Publikationsdatum:
2019
Beschreibung:
〈p〉Publication date: 2 January 2019〈/p〉
〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉
〈p〉Author(s): 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〈/p〉
〈h5〉Summary〈/h5〉
〈div〉〈p〉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.〈/p〉〈/div〉
〈h5〉Graphical Abstract〈/h5〉
〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319533-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉
Digitale ISSN:
2211-1247
Thema:
Biologie
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