Abstract
Mitogen-activated protein kinases (MAPKs) are integral to the mechanisms by which cells respond to physiological stimuli and a wide variety of environmental stresses. In Caenorhabditis elegans, the stress response is controlled by a c-Jun N-terminal kinase (JNK)-like MAPK signaling pathway, which is regulated by MLK-1 MAPK kinase kinase (MAPKKK), MEK-1 MAPKK, and KGB-1 JNK-like MAPK. In this study, we identify the max-2 gene encoding a C. elegans Ste20-related protein kinase as a component functioning upstream of the MLK-1-MEK-1-KGB-1 pathway. The max-2 loss-of-function mutation is defective in activation of KGB-1, resulting in hypersensitivity to heavy metals. Biochemical analysis reveals that MAX-2 activates MLK-1 through direct phosphorylation of a specific residue in the activation loop of the MLK-1 kinase domain. Our genetic data presented here also show that MIG-2 small GTPase functions upstream of MAX-2 in the KGB-1 pathway. These results suggest that MAX-2 and MIG-2 play a crucial role in mediating the heavy metal stress response regulated by the KGB-1 pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Caenorhabditis elegans / chemistry
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Caenorhabditis elegans / drug effects
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / metabolism*
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Caenorhabditis elegans Proteins / chemistry
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism*
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Copper / pharmacology
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Enzyme Activation
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Humans
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism*
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MAP Kinase Signaling System*
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Mitogen-Activated Protein Kinase Kinases / chemistry
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Molecular Sequence Data
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Phosphoserine / metabolism
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Protein Binding
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Stress, Physiological* / drug effects
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rac GTP-Binding Proteins / genetics
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rac GTP-Binding Proteins / metabolism*
Substances
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Caenorhabditis elegans Proteins
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Phosphoserine
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Copper
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Max-2 protein, C elegans
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Protein Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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KGB-1 protein, C elegans
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Mitogen-Activated Protein Kinase Kinases
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Mig-2 protein, C elegans
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rac GTP-Binding Proteins