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  • The EMBO Journal (2004) 23, 2226 - 2234
  • doi:10.1038/sj.emboj.7600226

Published online: 29 April 2004

The Caenorhabditis elegans MAPK phosphatase VHP-1 mediates a novel JNK-like signaling pathway in stress response

Tomoaki Mizuno1,2, Naoki Hisamoto1,2, Takashi Terada1,2, Tae Kondo1,2, Makoto Adachi3, Eisuke Nishida3, Dennis H Kim4,5, Frederick M Ausubel4,5 and Kunihiro Matsumoto1,2

  1. Department of Molecular Biology, Graduate School of Science, Institute for Advanced Research, Nagoya University, Nagoya, Japan
  2. CREST, Japan Science and Technology Corporation, Chikusa-ku, Nagoya, Japan
  3. Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan
  4. Department of Genetics, Harvard Medical School, Boston, MA, USA
  5. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA

Correspondence to:

Kunihiro Matsumoto, Department of Molecular Biology, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. Tel.: +81 52 789 3000; Fax: +81 52 789 2589 or 3001; E-mail: g44177a@nucc.cc.nagoya-u.ac.jp

Received 1 March 2004; Accepted 7 April 2004

Mitogen-activated protein kinases (MAPKs) are integral to the mechanisms by which cells respond to physiological stimuli and to a wide variety of environmental stresses. MAPK cascades can be inactivated at the MAPK activation step by members of the MAPK phosphatase (MKP) family. However, the components that act in MKP-regulated pathways have not been well characterized in the context of whole organisms. Here we characterize the Caenorhabditis elegans vhp-1 gene, encoding an MKP that acts preferentially on the c-Jun N-terminal kinase (JNK) and p38 MAPKs. We found that animals defective in vhp-1 are arrested during larval development. This vhp-1 defect is suppressed by loss-of-function mutations in the kgb-1, mek-1, and mlk-1 genes encoding a JNK-like MAPK, an MKK7-type MAPKK, and an MLK-type MAPKKK, respectively. The genetic and biochemical data presented here demonstrate a critical role for VHP-1 in the KGB-1 pathway. Loss-of-function mutations in each component in the KGB-1 pathway result in hypersensitivity to heavy metals. These results suggest that VHP-1 plays a pivotal role in the integration and fine-tuning of the stress response regulated by the KGB-1 MAPK pathway.

  • Keywords:

    • C. elegans,
    • heavy metal stress,
    • MAP kinase,
    • MAPK phosphatase