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.
Li
Hongwei
H
Department of Pathology, University of Southern California, Los Angeles, California 90089-9092, USA.
Kim
Jeong Hoon
JH
Koh
Stephen S
SS
Stallcup
Michael R
MR
D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020239:Receptor Cross-Talk; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C491310:GRIP1 protein, human; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D018091:Receptors, AMPA; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin