The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published 7 February 2005. doi:10.1084/jem.20041817
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 3, 333-339
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BRIEF DEFINITIVE REPORT

 Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling

Hisaaki Shinohara1,2, Akane Inoue1, Noriko Toyama-Sorimachi3, Yoshinori Nagai4, Tomoharu Yasuda1, Hiromi Suzuki5, Reiko Horai6, Yoichiro Iwakura6, Tadashi Yamamoto5, Hajime Karasuyama3, Kensuke Miyake4, and Yuji Yamanashi1,2

1 Department of Cell Regulation, Medical Research Institute
2 School of Biomedical Science, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
3 Department of Immune Regulation, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
4 Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
5 Department of Oncology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
6 Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

CORRESPONDENCE Yuji Yamanashi: yamanashi.creg{at}mri.tmd.ac.jp

Endotoxin, a bacterial lipopolysaccharide (LPS), causes fatal septic shock via Toll-like receptor (TLR)4 on effector cells of innate immunity like macrophages, where it activates nuclear factor {kappa}B (NF-{kappa}B) and mitogen-activated protein (MAP) kinases to induce proinflammatory cytokines such as tumor necrosis factor (TNF)-{alpha}. Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras–Erk signaling downstream of protein tyrosine kinases (PTKs). Here, we demonstrate that LPS rapidly induced the tyrosine phosphorylation and adaptor function of these proteins. The stimulation with LPS of macrophages from mice lacking Dok-1 or Dok-2 induced elevated Erk activation, but not the other MAP kinases or NF-{kappa}B, resulting in hyperproduction of TNF-{alpha} and nitric oxide. Furthermore, the mutant mice showed hyperproduction of TNF-{alpha} and hypersensitivity to LPS. However, macrophages from these mutant mice reacted normally to other pathogenic molecules, CpG oligodeoxynucleotides, poly(I:C) ribonucleotides, or Pam3CSK4 lipopeptide, which activated cognate TLRs but induced no tyrosine phosphorylation of Dok-1 or Dok-2. Forced expression of either adaptor, but not a mutant having a Tyr/Phe substitution, in macrophages inhibited LPS-induced Erk activation and TNF-{alpha} production. Thus, Dok-1 and Dok-2 are essential negative regulators downstream of TLR4, implying a novel PTK-dependent pathway in innate immunity.

H. Shinohara's present address is Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Kanagawa 230-0045, Japan.


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