Role of the Caenorhabditis elegans Shc adaptor protein in the c-Jun N-terminal kinase signaling pathway.
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 mitogen-activated protein kinase (MAPK) signaling pathway, which is regulated by MLK-1 MAPK kinase kinase (MAPKKK), MEK-1 MAPK kinase (MAPKK), and KGB-1 JNK-like MAPK. In this study, we identify the shc-1 gene, which encodes a C. elegans homolog of Shc, as a factor that specifically interacts with MEK-1. The shc-1 loss-of-function mutation is defective in activation of KGB-1, resulting in hypersensitivity to heavy metals. A specific tyrosine residue in the NPXY motif of MLK-1 creates a docking site for SHC-1 with the phosphotyrosine binding (PTB) domain. Introduction of a mutation that perturbs binding to the PTB domain or the NPXY motif abolishes the function of SHC-1 or MLK-1, respectively, thereby abolishing the resistance to heavy metal stress. These results suggest that SHC-1 acts as a scaffold to link MAPKKK to MAPKK activation in the KGB-1 MAPK signal transduction pathway.
Mizuno
Tomoaki
T
Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya, Japan.
Fujiki
Kota
K
Sasakawa
Aya
A
Hisamoto
Naoki
N
Matsumoto
Kunihiro
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D019216:Metals, Heavy / Q000633:toxicity; D009154:Mutation; D055765:Shc Signaling Adaptor Proteins / Q000502:physiology*; D015398:Signal Transduction; D013312:Stress, Physiological
D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; D019216:Metals, Heavy; D055765:Shc Signaling Adaptor Proteins; D048031:JNK Mitogen-Activated Protein Kinases; C524496:KGB-1 protein, C elegans; D048369:MAP Kinase Kinase 1