Synergistic effects of coactivators GRIP1 and beta-catenin on gene activation: cross-talk between androgen receptor and Wnt signaling pathways.

The p160 coactivators, such as GRIP1, bind nuclear receptors and help to mediate transcriptional activation. beta-Catenin binds to and serves as a coactivator for the nuclear receptor, androgen receptor (AR), and the Lymphoid Enhancer Factor/T Cell Factor family member, Lef1. Here we report that GRIP1 and beta-catenin can bind strongly to each other through the AD2 domain of GRIP1. Furthermore, GRIP1 and beta-catenin can synergistically enhance the activity of both AR and Lef1, and both coactivators are recruited specifically to AR-driven and Lef1-driven promoters. However, the mechanism of beta-catenin-GRIP1 coactivator function and synergy is different with AR and Lef1. While beta-catenin can bind directly to both AR and Lef1, GRIP1 can only bind directly to AR; the ability of GRIP1 to associate with and function as a coactivator for Lef1 is entirely dependent on the presence of beta-catenin. Thus, whereas GRIP1 coactivator function involves direct binding to nuclear receptors and most other classes of DNA-binding transcriptional activator proteins, the coactivator function of GRIP1 with Lef1 follows a novel paradigm where GRIP1 is recruited indirectly to Lef1 through their mutual association with beta-catenin. The beta-catenin-GRIP1 interaction represents another potential point of cross-talk between the AR and Wnt signaling pathways.