Transportin-2 plays a critical role in nucleocytoplasmic shuttling of oestrogen receptor-α

Oestrogen receptor-alpha (ER alpha) shuttles continuously between the nucleus and the cytoplasm, and functions as an oestrogen-dependent transcription factor in the nucleus and as an active mediator of signalling pathways, such as phosphatidylinositol 3-kinase (PI3K)/AKT, in the cytoplasm. However, little is known regarding the mechanism of ER alpha nucleocytoplasmic shuttling. In this study, we found that ER alpha is transported into the nucleus by importin-alpha/beta 1. Furthermore, we found that Transportin-2 (TNPO2) is involved in 17 beta -oestradiol (E2)-dependent cytoplasmic localisation of ER alpha. Interestingly, it was found that TNPO2 does not mediate nuclear export, but rather is involved in the cytoplasmic retention of ER alpha via the proline/tyrosine (PY) motifs. Moreover, we found that TNPO2 competitively binds to the basic nuclear localisation signal (NLS) of ER alpha with importin-alpha to inhibit importin-alpha/beta -dependent ER alpha nuclear import. Finally, we confirmed that TNPO2 knockdown enhances the nuclear localisation of wild-type ER alpha and reduces PI3K/AKT phosphorylation in the presence of E2. These results reveal that TNPO2 regulates nucleocytoplasmic shuttling and cytoplasmic retention of ER alpha, so that ER alpha has precise functions depending on the stimulation.