Journal
CELL DEATH AND DIFFERENTIATION
Volume 15, Issue 9, Pages 1510-1521Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2008.76
Keywords
neuronal survival; Ret; B-Raf; IKK
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Funding
- Ministerio de Educacion y Ciencia [BFU2004-03632, BFU2007-67619]
- NIH [AG13730, NS39358, AG13729, HD047396-01]
- Suport als Grups de Recerca
- Ministerio de Educacion y Ciencia
- Fondo de Investigaciones Sanitarias
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We analyzed the survival responses and downstream signaling elicited by GDNF on sympathetic neurons from different Ret knockin mice. Lack of tyrosine 1062, a multidocking site in Ret, completely prevented GDNF-mediated survival. Importantly, lack of tyrosine 981, although abrogating Akt phosphorylation, had no effect on neuronal survival, indicating that the PI 3-K/Akt pathway is not necessary for survival of sympathetic neurons. In contrast, silencing of B-Raf completely prevented not only GDNF-mediated but also NGF-mediated cell survival, independently of MEK-1/2. We identified IKKs as the main effectors of the protective effects of B-Raf. First, B-Raf interacted with and activated IKKs. Second, knockdown of IKKs reversed the protection afforded by a constitutively active form of B-Raf. Third, knockdown of IKKs prevented both NGF- and GDNF-mediated survival. In conclusion, our data delineate a novel survival pathway for sympathetic neurons linking B-Raf to IKKs, independently of both PI 3-K and MEK-1/2 pathways.
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