WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop.
β-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through a WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates WNT signaling through internalization and degradation of the receptor complex. Here, using a gain-of-function screen of the human kinome, we report that the AP2 associated kinase 1 (AAK1), a known CME enhancer, inhibits WNT signaling. Reciprocally, AAK1 genetic silencing or its pharmacological inhibition using a potent and selective inhibitor activates WNT signaling. Mechanistically, we show that AAK1 promotes clearance of LRP6 from the plasma membrane to suppress the WNT pathway. Time-course experiments support a transcription-uncoupled, WNT-driven negative feedback loop; prolonged WNT treatment drives AAK1-dependent phosphorylation of AP2M1, clathrin-coated pit maturation, and endocytosis of LRP6. We propose that, following WNT receptor activation, increased AAK1 function and CME limits WNT signaling longevity.
Duke Scholars
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Related Subject Headings
- Wnt Signaling Pathway
- Wnt Proteins
- Protein Serine-Threonine Kinases
- Protein Kinase Inhibitors
- Mice
- Male
- Low Density Lipoprotein Receptor-Related Protein-6
- Humans
- HEK293 Cells
- Feedback, Physiological
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Wnt Signaling Pathway
- Wnt Proteins
- Protein Serine-Threonine Kinases
- Protein Kinase Inhibitors
- Mice
- Male
- Low Density Lipoprotein Receptor-Related Protein-6
- Humans
- HEK293 Cells
- Feedback, Physiological