WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of LRP6 and establish a negative feedback loop

Journal article

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.

Authors: Agajanian, M; Walker, M; Axtman, A; Ruela-De-Sousa, R; Serafin, D

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Cell Reports
• Volume: 26
• Issue: 1
• Pages: 79-93.e8
• Publication date: 2019-01-02
• Acceptance date: 2018-12-03
• DOI: 10.1016/j.celrep.2018.12.023
• EISSN: 2211-1247
• ISSN: 2211-1247
• Pmid: 30605688
• Language: English
• Keywords: gain-of-function screen; AP2M1; endocytosis; feedback loop; AAK1; WNT signaling; LRP6; clathrin; kinase