TY - JOUR
T1 - Tumor necrosis factor receptor-1 can function through a Gαq/11-β-arrestin-1 signaling complex
AU - Kawamata, Yuji
AU - Imamura, Takeshi
AU - Babendure, Jennie L.
AU - Lu, Juu Chin
AU - Yoshizaki, Takeshi
AU - Olefsky, Jerrold M.
PY - 2007/9/28
Y1 - 2007/9/28
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M705869200
DO - 10.1074/jbc.M705869200
M3 - Article
C2 - 17664271
AN - SCOPUS:35348943287
SN - 0021-9258
VL - 282
SP - 28549
EP - 28556
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 39
ER -