The insulin/IGF-1 (DAF-2) receptor signaling pathway can diverge to regulate distinct processes, including development, reproduction and aging [1]. Regulation of all these processes requires the forkhead (FOXO) transcription factor, DAF-16 [2, 3]. Indeed, nuclear localization of DAF-16 is regulated by phosphorylation of DAF-16 by the AKT and SGK kinases [4, 5]. However, nuclear inclusion alone is not sufficient to regulate DAF-16 dependent events [4]. Therefore, we hypothesize that the autonomous regulation of these discrete processes is achieved through the interaction of DAF-16 with additional transcription factors. One such factor, SMK-1, appears to function within the insulin/IGF-1 pathway to regulate aging. Interestingly, reduced expression of SMK-1 does not alter processes such as dauer formation and reproduction. SMK-1 exhibits several characteristics of a co-factor of DAF-16: 1)
smk-1 RNAi suppresses the increased longevity of
daf-2 or
glp-1 mutant animals, but does not suppress the long lifespan of mitochondrial ETC pathway members. 2)
smk-1 RNAi reduces wild type lifespan, similar to
daf-16 mutations. However,
smk-1 RNAi does not shorten the lifespan of
daf-16 null mutant animals. 3) DAF-16 dependent transcripts require
smk-1 for full expression. 4) SMK-1 is localized within the nuclei of intestinal cells, the site of action for DAF-16 [6]. 5) The human
smk-1 orthologue, SMEK-1, physically interacts with FOXO3a, the human DAF-16 orthologue. 6) In human cells, overexpression of SMEK-1 increases expression of FOXO3a dependent transcripts. Taken together,
smk-1 appears to play a central role in the regulation of
daf-16's aging function. Its conserved interactions in human cells suggest that SMEK-1 is central to regulating stress response and longevity in mammals. 1. Dillin, A., Crawford, D.K., and Kenyon, C. (2002). Timing requirements for insulin/IGF-1 signaling in C. elegans. Science 298 , 830-834. 2. Kenyon, C., Chang, J., Gensch, E., Rudner, A., and Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type [see comments]. Nature 366 , 461-464. 3. Larsen, P.L., Albert, P.S., and Riddle, D.L. (1995). Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 139 , 1567-1583. 4. Lin, K., Hsin, H., Libina, N., and Kenyon, C. (2001). Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28 , 139-145. 5. Hertweck, M., Gobel, C., and Baumeister, R. (2004). C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. Dev Cell 6 , 577-588. 6. Libina, N., Berman, J.R., and Kenyon, C. (2003). Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 115 , 489-502.