β-Catenin's Nuclear Receptor Shuttle

Abstract

It is unclear how the cytoplasmic protein β-catenin moves into the nucleus to regulate transcription. It lacks a nuclear localization signal, is too large to translocate in a passive manner, and moves independently of the nuclear transport pathways involving importin and Ran. Three studies suggest that transport may occur through association with shuttling nuclear receptors. Yang et al. , Mulholland et al. , and Pawlowski et al. report a direct interaction between β-catenin and the androgen receptor (AR). When activated by ligands such as testosterone, AR moves into the nucleus to stimulate transcription of target genes. AR agonists promoted the translocation and nuclear localization of AR and β-catenin with similar kinetics. Other hormone-bound nuclear receptors, including those for progesterone, estrogen, and glucocorticoid, did not act as shuttles. Moreover, AR antagonists did not induce this effect, indicating that translocation of AR alone is not sufficient to carry β-catenin into the nucleus. The COOH-terminal DNA and ligand-binding domain of the AR and the Armadillo repeats of β-catenin were identified as the associating regions. The Wnt signaling pathway, which controls the balance of nuclear and cytosolic pools of β-catenin in some cells, was not activated by AR in the neuronal cell line examined by Pawlowski et al. Mulholland demonstrated that the translocation did not depend on adenomatous polyposis coli, another potential nuclear shuttle for β-catenin. Yang et al. showed that overexpression of the cell-surface protein E-cadherin in a prostate cancer cell line sequestered β-catenin and reduced AR-mediated transcription. The consequence of AR-β-catenin is uncertain as the reports show either suppression or augmentation of AR-mediated transcription in various reporter assays. Steroid receptors appear to offer another convenient ride for β-catenin's trip to the nucleus. J. E. Pawloski, J. R. Ertel, M. P. Allen, M. Xu, C. Butler, E. M. Wilson, M. E. Wierman, Liganded androgen receptor interaction with β-catenin. J. Biol. Chem. 277 , 20702-20710 (2002). [Abstract] [Full Text] F. Yang, X. Li, M. Sharmu, C. Y. Sasaki, D. L. Longo, B. Lim, Z. Sun, Linking β-catenin to androgen-signaling pathway. J. Biol. Chem. 277 , 11336-11344 (2002). [Abstract] [Full Text] D. J. Mulholland, H. Cheng, K. Reid, P. S. Rennie, C. C. Nelson, The androgen receptor can promote β-catenin nuclear translocation independently of adenomatous polyposis coli. J. Biol. Chem. 277 , 17933-17943 (2002). [Abstract] [Full Text]