Journal
DEVELOPMENTAL BIOLOGY
Volume 301, Issue 1, Pages 82-91Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2006.10.013
Keywords
14-3-3; ftt-2; par-5; daf-16; FOXO; dqf-2; insulin signaling
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Funding
- NIA NIH HHS [R56 AG024425, R01 AG024425-01, R01 AG024425-02, K08-AG21613, R01 AG024425] Funding Source: Medline
- NATIONAL INSTITUTE ON AGING [K08AG021613, R01AG024425, R56AG024425] Funding Source: NIH RePORTER
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The Caenorhabditis elegans daf-2/insulin-like signaling pathway is critical for regulating development, longevity, metabolism and stress resistance. We identified the 14-3-3 protein FTT-2 to be a new regulatory component of this pathway. We found that RNAi knock down of ftt-2 specifically enhanced the daf-2-mediated clatter formation phenotype. Furthermore, fitt-2 knock down caused the nuclear accumulation of DAF-16/FOXO, the forkhead transcription factor that is the major downstream effecter of daf-2/insulin-like signaling, and enhanced the transcriptional activities of DAF-16. In contrast to ftt-2, RNAi knock down of par-5/ftt-1, the only other gene predicted to encode a 14-3-3 protein in C. elegans, did not show any notable effect on clatter formation, DAF-16 localization, or DAF-16 downstream gene transcription, underscoring the functional specification of FTT-2 and PAR-5 despite their high sequence homology. Using co-immunoprecipitation, we revealed that FTT-2 formed a complex with GFP-fused DAF-16 in C. elegans. Our results indicate that FTT-2 binds to DAF-16 in C. elegans and regulates DAF-16 by sequestering it in the cytoplasm. A similar mechanism of regulation of FOXO by 14-3-3 has been reported in mammalian cells, highlighting the high degree of conservation of the daf-2/insulin-like signaling pathway. (c) 2006 Elsevier Inc. All rights reserved.
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