5 years ago

A Daple-Akt feed forward loop enhances non-canonical Wnt signals by compartmentalizing β-Catenin.

Ear, Buschman, Sun, Ghosh, Dunkel, Aznar
Cellular proliferation is antagonistically regulated by canonical and non-canonical Wnt signals; their dysbalance triggers cancers. We previously showed that a multimodular signal transducer, Daple, enhances PI3-K→Akt signals within the non-canonical 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 non-canonical Wnt signals by compartmentalizing β-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 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 on tumor cell phenotypes that are critical for cancer initiation and progression.

Publisher URL: http://doi.org/10.1091/mbc.E17-06-0405

DOI: 10.1091/mbc.E17-06-0405

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