β-Arrestin 2 is required for lysophosphatidic acid-induced NF-κB activation.

Lysophosphatidic acid (LPA) is a bioactive phospholipid and binds to its receptors, a family of G protein-coupled receptors (GPCR), which initiates multiple signaling cascades and leads to activation of several transcription factors, including NF-κB. Although LPA-induced signaling pathways have been intensively investigated, the molecular mechanism by which LPA activates NF-κB is not fully defined. In this work, we found that β-arrestin 2. but not β-arrestin 1, is required for LPA-induced NF-κB activation and interlukin-6 expression. Mechanistically, we found that β-arrestin 2 associated with CARMA3, a scaffold protein that plays an essential role in GPCR-induced NF-κB activation, suggesting that β-arrestin 2 may recruit CARMA3 to LPA receptors. Although β-arrestin 2 deficiency did not affect LPA-induced lKKα/β phosphorylation, it impaired LPA-induced IKK kinase activity, which is consistent with our previous findings that CARMA3 is required for IKKα/β activation but not for the inducible phosphorylation of lKKα/β. Together, our results provide the genetic evidence that β-arrestin 2 serves as a positive regulator in NF-κB signaling pathway by connecting CARMA3 to GPCRs. [ABSTRACT FROM AUTHOR]