Interaction of β-catenin and TIF2/GRIP1 in transcriptional activation by the androgen receptor

Abstract

The multifunctional oncoprotein β-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. β-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). β-Catenin can also bind directly to TIF2/GRIP1. Both N- and C-terminal regions of β-catenin are needed for optimal interaction with TIF2/GRIP1. We show that distinct residues of β-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. β-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, β-catenin, and TIF2/GRIP1 bind in a three-way interaction that mediates transcription. Lastly, we observed that a β-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 β-catenin may play an integral role in formation of the androgen-receptor transcriptional complex. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.