WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop
| Autor: | David H. Drewry, Carrow I. Wells, David M. Graham, Susanne Müller, P.H.C. Godoi, Roberta R. Ruela-de-Sousa, Nirav Kapadia, Matthew P. Walker, Megan J. Agajanian, Alex D. Rabinowitz, Fiona J. Sorrell, Meagan B. Ryan, James M. Bennett, Opher Gileadi, Alison D. Axtman, Timothy M. Willson, Tigist Y. Tamir, Yuko Nakamichi, Rafael M. Couñago, William J. Zuercher, Jonathan M. Elkins, D. Stephen Serafin, Michael B. Major, Melissa V. Gammons, Carina Gileadi, Oleg Fedorov, A.S. Santiago |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
LRP6 Male Receptor complex kinase education Protein Serine-Threonine Kinases Endocytosis General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Mice 0302 clinical medicine gain-of-function screen WNT signaling Animals Humans AP2M1 Protein Kinase Inhibitors Wnt Signaling Pathway Tissue homeostasis AAK1 Feedback Physiological Chemistry Wnt signaling pathway Receptor-mediated endocytosis Clathrin Cell biology Wnt Proteins 030104 developmental biology HEK293 Cells Low Density Lipoprotein Receptor-Related Protein-6 Signal transduction feedback loop 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports |
| ISSN: | 2211-1247 |
| Popis: | Summary 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. Graphical Abstract Highlights • Gain-of-function kinome screen identifies AAK1 as a repressor of WNT signaling • AAK1 promotes clathrin-mediated endocytosis of LRP6 • Selective AAK1 inhibitor stabilizes β-catenin and activates WNT signaling • WNT induces AAK1-dependent phosphorylation of AP2M1 and LRP6 endocytosis WNT signal transduction is essential for normal development and contributes to many human diseases. Agajanian et al. used a kinase gain-of-function screen to show that WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of the WNT receptor. This work identifies an AAK-driven negative feedback loop that downregulates WNT signaling. |
| Databáze: | OpenAIRE |
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