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

EMBO J. 2004 Jun 2;23(11):2226-34. doi: 10.1038/sj.emboj.7600226. Epub 2004 Apr 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / embryology
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Catalytic Domain
  • Cell Line
  • Chlorocebus aethiops
  • Cysteine / chemistry
  • Dual Specificity Phosphatase 1
  • Dual-Specificity Phosphatases
  • Embryo, Nonmammalian
  • Gene Deletion
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Larva
  • MAP Kinase Kinase 7 / chemistry
  • MAP Kinase Kinase 7 / genetics
  • MAP Kinase Kinase 7 / metabolism
  • MAP Kinase Kinase Kinases / chemistry
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Metals, Heavy / pharmacology
  • Metamorphosis, Biological
  • Molecular Sequence Data
  • Protein Phosphatase 1
  • Protein Structure, Tertiary
  • Protein Tyrosine Phosphatases / chemistry
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Caenorhabditis elegans Proteins
  • Metals, Heavy
  • Recombinant Fusion Proteins
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP Kinase Kinase 7
  • Protein Phosphatase 1
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1
  • Dual-Specificity Phosphatases
  • Protein Tyrosine Phosphatases
  • VHP-1 protein, C elegans
  • Cysteine