Abstract
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*
Substances
-
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