NDLI: A dual-kinase mechanism for Wnt coreceptor phosphorylation and activation

Content Provider	PubMed Central
Author	Zeng, Xin Tamai, Keiko Doble, Brad Li, Shitao Huang, He Habas, Raymond Okamura, Heidi Jim, Woodgett He, Xi
Abstract	Signalling by the Wnt family of secreted lipoproteins plays essential roles in development and disease1. The canonical Wnt/β-catenin pathway requires a single-span transmembrane receptor, LDL receptor related protein 6 (LRP6)2-4, whose phosphorylation at multiple PPPSP motifs is induced upon Wnt stimulation and critical for signal transduction5. The kinase responsible for LRP6 phosphorylation has not been identified. Here we provide biochemical and genetic evidence for a ‘dual-kinase’ mechanism for LRP6 phosphorylation and activation. Surprisingly, glycogen synthase kinase 3 (GSK3), which is known for its inhibitory role in Wnt signalling via promoting β-catenin phosphorylation and degradation, mediates LRP6 phosphorylation and activation. We demonstrate that Wnt induces sequential phosphorylation of LRP6 by GSK3 and casein kinase 1 (CK1), and this dual-phosphorylation promotes the engagement of LRP6 with the scaffolding protein Axin. We further show that a membrane-associated form of GSK3, contrary to cytosolic GSK3, stimulates Wnt signalling and Xenopus axis duplication. Our results identify two key kinases mediating Wnt coreceptor activation, reveal an unexpected and intricate logic of Wnt/β-catenin signalling, and illustrate GSK3 as a bona fide switch dictating both on and off states of a pivotal regulatory pathway.
Related Links	http://dx.doi.org/10.1038/nature04185
Ending Page	877
Page Count	5
Starting Page	873
File Format	PDF
ISSN	00280836
e-ISSN	14764687
Journal	Nature
Issue Number	7069
Volume Number	438
Language	English
Publisher Date	2005-12-08
Access Restriction	Open
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

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