Molecular Biology of the Cell
Molecular Biology of the Cell
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

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.