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

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dc.contributor.authorKenchappa, Rajappa S.
dc.contributor.authorTep, Chhavy
dc.contributor.authorKorade, Zeljka
dc.contributor.authorUrra, Soledad
dc.contributor.authorBronfman, Francisca C.
dc.contributor.authorYoon, Sung Ok
dc.contributor.authorCarter, Bruce D.
dc.date.accessioned2025-01-21T00:05:37Z
dc.date.available2025-01-21T00:05:37Z
dc.date.issued2010
dc.description.abstractDuring 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 gamma-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-alpha-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.
dc.fuente.origenWOS
dc.identifier.doi10.1074/jbc.M109.082834
dc.identifier.eissn1083-351X
dc.identifier.urihttps://doi.org/10.1074/jbc.M109.082834
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/95555
dc.identifier.wosidWOS:000279012000069
dc.issue.numero26
dc.language.isoen
dc.pagina.final20368
dc.pagina.inicio20358
dc.revistaJournal of biological chemistry
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titlep75 Neurotrophin Receptor-mediated Apoptosis in Sympathetic Neurons Involves a Biphasic Activation of JNK and Up-regulation of Tumor Necrosis Factor-α-converting Enzyme/ADAM17
dc.typeartículo
dc.volumen285
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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