Akt/PKB enhances non-canonical Wnt signals by compartmentalizing β-Catenin [article]

Nicolas Aznar, Nina Sun, Ying Dunkel, Jason Ear, Matthew Buschman, Pradipta Ghosh
2017 bioRxiv   pre-print
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 beta-catenin. Here we demonstrate that the PI3-K>Akt pathway also enhances non-canonical Wnt signals by compartmentalizing beta-catenin. By phosphorylating the phosphoinositide(PI)-binding domain of a multimodular signal transducer,
more » ... signal transducer, Daple, Akt abolishes the ability of Daple 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 non-canonical 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 crosstalk between Akt and the non-canonical Wnt pathway, but also reveals the impact of such crosstalk during cancer initiation and progression.
doi:10.1101/149351 fatcat:bmleuzs37zh3tieldwa52cupye