Cargando…

Cbl Negatively Regulates JNK Activation and Cell Death

Here, we explore the role of Cbl proteins in regulation of neuronal apoptosis. In two paradigms of neuron apoptosis – nerve growth factor (NGF) deprivation and DNA damage – cellular levels of c-Cbl and Cbl-b fell well before onset of death. NGF deprivation also induced rapid loss of tyrosine phospho...

Descripción completa

Detalles Bibliográficos
Autores principales: Sproul, Andrew A., Xu, Zhiheng, Wilhelm, Michael, Gire, Stephen, Greene, Lloyd A.
Formato: Texto
Lenguaje:English
Publicado: 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739106/
https://www.ncbi.nlm.nih.gov/pubmed/19546888
http://dx.doi.org/10.1038/cr.2009.74
_version_ 1782171558882574336
author Sproul, Andrew A.
Xu, Zhiheng
Wilhelm, Michael
Gire, Stephen
Greene, Lloyd A.
author_facet Sproul, Andrew A.
Xu, Zhiheng
Wilhelm, Michael
Gire, Stephen
Greene, Lloyd A.
author_sort Sproul, Andrew A.
collection PubMed
description Here, we explore the role of Cbl proteins in regulation of neuronal apoptosis. In two paradigms of neuron apoptosis – nerve growth factor (NGF) deprivation and DNA damage – cellular levels of c-Cbl and Cbl-b fell well before onset of death. NGF deprivation also induced rapid loss of tyrosine phosphorylation (and most likely, activation) of c-Cbl. Targeting c-Cbl and Cbl-b with siRNAs to mimic their loss/inactivation sensitized neuronal cells to death promoted by NGF deprivation or DNA damage. One potential mechanism by which Cbl proteins might affect neuron death is by regulation of apoptotic JNK signaling. We demonstrate that Cbl proteins interact with the JNK pathway components MLK3 and POSH and that knockdown of Cbl proteins is sufficient to increase JNK pathway activity. Furthermore, expression of c-Cbl blocks the ability of MLKs to signal to downstream components of the kinase cascade leading to JNK activation and protects neuronal cells from death induced by MLKs, but not from downstream JNK activators. On the basis of these findings, we propose that Cbls suppress cell death in healthy neurons at least in part by inhibiting the ability of MLKs to activate JNK signaling. Apoptotic stimuli lead to loss of Cbl protein/activity, thereby removing a critical brake on JNK activation and on cell death.
format Text
id pubmed-2739106
institution National Center for Biotechnology Information
language English
publishDate 2009
record_format MEDLINE/PubMed
spelling pubmed-27391062010-02-01 Cbl Negatively Regulates JNK Activation and Cell Death Sproul, Andrew A. Xu, Zhiheng Wilhelm, Michael Gire, Stephen Greene, Lloyd A. Cell Res Article Here, we explore the role of Cbl proteins in regulation of neuronal apoptosis. In two paradigms of neuron apoptosis – nerve growth factor (NGF) deprivation and DNA damage – cellular levels of c-Cbl and Cbl-b fell well before onset of death. NGF deprivation also induced rapid loss of tyrosine phosphorylation (and most likely, activation) of c-Cbl. Targeting c-Cbl and Cbl-b with siRNAs to mimic their loss/inactivation sensitized neuronal cells to death promoted by NGF deprivation or DNA damage. One potential mechanism by which Cbl proteins might affect neuron death is by regulation of apoptotic JNK signaling. We demonstrate that Cbl proteins interact with the JNK pathway components MLK3 and POSH and that knockdown of Cbl proteins is sufficient to increase JNK pathway activity. Furthermore, expression of c-Cbl blocks the ability of MLKs to signal to downstream components of the kinase cascade leading to JNK activation and protects neuronal cells from death induced by MLKs, but not from downstream JNK activators. On the basis of these findings, we propose that Cbls suppress cell death in healthy neurons at least in part by inhibiting the ability of MLKs to activate JNK signaling. Apoptotic stimuli lead to loss of Cbl protein/activity, thereby removing a critical brake on JNK activation and on cell death. 2009-08 /pmc/articles/PMC2739106/ /pubmed/19546888 http://dx.doi.org/10.1038/cr.2009.74 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Sproul, Andrew A.
Xu, Zhiheng
Wilhelm, Michael
Gire, Stephen
Greene, Lloyd A.
Cbl Negatively Regulates JNK Activation and Cell Death
title Cbl Negatively Regulates JNK Activation and Cell Death
title_full Cbl Negatively Regulates JNK Activation and Cell Death
title_fullStr Cbl Negatively Regulates JNK Activation and Cell Death
title_full_unstemmed Cbl Negatively Regulates JNK Activation and Cell Death
title_short Cbl Negatively Regulates JNK Activation and Cell Death
title_sort cbl negatively regulates jnk activation and cell death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739106/
https://www.ncbi.nlm.nih.gov/pubmed/19546888
http://dx.doi.org/10.1038/cr.2009.74
work_keys_str_mv AT sproulandrewa cblnegativelyregulatesjnkactivationandcelldeath
AT xuzhiheng cblnegativelyregulatesjnkactivationandcelldeath
AT wilhelmmichael cblnegativelyregulatesjnkactivationandcelldeath
AT girestephen cblnegativelyregulatesjnkactivationandcelldeath
AT greenelloyda cblnegativelyregulatesjnkactivationandcelldeath