.-A. (1996) Induction of cell death by endogenous nerve growth factor through its p75 receptor. Nature 383, 166–168.

    Article  PubMed  CAS  Google Scholar 

  • Freiberg R. A., Spencer D. M., Choate K. A., Peng P. D., Schreiber S. L., Crabtree G. R., and Khavari P. A. (1996) Specific triggering of the Fas signal transduction pathway in normal human keratinocytes. J. Biol. Chem. 271, 31,666–31,669.

    Article  CAS  Google Scholar 

  • Frisch S. M. and Francis H. (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol. 124, 619–626.

    Article  PubMed  CAS  Google Scholar 

  • Garcia I., Martinou I., Tsujimoto Y., and Martinou J. C. (1992) Prevention of programmed cell death of sympathetic neurons by the bcl-2 protooncogene. Science 258, 302–304.

    Article  PubMed  CAS  Google Scholar 

  • Girard D., Paquin R., and Beaulieu A. D. (1997) Responsiveness of human neutrophils to interleukin-4: induction of cytoskeletal rearrangements, de novo protein synthesis and delay of apoptosis. Biochem J. 325, 145–153.

    Google Scholar 

  • Hileman M. R., Rabizadeh S., Krishnan V. V., Bredesen D., Chapman B., Assa-Munt N., and Plesniak L. A. (1997) A cytoplasmic peptide of the neurotrophin receptor p75NTR: induction of apoptosis and NMR determined helical conformation. FEBS Lett. 415, 145–154.

    Article  PubMed  CAS  Google Scholar 

  • Huang B., Eberstadt M., Olejniczak E. T., Meadows R. P., and Fesik S. W. (1996) NMR structure and mutagenesis of the Fas (Apo-1/CD95) death domain. Nature 384, 638–641.

    Article  PubMed  CAS  Google Scholar 

  • Jacob L. and Zasloff M. (1994) Potential therapeutic applications of magainins and other antimicrobial agents of animal origin. Ciba Found. Symp. 186, 197–216.

    PubMed  CAS  Google Scholar 

  • Javadpour M. M., Juban M. M., Lo W. C., Bishop S. M., Alberty J. B., Cowell S. M., et al. (1996) De novo antimicrobial peptides with low mammalian cell toxicity. J. Med. Chem. 39, 3107–3113.

    Article  PubMed  CAS  Google Scholar 

  • Kane D. J., Ord T., Anton R., and Bredesen D. E. (1995) Expression of bcl-2 inhibits necrotic neural cell death. J. Neurosci. Res. 40, 269–275.

    Article  PubMed  CAS  Google Scholar 

  • Kaplan D. R. and Stephens R. M. (1994) Neurotrophin signal transduction by the Trk receptor. J. Neurobiol. 25, 1404–1417.

    Article  PubMed  CAS  Google Scholar 

  • Kim D. T., Mitchell D. J., Brockstedt D. G., Fong L., Nolan G. P., Fathman C. G., et al. (1997) Introduction of soluble proteins into the MHC class I pathway by conjugation to an HIV tat peptide. J. Immunol. 159, 1666–1668.

    PubMed  CAS  Google Scholar 

  • Levi-Montalcini R. (1966) The nerve growth factor: its mode of action on sensory and sympathetic nerve cells. Harvey Lect. 60, 217–259.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Martin D. P., Schmidt R. E., deStefano P. S., Lowry O. H., Carter J. G., and Johnson E. M. (1988) Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation. J. Cell Biol. 106, 829–844.

    Article  PubMed  CAS  Google Scholar 

  • Mehlen P., Rabizadeh S., Snipas S. J., Assa-Munt N., Salvesen G. S., and Bredesen D. E. (1998) The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 395, 801–804.

    Article  PubMed  CAS  Google Scholar 

  • Morgenstern J. P. and Land H. (1990) Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 18, 3587–3596.

    Article  PubMed  CAS  Google Scholar 

  • Muzio M., Salvesen G. S., and Dixit V. M. (1997) FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens. J. Biol. Chem. 272, 2952–2956.

    Article  PubMed  CAS  Google Scholar 

  • Nagata S. and Golstein P. (1995) The Fas death factor. Science 267, 1449–1456.

    Article  PubMed  CAS  Google Scholar 

  • Rabizadeh S. and Bredesen D. E. (1994) Is p75NGFR involved in developmental neural cell death? Dev. Neurosci. 16, 207–211.

    PubMed  CAS  Google Scholar 

  • Rabizadeh S., Oh J., Zhong L. T., Yang J., Bitler C. M., Butcher L. L., and Bredesen D. E. (1993) Induction of apoptosis by the low-affinity NGF receptor. Science 261, 345–348.

