-catenin signaling plays a key role in a variety of cellular contexts during embryonic development and tissue differentiation. Aberrant -catenin signaling has also been implicated in promoting human colorectal carcinomas as well as a variety of other cancers. To study the molecular and cell biological functions of -catenin in a controlled fashion, we created a regulatable form of activated -catenin by fusion to a modified estrogen receptor (ER) ligand-binding domain (G525R). Transfection of tissue culture cells with expression vectors encoding this hybrid protein allows the signal transduction function of -catenin to be induced by the synthetic estrogen, 4-hydroxytamoxifen, leading to regulated activation of a -catenin/LEF dependent reporter gene as well as induction of endogenous cyclin D1 expression. The activation of ER--catenin signaling rescues RK3E cells from anoikis and correlates with an increased phosphorylation of MAP kinase. The inhibition of anoikis by ER--catenin can be abolished by a mitogen-activated protein (MAP) kinase pathway inhibitor, PD98059. Evidence is also provided to show that ER--catenin downregulates cadherin protein levels. These findings support a key role for activated -catenin signaling in processes that contribute to tumor formation and progression.