Abstract
WNT signal transduction is essential for normal development and contributes to many human diseases. Agajanian et al. used a kinase gain-of-function screen to show that WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of the WNT receptor. This work identifies an AAK-driven negative feedback loop that downregulates WNT signaling.
Original language | English |
---|---|
Pages (from-to) | 79-93.e8 |
Journal | Cell Reports |
Volume | 26 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2 2019 |
Keywords
- AAK1
- AP2M1
- LRP6
- WNT signaling
- clathrin
- endocytosis
- feedback loop
- gain-of-function screen
- kinase
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In: Cell Reports, Vol. 26, No. 1, 02.01.2019, p. 79-93.e8.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop
AU - Agajanian, Megan J.
AU - Walker, Matthew P.
AU - Axtman, Alison D.
AU - Ruela-de-Sousa, Roberta R.
AU - Serafin, D. Stephen
AU - Rabinowitz, Alex D.
AU - Graham, David M.
AU - Ryan, Meagan B.
AU - Tamir, Tigist
AU - Nakamichi, Yuko
AU - Gammons, Melissa V.
AU - Bennett, James M.
AU - Couñago, Rafael M.
AU - Drewry, David H.
AU - Elkins, Jonathan M.
AU - Gileadi, Carina
AU - Gileadi, Opher
AU - Godoi, Paulo H.
AU - Kapadia, Nirav
AU - Müller, Susanne
AU - Santiago, André S.
AU - Sorrell, Fiona J.
AU - Wells, Carrow I.
AU - Fedorov, Oleg
AU - Willson, Timothy M.
AU - Zuercher, William J.
AU - Major, Michael B.
N1 - Funding Information: M.B.M. acknowledges support from the NIH ( RO1-CA187799 and U24-DK116204-01 ). M.J.A. received financial support from NIH T32 Predoctoral Training Grants in Pharmacology ( T32-GM007040-43 and T32-GM007040-42 ), an Initiative for Maximizing Student Diversity Grant ( R25-GM055336-16 ), and the NIH National Cancer Institute (NCI) NRSA Predoctoral Fellowship to Promote Diversity in Health-Related Research ( F31CA228289 ). M.P.W. received support from the Lymphoma Research Foundation ( 337444 ) and the NIH ( T32-CA009156-35 ). Y.N. was supported by grants-in-aid from the Japan Society for the Promotion of Science (JSPS) ( 15KK0356 and 16K11493 ). T.T. was supported by the Howard Hughes Medical Institute Gilliam Fellowship for Advanced Study. M.V.G. was supported by Cancer Research UK (grants C7379/A15291 and C7379/A24639 to Mariann Bienz). The UNC Flow Cytometry Core Facility is supported in part by Cancer Center Core Support Grant P30 CA016086 to the UNC Lineberger Comprehensive Cancer Center, and research reported in this publication was supported by the Center for AIDS Research (award number 5P30AI050410 ), and the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Structural Genomics Consortium (SGC) is a registered charity (number 1097737) that receives funds from AbbVie , Bayer Pharma AG , Boehringer Ingelheim , the Canada Foundation for Innovation , the Eshelman Institute for Innovation , Genome Canada , the Innovative Medicines Initiative ( European Union [EU]/European Federation of Pharmaceutical Industries and Associations [EFPIA]) (ULTRA-DD grant no. 115766), Janssen , Merck & Company , Merck KGaA , Novartis Pharma AG , the Ontario Ministry of Economic Development and Innovation , Pfizer , the São Paulo Research Foundation (FAPESP) ( 2013/50724-5 ), Takeda , and the Wellcome Trust ( 106169/ZZ14/Z ). R.R.R. received financial support from FAPESP ( 2016/17469-0 ). We would also like to thank Claire Strain-Damerell and Pavel Savitsky for cloning various mutants of AAK1 and BMP2K proteins that were used in the crystallization trials. Additionally, we thank Dr. Sean Conner for providing the AAK1 plasmids, Dr. Stephane Angers for kindly providing the HEK293T DVL TKO cells, and Dr. Mariann Bienz for providing comments and feedback. We would like to thank members of the Major laboratory for their feedback and expertise regarding experimental design and project direction. Funding Information: M.B.M. acknowledges support from the NIH (RO1-CA187799 and U24-DK116204-01). M.J.A. received financial support from NIH T32 Predoctoral Training Grants in Pharmacology (T32-GM007040-43 and T32-GM007040-42), an Initiative for Maximizing Student Diversity Grant (R25-GM055336-16), and the NIH National Cancer Institute (NCI) NRSA Predoctoral Fellowship to Promote Diversity in Health-Related Research (F31CA228289). M.P.W. received support from the Lymphoma Research Foundation (337444) and the NIH (T32-CA009156-35). Y.N. was supported by grants-in-aid from the Japan Society for the Promotion of Science (JSPS) (15KK0356 and 16K11493). T.T. was supported by the Howard Hughes Medical Institute Gilliam Fellowship for Advanced Study. M.V.G. was supported by Cancer Research UK (grants C7379/A15291 and C7379/A24639 to Mariann Bienz). The UNC Flow Cytometry Core Facility is supported in part by Cancer Center Core Support Grant P30 CA016086 to the UNC Lineberger Comprehensive