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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

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Autor(es):
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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]
Número total de Autores: 27
Afiliação do(s) autor(es):
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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
Número total de Afiliações: 12
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: 13/50724-5 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto
Beneficiário:Paulo Arruda
Linha de fomento: Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE
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
Linha de fomento: Bolsas no Brasil - Pós-Doutorado