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Molecular and Cellular Biology, December 2008, p. 7041-7049, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.00938-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Tomoaki Mizuno, Kota Fujiki, Aya Sasakawa, Naoki Hisamoto, and Kunihiro Matsumoto*

Department of Molecular Biology, Graduate School of Science, Nagoya University, and SORST, Japan Science and Technology Corporation, Chikusa-ku, Nagoya 464-8602, Japan

Received 12 June 2008/ Returned for modification 7 July 2008/ Accepted 12 September 2008

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.

* Corresponding author. Mailing address: Department of Molecular Biology, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. Phone: 81-52-789-3000. Fax: 81-52-789-2589. E-mail: g44177a{at}nucc.cc.nagoya-u.ac.jp

{triangledown} Published ahead of print on 22 September 2008.

Molecular and Cellular Biology, December 2008, p. 7041-7049, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.00938-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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