Analysis of Ret knockin mice reveals a critical role for IKKs, but not PI 3-K, in neurotrophic factor-induced survival of sympathetic neurons.

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2008Author
Rozen, Esteban Javier
Jain, Sanjay
Comella i Carnicé, Joan Xavier
Milbrandt, Jeffrey
Johnson, Eugene M.
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Encinas Martín, Mario;
Rozen, Esteban Javier;
Dolcet Roca, Xavier;
Jain, Sanjay;
Comella i Carnicé, Joan Xavier;
Milbrandt, Jeffrey;
Johnson, Eugene M.;
.
(2008)
.
Analysis of Ret knockin mice reveals a critical role for IKKs, but not PI 3-K, in neurotrophic factor-induced survival of sympathetic neurons..
Cell Death and Differentiation, 2008, vol. 15, núm. 9, p. 1510-1521.
https://doi.org/10.1038/cdd.2008.76.
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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, BRaf
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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Cell Death and Differentiation, 2008, vol. 15, núm. 9, p. 1510-1521European research projects
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