PT - JOURNAL ARTICLE AU - Nicolas Aznar AU - Nina Sun AU - Ying Dunkel AU - Jason Ear AU - Matthew D. Buschman AU - Pradipta Ghosh TI - Akt/PKB enhances non-canonical Wnt signals by compartmentalizing β-Catenin AID - 10.1101/149351 DP - 2017 Jan 01 TA - bioRxiv PG - 149351 4099 - http://biorxiv.org/content/early/2017/06/13/149351.short 4100 - http://biorxiv.org/content/early/2017/06/13/149351.full AB - Cellular proliferation is antagonistically regulated by canonical and non-canonical Wnt signals; their dysbalance triggers cancers. It is widely believed that the PI3-K→ Akt pathway enhances canonical Wnt signals by affecting transcriptional activity and stability of β-catenin. Here we demonstrate that the PI3-K→Akt pathway also enhances non-canonical Wnt signals by compartmentalizing β-catenin. By phosphorylating the phosphoinositide(PI)-binding domain of a multimodular signal transducer, Daple, Akt abolishes Daple’s ability to bind PI3-P-enriched endosomes that engage dynein motor complex for long-distance trafficking of β-catenin/E-cadherin complexes to pericentriolar recycling endosomes (PCREs). Phosphorylation compartmentalizes Daple/β-catenin/E-cadherin complexes to cell-cell contact sites, enhances non-canonical Wnt signals, and thereby, suppresses colony growth. Dephosphorylation compartmentalizes β-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 crosstalk between Akt and the non-canonical Wnt pathway, but also reveals the impact of such crosstalk during cancer initiation and progression.