Ubiquitin Modification Of Retinonic Acid Receptor γ2

Retinoic acid (RA ) and its receptors play a very important role in the development of the embryo.RA signal transduction is mainly mediated through it's two kinds of receptors, retinoic acid receptor(RARs) and retinoid X receptor(RXRs), each kind of receptor has 3 isoforms, a, 6, ?.Rar?2, one isoform of Rar?, is mainly expressed in embryonic carcinoma cells and embryonic stem cells as well as early development of embryo.It is reported that knockout Rar? in F9 cells make those cells lose the ability to differentiate induced by RA.And the transactivation function of Rar?2 is straightly related with it's Phosphorylation and ubiquitination.But what is Rar?2's E3 ubiquitin ligase is largely unknown.Cardoso et al. found that Rar?2 often co-locates with Wwp2, a HECT domain containing E3 ubiquitin ligase, in the development, indicating that Wwp2 may have functions in regulating RA signaling.In the current study, with overexpression experiment in HEK293 cells, we find that Wwp2 can affect Rar?2's protein level in the absence of RA, low concentration of Wwp2 can decreases Rar?2 protein level, while high concentration of Wwp2 increases Rar?2 protein level.Furthermore, CO-IP and GST pull down assay demonstrate that there is specific interaction between Wwp2 and Rar?2.In addition, we also find that Wwp2 can target Rar?2 for ubiquitination in vivo.In constract, the enzymetic mutant form of Wwp2 can not promoter ubinquitination of Rar?2.These findings indicate that Wwp2 is Rar?2's specific E3 ubiquitin ligase, and it may participate in the regulate of Rar?2's function.