1. A Transcription-uncoupled Negative Feedback Loop for the 1 WNT Pathway: WNT Activates the AAK1 Kinase to Promote Clathrin-mediated Endocytosis of LRP6
- Author
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Carina Gileadi, Jonathan M. Elkins, Meagan B. Ryan, Matthew P. Walker, Melissa V. Gammons, James M. Bennett, Timothy M. Willson, David H. Drewry, Alison D. Axtman, Oleg Fedorov, Carrow I. Wells, Rafael M. Couñago, Alex D. Rabinowitz, Michael B. Major, A.S. Santiago, William J. Zuercher, Roberta R. Ruela-de-Sousa, David M. Graham, P.H.C. Godoi, Nirav Kapadia, Opher Gileadi, F.J. Sorrell, Megan J. Agajanian, Susanne Müller, and D. Stephen Serafin
- Subjects
Receptor complex ,Chemistry ,Wnt signaling pathway ,LRP6 ,AAK1 ,Receptor-mediated endocytosis ,Signal transduction ,Endocytosis ,Tissue homeostasis ,Cell biology - Abstract
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 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, strongly inhibits WNT signaling. Reciprocally, silencing of AAK1 expression or pharmacological inhibition of AAK1 activity using a new potent and selective AAK1 inhibitor activates WNT signaling. We show that AAK1 and LRP6 co-complex, and that AAK1 promotes clathrinmediated endocytosis of LRP6 to suppress the WNT pathway. Our data reveal a transcription-uncoupled, WNT-driven negative feedback loop; prolonged WNT treatment drives AAK1-dependent phosphorylation of AP2M1, thus promoting clathrin-coated pit maturation. We propose that following WNT receptor activation and the ensuing transcriptional response, increased AAK1 function limits WNT signaling longevity.
- Published
- 2018
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