A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing β-catenin.

Cellular proliferation is antagonistically regulated by canonical and noncanonical Wnt signals; their dysbalance triggers cancers. We previously showed that a multimodular signal transducer, Daple, enhances PI3-K -> Akt signals within the noncanonical Wnt signaling pathway and antagonistically inhibits canonical Wnt responses. Here we demonstrate that the PI3-K -> Akt pathway serves as a positive feedback loop that further enhances noncanonical Wnt signals by compartmentalizing beta-catenin. By phosphorylating the phosphoinositide-(PI) binding domain of Daple, Akt abolishes Daple's ability to bind PI3-P-enriched endosomes that engage dynein motor complex for long-distance trafficking of beta-catenin/E-cadherin complexes to pericentriolar recycling endosomes (PCREs). Phosphorylation compartmentalizes Daple/beta-catenin/E-cadherin complexes to cell-cell contact sites, enhances noncanonical Wnt signals, and thereby suppresses colony growth. Dephosphorylation compartmentalizes beta-catenin on PCREs, a specialized compartment for prolonged unopposed canonical Wnt signaling, and enhances colony growth. Cancer-associated Daple mutants that are insensitive to Akt mimic a constitutively dephosphorylated state. This work not only identifies Daple as a platform for cross-talk between Akt and the noncanonical Wnt pathway but also reveals the impact of such cross-talk on tumor cell phenotypes that are critical for cancer initiation and progression.