Journal of Biological Chemistry
Volume 285, Issue 39, 24 September 2010, Pages 30274-30281
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Signal Transduction
The ERK-MAPK Pathway Regulates Longevity through SKN-1 and Insulin-like Signaling in Caenorhabditis elegans*

https://doi.org/10.1074/jbc.M110.146274Get rights and content
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It has not been determined yet whether the ERK-MAPK pathway regulates longevity of metazoans. Here, we show that the Caenorhabditis elegans ERK cascade promotes longevity through the two longevity-promoting transcription factors, SKN-1 and DAF-16. We find that RNAi of three genes, which constitute the ERK cascade (lin-45/RAF1, mek-2/MEK1/2, and mpk-1/ERK1/2), results in reduction of life span. Moreover, RNAi of lip-1, the gene encoding a MAPK phosphatase that inactivates MPK-1, increases life span. Epistasis analyses show that the ERK (MPK-1) cascade-mediated life span extension requires SKN-1, whose function is mediated, at least partly, through DAF-2/DAF-16 insulin-like signaling. MPK-1 phosphorylates SKN-1 on the key sites that are required for SKN-1 nuclear accumulation. Our results also show that one mechanism by which SKN-1 regulates insulin-like signaling is through the regulation of expression of insulin-like peptides. Our findings thus identify a novel ERK-MAPK-mediated signaling pathway that promotes longevity.

Aging
C. elegans
ERK
Signal Transduction
Transcription Factors
SKN-1
Insulin-like Signaling
Life Span

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*

This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to E. N.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and Tables S1 and S2.