HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 39, 28549-28556, September 28, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/39/28549    most recent M705869200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kawamata, Y. Articles by Olefsky, J. M. Search for Related Content PubMed PubMed Citation Articles by Kawamata, Y. Articles by Olefsky, J. M. Social Bookmarking                      What's this?

Tumor Necrosis Factor Receptor-1 Can Function through a G_q/11--Arrestin-1 Signaling Complex^*

From the Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093-0673

Tumor necrosis factor- (TNF) is a proinflammatory cytokine secreted from macrophages and adipocytes. It is well known that chronic TNF exposure can lead to insulin resistance both in vitro and in vivo and that elevated blood levels of TNF are observed in obese and/or diabetic individuals. TNF has many acute biologic effects, mediated by a complex intracellular signaling pathway. In these studies we have identified new G-protein signaling components to this pathway in 3T3-L1 adipocytes. We found that -arrestin-1 is associated with TRAF2 (TNF receptor-associated factor 2), an adaptor protein of TNF receptors, and that TNF acutely stimulates tyrosine phosphorylation of G_q/11 with an increase in G_q/11 activity. Small interfering RNA-mediated knockdown of -arrestin-1 inhibits TNF-induced tyrosine phosphorylation of G_q/11 by interruption of Src kinase activation. TNF stimulates lipolysis in 3T3-L1 adipocytes, and -arrestin-1 knockdown blocks the effects of TNF to stimulate ERK activation and glycerol release. TNF also led to activation of JNK with increased expression of the proinflammatory gene, monocyte chemoattractant protein-1 and matrix metalloproteinase 3, and -arrestin-1 knockdown inhibited both of these effects. Taken together these results reveal novel elements of TNF action; 1) the trimeric G-protein component G_q/11 and the adapter protein -arrestin-1 can function as signaling molecules in the TNF action cascade; 2) -arrestin-1 can couple TNF stimulation to ERK activation and lipolysis; 3) -arrestin-1 and G_q/11 can mediate TNF-induced phosphatidylinositol 3-kinase activation and inflammatory gene expression.

Received for publication, July 17, 2007

^* This work was supported by National Institutes of Health Research Grant DK 33651, University of California Discovery Program Project bio03-10383 (BioStar), and United States and Israel Binational Scientific Foundation Grant 2003238. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: University of California, San Diego, Dept. of Medicine (0673), 9500 Gilman Dr., La Jolla, CA 92093. Tel.: 858-534-6651; Fax: 858-534-6653; E-mail: jolefsky{at}ucsd.edu.

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

This article has been cited by other articles:

				A. Lymperopoulos, G. Rengo, C. Zincarelli, J. Kim, S. Soltys, and W. J. Koch An adrenal {beta}-arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo PNAS, April 7, 2009; 106(14): 5825 - 5830. [Abstract] [Full Text] [PDF]

				N. Sonoda, T. Imamura, T. Yoshizaki, J. L. Babendure, J.-C. Lu, and J. M. Olefsky {beta}-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic {beta} cells PNAS, May 6, 2008; 105(18): 6614 - 6619. [Abstract] [Full Text] [PDF]