    Article  PubMed  CAS  Google Scholar 

  • Rabizadeh S., Ye X., Wang J. J., and Bredesen D. E. (1999) Neurotrophin dependence mediated by p75NTR: contrast between rescue by BDNF and NGF. Cell Death Differ. 6, 1222–1227.

    Article  PubMed  CAS  Google Scholar 

  • Raff M. C. (1992) Social controls on cell survival and cell death. Nature 356, 397–400.

    Article  PubMed  CAS  Google Scholar 

  • Rovelli G., Heller R. A., Canossa M., and Shooter E. M. (1993) Chimeric tumor necrosis factor-TrkA receptors reveal that ligand-dependent activation of the TrkA tyrosine kinase is sufficient for differentiation and survival of PC12 cells. Proc. Natl. Acad. Sci. USA 90, 8717–8721.

    Article  PubMed  CAS  Google Scholar 

  • Sambrook J., Fritsch E. F., and Maniatis T. (1989) Molecular Cloning: A Laboratory Manual, C. Nolan, ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

    Google Scholar 

  • Sansom M. S. (1991) The biophysics of peptide models of ion channels. Prog. Biophys. Mol. Biol. 55, 139–235.

    Article  PubMed  CAS  Google Scholar 

  • Sauer H., Nishimura M. C., and Phillips H. S. (1996) Deletion of the p75NTR gene attenuates septal cholinergic cell loss in mice heterozygous for a deletion of the NGF gene. Soc. Neurosci. Abs. 22, 513.

    Google Scholar 

  • Spencer D. M., Wandless T. J., Schreiber S. L., and Crabtree G. R. (1993) Controlling signal transduction with synthetic ligands. Science 262, 1019–1024.

    Article  PubMed  CAS  Google Scholar 

  • Tartaglia L. A., Goeddel D. V., Reynolds C., Figari I. S., Weber R. F., Fendly B. M., and Palladino M. A. J. (1993) Stimulation of human T-cell proliferation by specific activation of the 75-kDa tumor necrosis factor receptor. J. Immunol. 151, 4637–4641.

    PubMed  CAS  Google Scholar 

  • Troy C. M., Stefanis L., Greene L. A., and Shelanski M. L. (1997) Nedd2 is required for apoptosis after trophic factor withdrawal, but not superoxide dismutase (SOD1) downregulation, in sympathetic neurons and PC12 cells. J. Neurosci. 17, 1911–1918.

    PubMed  CAS  Google Scholar 

  • Van der Zee C. E., Ross G. M., Riopelle R. J., and Hagg T. (1996) Survival of cholinergic forebrain neurons in developing p75NGFR-deficient mice. Science 274, 1729–1732.

    Article  PubMed  Google Scholar 

  • Wang J., Rabizadeh S., Tasinato A., Sperandio S., Ye X., Green M., et al. (2000) Dimerization-dependent block of the pro-apoptotic effect of p75NTR. J. Neurosci. Res. 60, 587–593.

    Article  PubMed  CAS  Google Scholar 

  • Yan G. M., Lin S. Z., Irwin R. P., and Paul S. M. (1995) Activation of G proteins bidirectionally affects apoptosis of cultured cerebellar granule neurons. J. Neurochem. 65, 2425–2431.

    Article  PubMed  CAS  Google Scholar 

  • Yan G. M., Ni B., Weller M., Wood K. A., and Paul S. M. (1994) Depolarization or glutamate receptor activation blocks apoptotic cell death of cultured cerebellar granule neurons. Brain Res. 656, 43–51.

    Article  PubMed  CAS  Google Scholar 

  • Ye X., Mehlen P., Rabizadeh S., Van Arsdale T., Zhang H., Shin H., et al. (1999) TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction. J. Biol. Chem. 274, 30,202–30,208.

    CAS  Google Scholar 

  • Yeo T., Chua-Couzens J., Valletta J., Butcher L. L., Bredesen D. E., Mobley W. C., and Longo F. M. (1997) Absence of p75NTR causes increased basal forebrain cholinergic neuron size, ChAT activity and target innervation. J. Neurosci. 17, 7594–7605.

    PubMed  CAS  Google Scholar 

  • Zhong L. T., Sarafian T., Kane D. J., Charles A. C., Mah S. P., Edwards R. H., and Bredesen D. E. (1993) Bcl-2 inhibits death of central neural cells induced by multiple agents. Proc. Natl. Acad. Sci. USA 90, 4533–4537.

    Article  PubMed  CAS  Google Scholar 

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Rabizadeh, S., Ye, X., Sperandio, S. et al. Neurotrophin dependence domain. J Mol Neurosci 15, 215–229 (2000). https://doi.org/10.1385/JMN:15:3:215

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