| 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 |