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Article

Role of the Caenorhabditis elegans Shc Adaptor Protein in the c-Jun N-Terminal Kinase Signaling Pathway

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Pages 7041-7049 | Received 12 Jun 2008, Accepted 12 Sep 2008, Published online: 27 Mar 2023
 

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 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.

ACKNOWLEDGMENTS

We thank Y. Kohara, the National Bioresource Project for the Nematode (NBRP, Tokyo Women's Medical University School of Medicine, Tokyo), and the Caenorhabditis Genetics Center for materials.

This work was supported by special grants for SORST and Advanced Research on Cancer from the Ministry of Education, Culture and Science of Japan (K.M.).

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