Cancer Center, and research reported in this publication was supported by the Center for AIDS Research (award number 5P30AI050410), and the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Structural Genomics Consortium (SGC) is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Foundation for Innovation, the Eshelman Institute for Innovation, Genome Canada, the Innovative Medicines Initiative (European Union [EU]/European Federation of Pharmaceutical Industries and Associations [EFPIA]) (ULTRA-DD grant no. 115766), Janssen, Merck & Company, Merck KGaA, Novartis Pharma AG, the Ontario Ministry of Economic Development and Innovation, Pfizer, the S?o Paulo Research Foundation (FAPESP) (2013/50724-5), Takeda, and the Wellcome Trust (106169/ZZ14/Z). R.R.R. received financial support from FAPESP (2016/17469-0). We would also like to thank Claire Strain-Damerell and Pavel Savitsky for cloning various mutants of AAK1 and BMP2K proteins that were used in the crystallization trials. Additionally, we thank Dr. Sean Conner for providing the AAK1 plasmids, Dr. Stephane Angers for kindly providing the HEK293T DVL TKO cells, and Dr. Mariann Bienz for providing comments and feedback. We would like to thank members of the Major laboratory for their feedback and expertise regarding experimental design and project direction. Funding Information: M.B.M. acknowledges support from the NIH (RO1-CA187799 and U24-DK116204-01). M.J.A. received financial support from NIH T32 Predoctoral Training Grants in Pharmacology (T32-GM007040-43 and T32-GM007040-42), an Initiative for Maximizing Student Diversity Grant (R25-GM055336-16), and the NIH National Cancer Institute (NCI) NRSA Predoctoral Fellowship to Promote Diversity in Health-Related Research (F31CA228289). M.P.W. received support from the Lymphoma Research Foundation (337444) and the NIH (T32-CA009156-35). Y.N. was supported by grants-in-aid from the Japan Society for the Promotion of Science (JSPS) (15KK0356 and 16K11493). T.T. was supported by the Howard Hughes Medical Institute Gilliam Fellowship for Advanced Study. M.V.G. was supported by Cancer Research UK (grants C7379/A15291 and C7379/A24639 to Mariann Bienz). The UNC Flow Cytometry Core Facility is supported in part by Cancer Center Core Support Grant P30 CA016086 to the UNC Lineberger Comprehensive Cancer Center, and research reported in this publication was supported by the Center for AIDS Research (award number 5P30AI050410), and the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Structural Genomics Consortium (SGC) is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Foundation for Innovation, the Eshelman Institute for Innovation, Genome Canada, the Innovative Medicines Initiative (European Union [EU]/European Federation of Pharmaceutical Industries and Associations [EFPIA]) (ULTRA-DD grant no. 115766), Janssen, Merck & Company, Merck KGaA, Novartis Pharma AG, the Ontario Ministry of Economic Development and Innovation, Pfizer, the São Paulo Research Foundation (FAPESP) (2013/50724-5), Takeda, and the Wellcome Trust (106169/ZZ14/Z). R.R.R. received financial support from FAPESP (2016/17469-0). We would also like to thank Claire Strain-Damerell and Pavel Savitsky for cloning various mutants of AAK1 and BMP2K proteins that were used in the crystallization trials. Additionally, we thank Dr. Sean Conner for providing the AAK1 plasmids, Dr. Stephane Angers for kindly providing the HEK293T DVL TKO cells, and Dr. Mariann Bienz for providing comments and feedback. We would like to thank members of the Major laboratory for their feedback and expertise regarding experimental design and project direction. Publisher Copyright: © 2018 The Authors
PY - 2019/1/2
Y1 - 2019/1/2
N2 - WNT signal transduction is essential for normal development and contributes to many human diseases. Agajanian et al. used a kinase gain-of-function screen to show that WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of the WNT receptor. This work identifies an AAK-driven negative feedback loop that downregulates WNT signaling.
AB - WNT signal transduction is essential for normal development and contributes to many human diseases. Agajanian et al. used a kinase gain-of-function screen to show that WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of the WNT receptor. This work identifies an AAK-driven negative feedback loop that downregulates WNT signaling.
KW - AAK1
KW - AP2M1
KW - LRP6
KW - WNT signaling
KW - clathrin
KW - endocytosis
KW - feedback loop
KW - gain-of-function screen
KW - kinase
UR - http://www.scopus.com/inward/record.url?scp=85059112535&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2018.12.023
DO - 10.1016/j.celrep.2018.12.023
M3 - Article
C2 - 30605688
AN - SCOPUS:85059112535
SN - 2211-1247
VL - 26
SP - 79-93.e8
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -