The Caenorhabditis elegans MAPK phosphatase VHP-1 mediates a novel JNK-like signaling pathway in stress response.
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.
Mizuno
Tomoaki
T
Department of Molecular Biology, Graduate School of Science, Institute for Advanced Research, Nagoya University, Nagoya, Japan.
Hisamoto
Naoki
N
Terada
Takashi
T
Kondo
Tae
T
Adachi
Makoto
M
Nishida
Eisuke
E
Kim
Dennis H
DH
Ausubel
Frederick M
FM
Matsumoto
Kunihiro
K
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000196:embryology / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D002460:Cell Line; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000737:chemistry; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; D004625:Embryo, Nonmammalian; D017353:Gene Deletion; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007814:Larva; D048688:MAP Kinase Kinase 7 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019216:Metals, Heavy / Q000494:pharmacology; D008675:Metamorphosis, Biological; D008969:Molecular Sequence Data; D054645:Protein Phosphatase 1; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D019216:Metals, Heavy; D011993:Recombinant Fusion Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D048688:MAP Kinase Kinase 7; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases; C501201:VHP-1 protein, C elegans; D003545:Cysteine