WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop.

WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop.

Cell reports (2019-01-04)

Megan J Agajanian, Matthew P Walker, Alison D Axtman, Roberta R Ruela-de-Sousa, D Stephen Serafin, Alex D Rabinowitz, David M Graham, Meagan B Ryan, Tigist Tamir, Yuko Nakamichi, Melissa V Gammons, James M Bennett, Rafael M Couñago, David H Drewry, Jonathan M Elkins, Carina Gileadi, Opher Gileadi, Paulo H Godoi, Nirav Kapadia, Susanne Müller, André S Santiago, Fiona J Sorrell, Carrow I Wells, Oleg Fedorov, Timothy M Willson, William J Zuercher, Michael B Major

PMID30605688

摘要

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.