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A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing β-catenin
Nicolas Aznar1, Nina Sun2, Ying Dunkel2
1Department of Medicine, University of California, San Diego, La Jolla, CA 92093 naznar@ucsd.edu prghosh@ucsd.edu.
Abstract:
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 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 noncanonical 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 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.
Insights
The PI3-K→Akt pathway enhances noncanonical Wnt signals by controlling Daple, a key regulator of cellular proliferation and cancer. This cross-talk impacts tumor growth and progression.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Biology
Background:
- Cellular proliferation is tightly regulated by Wnt signaling pathways, with dysregulation linked to cancer.
- Daple (Dishevelled associated protein with a PDZ and LIM domain) acts as a signal transducer, modulating both canonical and noncanonical Wnt responses.
Purpose of the Study:
- To elucidate the role of the PI3-K→Akt pathway in regulating noncanonical Wnt signaling via Daple.
- To investigate how Daple's interaction with PI3-K→Akt signaling influences cellular proliferation and tumor cell phenotypes.
Main Methods:
- Investigated the mechanism by which Akt phosphorylates Daple.
- Utilized cell-based assays to examine the localization of Daple, β-catenin, and E-cadherin complexes.
- Analyzed the impact of Daple phosphorylation status on noncanonical Wnt signaling and colony growth.
Main Results:
- Akt-mediated phosphorylation of Daple disrupts its binding to PI3-P-enriched endosomes, preventing β-catenin/E-cadherin trafficking to pericentriolar recycling endosomes (PCREs).
- Phosphorylation sequesters Daple/β-catenin/E-cadherin at cell-cell contacts, enhancing noncanonical Wnt signals and suppressing colony growth.
- Dephosphorylation leads to β-catenin compartmentalization on PCREs, promoting canonical Wnt signaling and colony growth.
Conclusions:
- Daple acts as a crucial platform for cross-talk between the PI3-K→Akt pathway and noncanonical Wnt signaling.
- This cross-talk mechanism significantly influences tumor cell proliferation and phenotypes relevant to cancer initiation and progression.
- Dysregulation of Daple's phosphorylation state, as seen in cancer-associated mutants, can drive tumorigenesis by favoring canonical Wnt signaling.
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