Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text (PDF, 790K) Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Van Epps, H. L. Search for Related Content PubMed Articles by Van Epps, H. L. Related Collections Related Article Social Bookmarking                            What's this?

Two adaptor proteins prevent cells from overreacting to bacterial lipopolysaccaride (LPS), report Shinohara et al. on page 333. Dok-1 and Dok-2 dampen intracellular signals from the LPS receptor, Toll-like receptor 4 (TLR4), which may help explain how cells mount a potent response to invading bacteria without also triggering destructive inflammatory responses.

Dok-1 and Dok-2 are adaptor proteins found in hematopoietic cells that are activated by tyrosine kinases in response to antigen and cytokine receptor signals. Once activated, they suppress intracellular signals by inhibiting the GTPase Ras, thereby keeping cellular activation and multiplication under control. The importance of this control is evident in mice lacking both proteins, which have been shown to develop leukemia.

Shinohara et al. now provide evidence that these proteins also inhibit LPS-induced TLR4 signals. Dok-1 and Dok-2 are tyrosine phosphorylated within 1 minute of LPS treatment, and cells lacking either protein displayed enhanced Erk activation in response to LPS. Mice lacking these proteins died from an unchecked production of the inflammatory cytokine TNF, a cause of endotoxic shock, when given a normally sublethal dose of LPS.

This is the first standby pathway described for TLR4 inhibition in macrophages; all other macrophage TLR4 regulators are inducible, suggesting that Dok-1 and Dok-2 may be primarily responsible for controlling the rapid process of primary endotoxic shock in these cells.

hvanepps{at}rockefeller.edu

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Article

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

Hisaaki Shinohara, Akane Inoue, Noriko Toyama-Sorimachi, Yoshinori Nagai, Tomoharu Yasuda, Hiromi Suzuki, Reiko Horai, Yoichiro Iwakura, Tadashi Yamamoto, Hajime Karasuyama, Kensuke Miyake, and Yuji Yamanashi
J. Exp. Med. 2005 201: 333-339. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 790K) Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Van Epps, H. L. Search for Related Content PubMed Articles by Van Epps, H. L. Related Collections Related Article Social Bookmarking                            What's this?