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-catenin/Tcf Signalling: Wnt you like to know?
Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA; The Prostate Centre at Vancouver General Hospital, Vancouver, BC, CANADA; USC/Norris Cancer Center, Keck School of Medicine, Los Angeles, CA.
* To whom correspondence should be addressed. E-mail: dmulholland{at}mednet.ucla.edu,.
The cross regulation of Wnt/
-catenin/Tcf ligands, kinases and transcription factors with members of the nuclear receptor (NR) family has emerged as a clinically and developmentally important area of endocrine cell biology. Interactions between these signaling pathways result in a diverse array of cellular effects including altered cellular adhesion, tissue morphogenesis and oncogenesis. Analyses of NR interactions with canonical Wnt signaling reveal two broad themes: Wnt/-catenin modulation of NRs (theme I) and ligand dependent NR inhibition of the Wnt/-catenin/Tcf cascade (theme II). -catenin, a promiscuous Wnt signaling member, has been studied intensively in relation to the androgen receptor (AR). -catenin acts as a co-activator of AR transcription and is also involved in co-trafficking, increasing cell proliferation and prostate pathogenesis. T-Cell factor, a transcriptional mediator of -catenin and AR, engage in a dynamic reciprocity of nuclear -catenin, p300/CBP and TIF2/GRIP, thereby facilitating hormone dependent coactivation and transrepression. -catenin responds in an equally dynamic manner with other NRs including the retinoic acid receptor (RAR), vitamin D receptor (VDR), glucocorticoid receptor (GR), progesterone receptor (PR), thyroid receptor (TR), estrogen receptor (ER) and peroxisome proliferator activated receptor (PPAR). The NR ligands, VitD3, trans/cis RA, glucocorticoids and thiazolidines, induce dramatic changes in the physiology of cells harboring high Wnt/-cat/Tcf activity. Wnt signaling regulates directly or indirectly developmental processes such as ductal branching and adipogenesis, two processes dependent upon NR function. -catenin has been intensively studied in colorectal cancer, however, it is now evident that -catenin may be important in cancers of the breast, prostate and thyroid. This review will focus on the cross regulation of AR and Wnt/-catenin/Tcf but will also consider the dynamic manner in which RAR/RXR, GR, TR, VDR, ER and PPAR modulate canonical Wnt signaling. Whereas many commonalities exist by which NRs interact with the Wnt/-catenin signaling pathway, striking cell line and tissue specific differences require deciphering and application to endocrine pathology.
-catenin •
Nuclear Receptors
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