E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner

E-cadherin is a tumor suppressor protein with a well-established role in ce ll-cell adhesion. Adhesion could contribute to tumor suppression either by physically joining cells or by facilitating other juxtacrine signaling even ts. Alternatively, E-cadherin tumor suppressor activity could result from b inding and antagonizing the nuclear signaling function of beta -catenin, a known proto-oncogene. To distinguish between an adhesion- versus a beta -ca tenin signaling-dependent mechanism, chimeric cadherin constructs were expr essed in the SW480 colorectal tumor cell line. Expression of wild-type E-ca dherin significantly inhibits the growth of this cell line. Growth inhibito ry activity is retained by all constructs that have the beta -catenin bindi ng region of the cytoplasmic domain but not by E-cadherin constructs that e xhibit adhesive activity, but lack the beta -catenin binding region. This g rowth suppression correlates with a reduction in beta -catenin/T cell facto r (TCF) reporter gene activity. Importantly, direct inhibition of beta -cat enin/TCF signaling inhibits the growth of SW480 cells, and the growth inhib itory activity of E-cadherin is rescued by constitutively activated forms o f TCE Thus the growth suppressor activity of E-cadherin is adhesion indepen dent and results from an inhibition of the beta -catenin/TCF signaling path way, suggesting that loss of E-cadherin expression can contribute to upregu lation of this pathway in human cancers. E-cadherin-mediated growth suppres sion was not accompanied by overall depletion of beta -catenin from the cyt osol and nucleus This appears to be due to the existence of a large pool of cytosolic beta -catenin in SW480 cells that is refractory to both cadherin binding and TCF binding. Thus, a small pool of beta -catenin that can bind TCF (i.e., the transcriptionally active pool) can be selectively depleted by E-cadherin expression. The existence of functionally distinct pools of c ytosolic beta -catenin suggests that there are mechanisms to regulate beta -catenin signaling in addition to controlling its level of accumulation.