The ERK-MAPK pathway regulates longevity through SKN-1 and insulin-like signaling in Caenorhabditis elegans

J Biol Chem. 2010 Sep 24;285(39):30274-81. doi: 10.1074/jbc.M110.146274. Epub 2010 Jul 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Epistasis, Genetic / physiology
  • Forkhead Transcription Factors
  • Insulin / genetics
  • Insulin / metabolism
  • Longevity / physiology*
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Phosphorylation / physiology
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • raf Kinases / genetics
  • raf Kinases / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Insulin
  • Transcription Factors
  • daf-16 protein, C elegans
  • skn-1 protein, C elegans
  • DAF-2 protein, C elegans
  • Receptor, Insulin
  • lin-45 protein, C elegans
  • raf Kinases
  • Mitogen-Activated Protein Kinase 1
  • mpk-1 protein, C elegans