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First published online 12 December 2007
doi: 10.1242/dev.013540

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

Xin Zeng^1,*, He Huang^1,*, Keiko Tamai^1,, Xinjun Zhang¹, Yuko Harada¹, Chika Yokota¹, Karla Almeida¹, Jianbo Wang², Brad Doble³, Jim Woodgett³, Anthony Wynshaw-Boris², Jen-Chieh Hsieh⁴ and Xi He^1,

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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				X. Zeng, H. Huang, K. Tamai, X. Zhang, Y. Harada, C. Yokota, K. Almeida, J. Wang, B. Doble, J. Woodgett, et al. Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions J. Cell Sci., January 15, 2008; 121(2): e1 - e1. [Full Text]