ArticleCell reports2019
WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop.
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Article in Cell reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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42 citing papers in PubMed, 95 citations in OpenAlex.
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- Exploring the AAK1 Phospho-signaling Landscape Through Phospho-centric Co-regulation Network.Cell biochemistry and biophysics · 2026Article
- Development of a Chemical Probe to Enable Characterization of the Casein Kinase 1γ Subfamily.Journal of medicinal chemistry · 2026Article
- Discovery and optimization of AAK1 inhibitors based on 1H-indazole scaffold for the potential treatment of SARS-CoV-2 infection.Molecular diversity · 2026Article
- AAK1 activation-mediated iron trafficking drives ferroptotic cell death.Nature communications · 2025Article
- SNX10 enhances HCoV-OC43 infection by facilitating viral entry and inhibiting virus-triggered autophagy.Virologica Sinica · 2025Article
- Development of a chemical probe to enable characterization of the casein kinase 1γ subfamily.bioRxiv : the preprint server for biology · 2025Article
- Wnt signalosome assembly is governed by conformational flexibility of Axin and by the AP2 clathrin adaptor.Nature communications · 2025Article
- Integrative Analysis of Whole-Genome and Transcriptomic Data Reveals Novel Variants in Differentially Expressed Long Noncoding RNAs Associated with Asthenozoospermia.Non-coding RNA · 2025Article
- Targeting the NOTCH2/ADAM10/TCF7L2 Axis-Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Frizzled receptors: gatekeepers of Wnt signaling in development and disease.Frontiers in cell and developmental biology · 2025Review
- Article
- EGFR-dependent endocytosis of Wnt9a and Fzd9b promotes β-catenin signaling during hematopoietic stem cell development in zebrafish.Science signaling · 2024Article
- Development of a novel AAK1 inhibitor via Kinobeads-based screening.Scientific reports · 2024Article
- Recent progress in discovery of novel AAK1 inhibitors: from pain therapy to potential anti-viral agents.Journal of enzyme inhibition and medicinal chemistry · 2023Review
- Temporal phosphoproteomic analysis of VEGF-A signaling in HUVECs: an insight into early signaling events associated with angiogenesis.Journal of cell communication and signaling · 2023Article
- Phosphorylation of ADAPTOR PROTEIN-2 μ-adaptin by ADAPTOR-ASSOCIATED KINASE1 regulates the tropic growth of Arabidopsis roots.The Plant cell · 2023Article
- Extracellular vesicle-transmitted miR-671-5p alleviates lung inflammation and injury by regulating the AAK1/NF-κB axis.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Multiplexed kinase interactome profiling quantifies cellular network activity and plasticity.Molecular cell · 2023Article
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Authors and funding
27 authors at 7 institutions in 5 countries.
Megan J AgajanianLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Matthew P WalkerLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Alison D AxtmanStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Roberta R Ruela-de-SousaStructural Genomics Consortium, Universidade Estadual de Campinas - UNICAMP, Campinas, SP 13083-970, Brazil.
D Stephen SerafinLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Alex D RabinowitzLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
David M GrahamDepartment of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Meagan B RyanLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Tigist TamirLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Yuko NakamichiLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Institute for Oral Science, Matsumoto Dental University, Nagano 399-0704, Japan.
Melissa V GammonsMRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0SL, UK.
James M BennettStructural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
Rafael M CouñagoStructural Genomics Consortium, Universidade Estadual de Campinas - UNICAMP, Campinas, SP 13083-970, Brazil.
David H DrewryStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jonathan M ElkinsStructural Genomics Consortium, Universidade Estadual de Campinas - UNICAMP, Campinas, SP 13083-970, Brazil; Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
Carina GileadiStructural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
Opher GileadiStructural Genomics Consortium, Universidade Estadual de Campinas - UNICAMP, Campinas, SP 13083-970, Brazil; Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
Paulo H GodoiStructural Genomics Consortium, Universidade Estadual de Campinas - UNICAMP, Campinas, SP 13083-970, Brazil.
Nirav KapadiaStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Susanne MüllerStructural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main 60438, Germany.
André S SantiagoStructural Genomics Consortium, Universidade Estadual de Campinas - UNICAMP, Campinas, SP 13083-970, Brazil.
Fiona J SorrellStructural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
Carrow I WellsStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Oleg FedorovStructural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
Timothy M WillsonStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
William J ZuercherLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Michael B MajorLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: benmajor@med.unc.edu.
University of North Carolina at Chapel Hill · USUniversidade Estadual de Campinas (UNICAMP) · BRGenomics England · GBUniversity of Oxford · GBGoethe University Frankfurt · DEMatsumoto Dental University · JPMRC Laboratory of Molecular Biology · GB
Funding
Virology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI David Darr · 1985 to 2026
$201.5MVirology, Immunology, and Microbiology CoreP30AI050410 · NIAID · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DAVID M. MARGOLIS · 2001 to 2026
$76.9MIntegrated Training in Cancer Model SystemsT32CA009156 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J. · 1985 to 2020
$19.7MIlluminating Function of the Understudied Druggable KinomeU24DK116204 · NIDDK · UNIV OF NORTH CAROLINA CHAPEL HILL · PI JOHNSON, GARY L. · 2017 to 2022
$13.6MUNC Initiative for Maximizing Student DevelopmentR25GM055336 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI COOK, JEANETTE GOWEN, KASH, THOMAS L. · 1996 to 2023
$12.1MPREDOCTORAL TRAINING IN PHARMACOLOGICAL SCIST32GM007040 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI NICHOLAS, ROBERT A · 1985 to 2019
$6.0MCANCER CELL BIOLOGY TRAINING PROGRAMT32CA071341 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI CHANNING J. DER, Yuliya Pylayeva-Gupta · 1996 to 2026
$5.0MRole of FOXP1 and WNT signaling in B-cell LymphomaR01CA187799 · NCI · WASHINGTON UNIVERSITY · PI MAJOR, MICHAEL BENJAMIN · 2015 to 2019
$1.5MNew Roles for the WTX Tumor Suppressor and Endocytosis in WNT signalingF31CA228289 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI AGAJANIAN, MEGAN · 2018 to 2018
$22kCancer Research UK 15291Cancer Research UK 24639Cancer Research UK C7379/A15291Cancer Research UK C7379/A24639Howard Hughes Medical InstituteNCI NIH HHS F31 CA228289NCI NIH HHS P30 CA016086NCI NIH HHS R01 CA187799NCI NIH HHS T32 CA009156NCI NIH HHS T32 CA071341NIAID NIH HHS P30 AI050410NIDDK NIH HHS U24 DK116204NIGMS NIH HHS R25 GM055336NIGMS NIH HHS T32 GM007040Wellcome TrustWellcome Trust 106169/ZZ14/Z
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.
Indexed as
AnimalsClathrinEndocytosisFeedback, PhysiologicalHEK293 CellsHumansLow Density Lipoprotein Receptor-Related Protein-6MaleMiceProtein Kinase InhibitorsProtein Serine-Threonine KinasesWnt ProteinsWnt Signaling PathwayAAK1 protein, humanAak1 protein, mouseClathrinLow Density Lipoprotein Receptor-Related Protein-6LRP6 protein, humanLrp6 protein, mouseProtein Kinase InhibitorsProtein Serine-Threonine KinasesWnt ProteinsAAK1AP2M1clathrinendocytosisfeedback loopgain-of-function screenkinaseLRP6WNT signaling
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