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PMID: 18077588 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions.

Development (Cambridge, England) ·Vol. 135 ·No. 2 ·2008-01-00 ·Pages 367-75

Zeng X, Huang H, Tamai K, Zhang X, Harada Y, Yokota C, Almeida K, Wang J, Doble B, Woodgett J, Wynshaw-Boris A, Hsieh JC, He X

Abstract

Canonical Wnt/beta-catenin signaling has central roles in development and diseases, and is initiated by the action of the frizzled (Fz) receptor, its coreceptor LDL receptor-related protein 6 (Lrp6), and the cytoplasmic dishevelled (Dvl) protein. The functional relationships among Fz, Lrp6 and Dvl have long been enigmatic. We demonstrated previously that Wnt-induced Lrp6 phosphorylation via glycogen synthase kinase 3 (Gsk3) initiates Wnt/beta-catenin signaling. Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. We also show that axin, a key scaffolding protein in the Wnt pathway, is required for Lrp6 phosphorylation via its ability to recruit Gsk3, and inhibition of Gsk3 at the plasma membrane blocks Wnt/beta-catenin signaling. Our results suggest a model that upon Wnt-induced Fz-Lrp6 complex formation, Fz recruitment of Dvl in turn recruits the axin-Gsk3 complex, thereby promoting Lrp6 phosphorylation to initiate beta-catenin signaling. We discuss the dual roles of the axin-Gsk3 complex and signal amplification by Lrp6-axin interaction during Wnt/beta-catenin signaling.

MeSH Terms
Adaptor Proteins, Signal Transducing/chemistry,metabolism Animals Axin Protein Cell Line Cell Membrane/drug effects,metabolism Dishevelled Proteins Embryo, Nonmammalian/cytology,drug effects,metabolism Enzyme Inhibitors/pharmacology Frizzled Receptors/chemistry,metabolism Glycogen Synthase Kinase 3/antagonists & inhibitors Humans Low Density Lipoprotein Receptor-Related Protein-6 Mice Models, Biological Phosphoproteins/chemistry,metabolism Phosphorylation/drug effects Protein Binding/drug effects Protein Structure, Tertiary Receptors, LDL/metabolism Repressor Proteins/metabolism Signal Transduction/drug effects Wnt Proteins/metabolism Xenopus Xenopus Proteins beta Catenin/metabolism
Chemicals
Adaptor Proteins, Signal Transducing Axin Protein DVL1 protein, Xenopus Dishevelled Proteins Enzyme Inhibitors Frizzled Receptors LRP6 protein, human Low Density Lipoprotein Receptor-Related Protein-6 Lrp6 protein, mouse Phosphoproteins Receptors, LDL Repressor Proteins Wnt Proteins Xenopus Proteins axin1 protein, Xenopus beta Catenin Glycogen Synthase Kinase 3
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Zeng Xin
The F. M. Kirby Neurobiology Center, Children's Hospital Boston, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
Huang He
Tamai Keiko
Zhang Xinjun
Harada Yuko
Yokota Chika
Almeida Karla
Wang Jianbo
Doble Brad
Woodgett Jim
Wynshaw-Boris Anthony
Hsieh Jen-Chieh
He Xi
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Article Info
Journal
Development (Cambridge, England)
Abbr.
Development
ISSN
0950-1991
DOI
10.1242/dev.013540
Published
2008-01-00
Epub
2007-00-12
Pages
367-75
Language
English
Region
England
NLM ID
8701744
PMCID
PMC5328672
Subset
IM
Grants
CIHR · 12043 · Canada
NINDS NIH HHS · R01 NS073159 · United States
External Links
PubMed source DOI: 10.1242/dev.013540 PMC Full Text View journal details
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