WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop

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Agajanian, Megan J. ^{[1, 2]} ; Walker, Matthew P. ^[1] ; Axtman, Alison D. ^{[3, 4]} ; Ruela-de-Sousa, Roberta R. ^[5] ; Serafin, D. Stephen ^{[1, 6]} ; Rabinowitz, Alex D. ^[1] ; Graham, David M. ^[6] ; Ryan, Meagan B. ^{[1, 2]} ; Tamir, Tigist ^{[1, 2]} ; Nakamichi, Yuko ^{[1, 7]} ; Gammons, Melissa V. ^[8] ; Bennett, James M. ^{[9, 10]} ; Counago, Rafael M. ^[5] ; Drewry, David H. ^{[3, 4]} ; Elkins, Jonathan M. ^{[5, 9, 10]} ; Gileadi, Carina ^{[9, 10]} ; Gileadi, Opher ^{[5, 9, 10]} ; Godoi, Paulo H. ^[5] ; Kapadia, Nirav ^{[3, 4]} ; Mueller, Susanne ^[11] ; Santiago, Andre S. ^[5] ; Sorrell, Fiona J. ^{[9, 10]} ; Wells, Carrow I. ^{[3, 4]} ; Fedorov, Oleg ^{[9, 10]} ; Willson, Timothy M. ^{[3, 4]} ; Zuercher, William J. ^{[1, 3, 4]} ; Major, Michael B. ^{[1, 2, 6, 12]}

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^[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 - USA

^[2] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 - USA

^[3] Univ N Carolina, UNC Eshelman Sch Pharm, Struct Genom Consortium, Chapel Hill, NC 27599 - USA

^[4] Univ N Carolina, UNC Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 - USA

^[5] Univ Estadual Campinas, UNICAMP, Struct Genom Consortium, BR-13083970 Campinas, SP - Brazil

^[6] Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 - USA

^[7] Matsumoto Dent Univ, Inst Oral Sci, Nagano 3990704 - Japan

^[8] Cambridge Biomed Campus, MRC Lab Mol Biol, Cambridge CB2 0SL - England

^[9] Univ Oxford, Struct Genom Consortium, Old Rd Campus, Res Bldg, Oxford OX3 7DQ - England

^[10] Univ Oxford, Nuffield Dept Clin Med, Target Discovery Inst, Old Rd Campus, Res Bldg, Oxford OX3 7DQ - England

^[11] Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, Struct Genom Consortium, D-60438 Frankfurt - Germany

^[12] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 - USA

• Tipo de documento: Artigo Científico
• Fonte: CELL REPORTS; v. 26, n. 1, p. 79+, JAN 2 2019.
• Citações Web of Science: 2

Resumo

beta-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. (AU)

• Processo FAPESP: 16/17469-0 - Desenvolvimento de ensaios celulares para avaliar e quantificar as alterações fenotípicas da inibição química da Vaccinia-Related Kinase 1 (VRK1)
• Beneficiário: Roberta Regina Ruela de Sousa
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/50724-5 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto
• Beneficiário: Paulo Arruda
• Modalidade de apoio: Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE