Regulation of Tcf7l1 DNA binding and protein stability as principle mechanisms of Wnt/β-catenin signaling.

Wnt/β-catenin signal transduction requires direct binding of β-catenin to Tcf/Lef proteins, an event classically associated with stimulating transcription by recruiting co-activators. This molecular cascade plays critical roles throughout embryonic development and normal postnatal life by affecting stem cell characteristics and tumor formation. Here, we show this pathway utilizes a fundamentally different mechanism to regulate Tcf7l1 (formerly named Tcf3) activity. β-catenin inactivates Tcf7l1 without a switch to a co-activator complex by removing it from DNA, an effect leading to Tcf7l1 protein degradation. Mouse genetic experiments demonstrate that Tcf7l1 inactivation is the only required effect of the Tcf7l1-β-catenin interaction. Given the expression of Tcf7l1 in pluripotent embryonic and adult stem cells, and in poorly differentiated breast cancer, these finding provide new mechanistic insights into the regulation of pluripotency and the role of Wnt/β-catenin in breast cancer.