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First published online 12 December 2007
doi: 10.1242/dev.013540
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1 The F. M. Kirby Neurobiology Center, Children's Hospital Boston, Department of
Neurology, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Pediatrics and Medicine, University of California, San Diego, La
Jolla, CA 92093-0627, USA.
3 Samuel Lunenfeld Research Institute, 600 University Avenue, Toronto, Ontario,
M5G 1X5, Canada.
4 Department of Biochemistry and Cell Biology, Center for Developmental
Genetics, State University of New York, Stony Brook, Stony Brook, NY 11794,
USA.
Author for correspondence (e-mail:
xi.he{at}childrens.harvard.edu)
Accepted 15 October 2007
Canonical Wnt/β-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/β-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/β-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 β-catenin signaling. We discuss the dual roles of the axin-Gsk3 complex and signal amplification by Lrp6-axin interaction during Wnt/β-catenin signaling.
Key words: Axin, Dishevelled, Frizzled, Gsk3, Lrp6, Wnt
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