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

DOI: 10.1016/j.celrep.2018.12.023 DOI Help

Authors: Megan J. Agajanian (University of North Carolina at Chapel Hill) , Matthew P. Walker (University of North Carolina at Chapel Hill) , Alison D. Axtman (Structural Genomics Consortium, University of North Carolina) , Roberta R. Ruela-de-sousa (Structural Genomics Consortium, Universidade Estadual de Campinas – UNICAMP) , D. Stephen Serafin (University of North Carolina at Chapel Hill) , Alex D. Rabinowitz (University of North Carolina at Chapel Hill) , David M. Graham (University of North Carolina at Chapel Hill) , Meagan B. Ryan (University of North Carolina at Chapel Hill) , Tigist Tamir (University of North Carolina at Chapel Hill) , Yuko Nakamichi (University of North Carolina at Chapel Hill; Matsumoto Dental University) , Melissa V. Gammons (MRC Laboratory of Molecular Biology) , James M. Bennett (Structural Genomics Consortium and Target Discovery Institute, University of Oxford) , Rafael M. Counago (Structural Genomics Consortium, Universidade Estadual de Campinas – UNICAMP) , David H. Drewry (Structural Genomics Consortium, University of North Carolina) , Jonathan M. Elkins (Structural Genomics Consortium, University of North Carolina; Structural Genomics Consortium and Target Discovery Institute, University of Oxford) , Carina Gileadi (Structural Genomics Consortium and Target Discovery Institute, University of Oxford) , Opher Gileadi (Structural Genomics Consortium, Universidade Estadual de Campinas – UNICAMP; Structural Genomics Consortium and Target Discovery Institute, University of Oxford) , Paulo H. Godoi (Structural Genomics Consortium, Universidade Estadual de Campinas – UNICAMP) , Nirav Kapadia (Structural Genomics Consortium, University of North Carolina at Chapel Hill) , Susanne Müller (Structural Genomics Consortium, Goethe University) , André S. Santiago (Structural Genomics Consortium, Universidade Estadual de Campinas – UNICAMP) , Fiona J. Sorrell (Structural Genomics Consortium and Target Discovery Institute, University of Oxford) , Carrow I. Wells (Structural Genomics Consortium, University of North Carolina at Chapel Hill) , Oleg Fedorov (Structural Genomics Consortium and Target Discovery Institute, University of Oxford) , Timothy M. Willson (Structural Genomics Consortium, University of North Carolina at Chapel Hill) , William J. Zuercher (Structural Genomics Consortium, University of North Carolina at Chapel Hill) , Michael B. Major (University of North Carolina at Chapel Hill)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Reports , VOL 26 , PAGES 79 - 93.e8

State: Published (Approved)
Published: January 2019

Open Access Open Access

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 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.

Keywords: WNT signaling; endocytosis; gain-of-function screen; AAK1; clathrin; kinase; AP2M1; LRP6; feedback loop

Subject Areas: Biology and Bio-materials


Beamlines: I02-Macromolecular Crystallography

Documents:
1-s2.0-S2211124718319533-main.pdf