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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.
Pubmed ID: 30605688 RIS Download
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View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HT-1080 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
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View all literature mentionsThis monoclonal targets Human LRP-6 MAb (Clone 255302)
View all literature mentionsThis monoclonal targets β-Actin
View all literature mentionsThis polyclonal targets Phospho-LRP6 (Ser1490)
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View all literature mentionsThis monoclonal targets Lrp6
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis monoclonal targets Human Tubulin, beta
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View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis monoclonal targets AP2M1 (phospho T156) antibody [EPR4700]
View all literature mentionsThis monoclonal targets LRP6 (C47E12) Rabbit mAb
View all literature mentionsThis monoclonal targets AP2M1
View all literature mentionsThis monoclonal targets Clathrin Heavy Chain (D3C6) XP Rabbit mAb
View all literature mentionsThis monoclonal targets GSK-3 beta
View all literature mentionsThis polyclonal targets AAK1
View all literature mentionsThis unknown targets Mouse IgG (H+L)
View all literature mentionsThis monoclonal targets FLAG
View all literature mentionsThis polyclonal targets Phospho-beta-Catenin (Ser33/37/Thr41)
View all literature mentionsThis monoclonal targets PIP4K2A
View all literature mentionsThis unknown targets Mouse
View all literature mentionsThis monoclonal targets HA
View all literature mentionsThis unknown targets Mouse
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis monoclonal targets Human LRP-6 MAb (Clone 255302)
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis unknown targets Mouse IgG (H+L)
View all literature mentionsThis unknown targets AP2M1
View all literature mentionsThis monoclonal targets GSK-3 beta
View all literature mentionsThis monoclonal targets β-Actin
View all literature mentionsThis monoclonal targets AP2M1
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis monoclonal targets HA
View all literature mentionsThis monoclonal targets Lrp6
View all literature mentionsThis monoclonal targets FLAG
View all literature mentionsThis monoclonal targets Human Tubulin, beta
View all literature mentionsThis monoclonal targets AP2M1 (phospho T156) antibody [EPR4700]
View all literature mentionsThis monoclonal targets PIP4K2A
View all literature mentionsThis monoclonal targets LRP6 (C47E12) Rabbit mAb
View all literature mentionsThis polyclonal targets Human AP2M1, phospho (Thr156)
View all literature mentionsThis polyclonal targets Phospho-LRP6 (Ser1490)
View all literature mentionsThis polyclonal targets Phospho-beta-Catenin (Ser33/37/Thr41)
View all literature mentionsThis polyclonal targets AAK1
View all literature mentionsThis polyclonal targets AAK1
View all literature mentionsThis polyclonal targets Phospho-LRP6 (Ser1490)
View all literature mentionsThis monoclonal targets FLAG
View all literature mentionsThis monoclonal targets PIP4K2A
View all literature mentionsThis polyclonal targets Human AP2M1, phospho (Thr156)
View all literature mentionsThis polyclonal targets Phospho-beta-Catenin (Ser33/37/Thr41)
View all literature mentionsThis monoclonal targets HA
View all literature mentionsThis monoclonal targets LRP6 (C47E12) Rabbit mAb
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis unknown targets AP2M1
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis monoclonal targets β-Actin
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis monoclonal targets AP2M1 (phospho T156) antibody [EPR4700]
View all literature mentionsThis monoclonal targets GSK-3 beta
View all literature mentionsThis monoclonal targets Lrp6
View all literature mentionsThis monoclonal targets AP2M1
View all literature mentionsThis monoclonal targets Human Tubulin, beta
View all literature mentionsThis unknown targets Mouse IgG (H+L)
View all literature mentionsThis unknown targets Mouse
View all literature mentionsThis monoclonal targets Human LRP-6 MAb (Clone 255302)
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