Tumor Necrosis Factor Receptor-associated Factor-6 and Ribosomal S6 Kinase Intracellular Pathways Link the Angiotensin II AT1 Receptor to the Phosphorylation and Activation of the I kappa B Kinase Complex in Vascular Smooth Muscle Cells

作者：Doyon Priscilla; Servant Marc J^*

来源：Journal of Biological Chemistry, 2010, 285(40): 30708-30718.

DOI：10.1074/jbc.M110.126433

Activation of NF-kappa B transcription factors by locally produced angiotensin II (Ang II) is proposed to be involved in chronic inflammatory reactions leading to atherosclerosis development. However, a clear understanding of the signaling cascades coupling the Ang II AT1 receptors to the activation of NF-kappa B transcription factors is still lacking. Using primary cultured aortic vascular smooth muscle cells, we show that activation of the IKK complex and NF-kappa B transcription factors by Ang II is regulated by phosphorylation of the catalytic subunit IKK beta on serine residues 177 and 181 in the activation T-loop. The use of pharmacological inhibitors against conventional protein kinases C (PKCs), mitogen-activated/extracellular signal-regulated kinase (MEK) 1/2, ribosomal S6 kinase (RSK), and silencing RNA technology targeting PKC alpha, IKK beta subunit, tumor growth factor beta-activating kinase-1 (TAK1), the E3 ubiquitin ligase tumor necrosis factor receptor-associated factor-6 (TRAF6), and RSK isoforms, demonstrates the requirement of two distinct signaling pathway for the phosphorylation of IKK beta and the activation of the IKK complex by Ang II. Rapid phosphorylation of IKK beta requires a second messenger-dependent pathway composed of PKC alpha-TRAF6-TAK1, whereas sustained phosphorylation and activation of IKK beta requires the MEK1/2-ERK1/2-RSK pathway. Importantly, simultaneously targeting components of these two pathways completely blunts the phosphorylation of IKK beta and the proinflammatory effect of the octapeptide. This is the first report demonstrating activation of TAK1 by the AT1R. We propose a model whereby TRAF6-TAK1 and ERK-RSK intracellular pathways independently and sequentially converge to the T-loop phosphorylation for full activation of IKK beta, which is an essential step in the proinflammatory activity of Ang II.

• 出版日期2010-10-1