P75 Neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-α-converting enzyme/ADAM17

Rajappa S. Kenchappa, Chhavy Tep, Zeljka Korade, Soledad Urra, Francisca C. Bronfman, Sung Ok Yoon, Bruce D. Carter

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Abstract

During the development of the sympathetic nervous system, the p75 neurotrophin receptor (p75NTR) has a dual function: promoting survival together with TrkA in response to NGF, but inducing cell death upon binding pro or mature brain-derived neurotrophic factor (BDNF). Apoptotic signaling through p75NTR requires activation of the stress kinase, JNK. However, the receptor also undergoes regulated proteolysis, first by a metalloprotease, and then by γ-secretase, in response to pro-apoptotic ligands and this is necessary for receptor mediated neuronal death (Kenchappa, R. S., Zampieri, N., Chao, M. V., Barker, P. A., Teng, H. K., Hempstead, B. L., and Carter, B. D. (2006) Neuron 50, 219-232). Hence, the relationship between JNK activation and receptor proteolysis remains to be defined. Here, we report that JNK3 activation is necessary for p75NTR cleavage; however, following release of the intracellular domain, there is a secondary activation of JNK3 that is cleavage dependent. Receptor proteolysis and apoptosis were prevented in sympathetic neurons from jnk3-/- mice, while activation of JNK by ectopic expression of MEKK1 induced p75NTR cleavage and cell death. Proteolysis of the receptor was not detected until 6 h after BDNF treatment, suggesting that JNK3 promotes cleavage through a transcriptional mechanism. In support of this hypothesis, BDNF up-regulated tumor necrosis factor-α-converting enzyme (TACE)/ADAM17 mRNA and protein in wildtype, but not jnk3-/- sympathetic neurons. Down-regulation of TACE by RNA interference blocked BDNF-induced p75NTR cleavage and apoptosis, indicating that this metalloprotease is responsible for the initial processing of the receptor. Together, these results demonstrate that p75NTR-mediated activation of JNK3 is required for up-regulation of TACE, which promotes receptor proteolysis, leading to prolonged activation of JNK3 and subsequent apoptosis in sympathetic neurons.

Original languageEnglish (US)
Pages (from-to)20358-20368
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number26
DOIs
StatePublished - Jun 25 2010

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Nerve Growth Factor Receptor
Proteolysis
Neurons
Up-Regulation
Tumor Necrosis Factor-alpha
Chemical activation
Brain-Derived Neurotrophic Factor
Apoptosis
Enzymes
Metalloproteases
Cell death
Cell Death
MAP Kinase Kinase 4
Amyloid Precursor Protein Secretases
Sympathetic Nervous System
Nerve Growth Factor
RNA Interference
Neurology
ADAM17 Protein
Down-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

P75 Neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-α-converting enzyme/ADAM17. / Kenchappa, Rajappa S.; Tep, Chhavy; Korade, Zeljka; Urra, Soledad; Bronfman, Francisca C.; Yoon, Sung Ok; Carter, Bruce D.

In: Journal of Biological Chemistry, Vol. 285, No. 26, 25.06.2010, p. 20358-20368.

Research output: Contribution to journalArticle

Kenchappa, Rajappa S. ; Tep, Chhavy ; Korade, Zeljka ; Urra, Soledad ; Bronfman, Francisca C. ; Yoon, Sung Ok ; Carter, Bruce D. / P75 Neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-α-converting enzyme/ADAM17. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 26. pp. 20358-20368.
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abstract = "During the development of the sympathetic nervous system, the p75 neurotrophin receptor (p75NTR) has a dual function: promoting survival together with TrkA in response to NGF, but inducing cell death upon binding pro or mature brain-derived neurotrophic factor (BDNF). Apoptotic signaling through p75NTR requires activation of the stress kinase, JNK. However, the receptor also undergoes regulated proteolysis, first by a metalloprotease, and then by γ-secretase, in response to pro-apoptotic ligands and this is necessary for receptor mediated neuronal death (Kenchappa, R. S., Zampieri, N., Chao, M. V., Barker, P. A., Teng, H. K., Hempstead, B. L., and Carter, B. D. (2006) Neuron 50, 219-232). Hence, the relationship between JNK activation and receptor proteolysis remains to be defined. Here, we report that JNK3 activation is necessary for p75NTR cleavage; however, following release of the intracellular domain, there is a secondary activation of JNK3 that is cleavage dependent. Receptor proteolysis and apoptosis were prevented in sympathetic neurons from jnk3-/- mice, while activation of JNK by ectopic expression of MEKK1 induced p75NTR cleavage and cell death. Proteolysis of the receptor was not detected until 6 h after BDNF treatment, suggesting that JNK3 promotes cleavage through a transcriptional mechanism. In support of this hypothesis, BDNF up-regulated tumor necrosis factor-α-converting enzyme (TACE)/ADAM17 mRNA and protein in wildtype, but not jnk3-/- sympathetic neurons. Down-regulation of TACE by RNA interference blocked BDNF-induced p75NTR cleavage and apoptosis, indicating that this metalloprotease is responsible for the initial processing of the receptor. Together, these results demonstrate that p75NTR-mediated activation of JNK3 is required for up-regulation of TACE, which promotes receptor proteolysis, leading to prolonged activation of JNK3 and subsequent apoptosis in sympathetic neurons.",
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T1 - P75 Neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-α-converting enzyme/ADAM17

AU - Kenchappa, Rajappa S.

AU - Tep, Chhavy

AU - Korade, Zeljka

AU - Urra, Soledad

AU - Bronfman, Francisca C.

AU - Yoon, Sung Ok

AU - Carter, Bruce D.

PY - 2010/6/25

Y1 - 2010/6/25

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