A11
Lysophosphatidic acid-induced NF-kappaB activation is dependent on beta-arrestin 2
Jiyuan Sun, Xin Lin
The University of Texas M.D. Anderson Cancer Center, Houston, USA
Lysophosphatidic acid (LPA) is a bioactive phospholipid and a ligand of G protein-coupled receptors (GPCR), which initiates multiple signaling cascades and activates NF-κB. NF-κB critically regulates a large number of gene expressions in normal cellular process, and is persistently active in many diseases, such as cancer. In our previous studies, we have demonstrated that LPA-induced NF-κB activation is dependent on a novel scaffold protein, CARMA3. However, how CARMA3 is recruited to receptors upon LPA stimulation remains to be determined.
β-arrestins are a family of proteins involved in desensitization of GPCR signaling. It has been shown that β-arrestins also serve as signaling adaptor proteins, and mediate signaling pathways. Therefore, we have hypothesised that β-arrestins may link CARMA3 to the LPA receptor, and facilitate LPA-induced NF-κB activation.
Using β-arrestin-deficient MEF cells, we found that β-arrestin 2, but not β-arrestin 1, was required for LPA-induced NF-κB activation, and NF-κB-dependent interlukin-6 production. Mechanistically, we demonstrated the inducible endogenous association of β-arrestin 2 and CARMA3 in response to LPA stimulation, and we found 60-320 residues of β-arrestin 2 was associated with the CARD domain of CARMA3. Together, it suggests that β-arrestin 2 may link CARMA3 to LPA receptors, and mediate LPA-induced NF-κB activation. -arrestin 2 deficiency impaired LPA-induced IKK kinase activity,bMoreover, we found phosphorylation, which isb/awhile it did not affect LPA-induced IKK consistent with our previous findings in CARMA3-deficient MEFs.
-arrestinbIn summary, our results provide the genetic evidence that 2 B signaling pathway by connectingkserves as a positive regulator in NF- -arrestin 2bCARMA3 to LPA receptors. Additionally, we demonstrate that is activation, but not for the inducibleb/arequired for IKK . Because the signaling pathways around theb/aphosphorylation of IKK membrane-proximal region of LPA receptor and GPCRs are quite conserved, our results also suggest Bka possible link between other GPCRs and CARMA3-mediated NF- -arrestins in LPA-inducedbactivation. To characterise the role of BkNF- signaling pathways will help to identify new drug targets for clinical therapeutics.
