Interaction of β-Catenin and TIF2/GRIP1 in Transcriptional Activation by the Androgen Receptor

The multifunctional oncoprotein beta-catenin interacts with the activation function-2 domain of androgen receptor (AR) to stimulate androgen receptor transcriptional activity, increase sensitivity, and broaden specificity of ligand interactions. beta-Catenin interacts with androgen receptor in close proximity to the binding groove for P160 coactivators such as transcriptional intermediary factor-2 (TIF2)/glucocorticoid receptor interacting protein-1 (GRIP1). beta-Catenin can also bind directly to TIF2/GRIP1. Both N- and C-terminal regions of beta-catenin are needed for optimal interaction with TIF2/GRIP1. We show that distinct residues of beta-catenin are responsible for both binding and functional interactions with androgen receptor and with TCF4, thus allowing the introduction of missense mutations that selectively affect these interactions. beta-Catenin and TIF2/GRIP1 are each able to mediate binding between the other and androgen receptor in functional interactions that enhance ligand-dependent transcription. The data strongly imply that AR, beta-catenin, and TIF2/GRIP1 bind in a three-way interaction that mediates transcription. Lastly, we observed that a beta-catenin C-terminal peptide containing 229 amino acids can bind TIF2/GRIP1 and AR but has a profound dominant inhibitory effect on ligand-dependent transcription. We propose that beta-catenin may play an integral role in formation of the androgen-receptor transcriptional complex.