Advanced search
Start date
Betweenand
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

Full text
Author(s):
Show less -
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]
Total Authors: 27
Affiliation:
Show less -
[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
Total Affiliations: 12
Document type: Journal article
Source: CELL REPORTS; v. 26, n. 1, p. 79+, JAN 2 2019.
Web of Science Citations: 2
Abstract

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)

FAPESP's process: 16/17469-0 - Development of celular assays to measure and to discover the phenotypic consequences of chemical inhibition of Vaccinia-Related Kinase 1 (VRK1)
Grantee:Roberta Regina Ruela de Sousa
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research
Grantee:Paulo Arruda
Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE