Tumor necrosis factor receptor-1 can function through a Gαq/11-β-arrestin-1 signaling complex

Yuji Kawamata, Takeshi Imamura, Jennie L. Babendure, Juu Chin Lu, Takeshi Yoshizaki, Jerrold M. Olefsky

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)28549-28556
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number39
DOIs
StatePublished - Sep 28 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kawamata, Y., Imamura, T., Babendure, J. L., Lu, J. C., Yoshizaki, T., & Olefsky, J. M. (2007). Tumor necrosis factor receptor-1 can function through a Gαq/11-β-arrestin-1 signaling complex. Journal of Biological Chemistry, 282(39), 28549-28556. https://doi.org/10.1074/jbc.M705869200