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  • Title: Beta-arrestin 2 is required for lysophosphatidic acid-induced NF-kappaB activation.
    Author: Sun J, Lin X.
    Journal: Proc Natl Acad Sci U S A; 2008 Nov 04; 105(44):17085-90. PubMed ID: 18952848.
    Abstract:
    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-kappaB. Although LPA-induced signaling pathways have been intensively investigated, the molecular mechanism by which LPA activates NF-kappaB is not fully defined. In this work, we found that beta-arrestin 2, but not beta-arrestin 1, is required for LPA-induced NF-kappaB activation and interlukin-6 expression. Mechanistically, we found that beta-arrestin 2 associated with CARMA3, a scaffold protein that plays an essential role in GPCR-induced NF-kappaB activation, suggesting that beta-arrestin 2 may recruit CARMA3 to LPA receptors. Although beta-arrestin 2 deficiency did not affect LPA-induced IKKalpha/beta phosphorylation, it impaired LPA-induced IKK kinase activity, which is consistent with our previous findings that CARMA3 is required for IKKalpha/beta activation but not for the inducible phosphorylation of IKKalpha/beta. Together, our results provide the genetic evidence that beta-arrestin 2 serves as a positive regulator in NF-kappaB signaling pathway by connecting CARMA3 to GPCRs.
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