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Development
2008 Jan 01;1352:367-75. 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.
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
.
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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.
Bafico,
Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow.
2001, Pubmed
Bafico,
Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow.
2001,
Pubmed
Baig-Lewis,
Wingless/Wnt signal transduction requires distinct initiation and amplification steps that both depend on Arrow/LRP.
2007,
Pubmed
Behrens,
Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta.
1998,
Pubmed
,
Xenbase
Bilic,
Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation.
2007,
Pubmed
Binnerts,
R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6.
2007,
Pubmed
Bryja,
Beta-arrestin is a necessary component of Wnt/beta-catenin signaling in vitro and in vivo.
2007,
Pubmed
,
Xenbase
Cadigan,
Wnt signaling: complexity at the surface.
2006,
Pubmed
Chia,
Mouse axin and axin2/conductin proteins are functionally equivalent in vivo.
2005,
Pubmed
Clevers,
Wnt/beta-catenin signaling in development and disease.
2006,
Pubmed
Cliffe,
A role of Dishevelled in relocating Axin to the plasma membrane during wingless signaling.
2003,
Pubmed
Cong,
Wnt signals across the plasma membrane to activate the beta-catenin pathway by forming oligomers containing its receptors, Frizzled and LRP.
2004,
Pubmed
Davidson,
Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction.
2005,
Pubmed
,
Xenbase
Doble,
Functional redundancy of GSK-3alpha and GSK-3beta in Wnt/beta-catenin signaling shown by using an allelic series of embryonic stem cell lines.
2007,
Pubmed
Fagotto,
Domains of axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization.
1999,
Pubmed
,
Xenbase
Fujii,
An antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent tumor cell growth.
2007,
Pubmed
Habas,
Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1.
2001,
Pubmed
,
Xenbase
He,
LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way.
2004,
Pubmed
Hedgepeth,
Regulation of glycogen synthase kinase 3beta and downstream Wnt signaling by axin.
1999,
Pubmed
,
Xenbase
Heisenberg,
A mutation in the Gsk3-binding domain of zebrafish Masterblind/Axin1 leads to a fate transformation of telencephalon and eyes to diencephalon.
2001,
Pubmed
Holmen,
Wnt-independent activation of beta-catenin mediated by a Dkk1-Fz5 fusion protein.
2005,
Pubmed
Huang,
The Frizzled family: receptors for multiple signal transduction pathways.
2004,
Pubmed
Jiang,
Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators.
2005,
Pubmed
Khan,
Analysis of endogenous LRP6 function reveals a novel feedback mechanism by which Wnt negatively regulates its receptor.
2007,
Pubmed
Kikuchi,
Modulation of Wnt signaling by Axin and Axil.
1999,
Pubmed
,
Xenbase
Kimelman,
beta-catenin destruction complex: insights and questions from a structural perspective.
2006,
Pubmed
Kishida,
DIX domains of Dvl and axin are necessary for protein interactions and their ability to regulate beta-catenin stability.
1999,
Pubmed
Li,
Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1.
1999,
Pubmed
,
Xenbase
Li,
Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled.
2002,
Pubmed
Liu,
The mechanism of endogenous receptor activation functionally distinguishes prototype canonical and noncanonical Wnts.
2005,
Pubmed
Liu,
Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism.
2002,
Pubmed
,
Xenbase
Logan,
The Wnt signaling pathway in development and disease.
2004,
Pubmed
Mao,
LDL-receptor-related protein 6 is a receptor for Dickkopf proteins.
2001,
Pubmed
,
Xenbase
Pinson,
An LDL-receptor-related protein mediates Wnt signalling in mice.
2000,
Pubmed
Povelones,
Genetic evidence that Drosophila frizzled controls planar cell polarity and Armadillo signaling by a common mechanism.
2005,
Pubmed
Rothbächer,
Dishevelled phosphorylation, subcellular localization and multimerization regulate its role in early embryogenesis.
2000,
Pubmed
,
Xenbase
Salic,
Control of beta-catenin stability: reconstitution of the cytoplasmic steps of the wnt pathway in Xenopus egg extracts.
2000,
Pubmed
,
Xenbase
Schwarz-Romond,
Dynamic recruitment of axin by Dishevelled protein assemblies.
2007,
Pubmed
Schwarz-Romond,
The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization.
2007,
Pubmed
Schweizer,
Wnt/Wingless signaling through beta-catenin requires the function of both LRP/Arrow and frizzled classes of receptors.
2003,
Pubmed
Semënov,
Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6.
2001,
Pubmed
,
Xenbase
Shan,
Identification of a specific inhibitor of the dishevelled PDZ domain.
2005,
Pubmed
,
Xenbase
Smalley,
Interaction of axin and Dvl-2 proteins regulates Dvl-2-stimulated TCF-dependent transcription.
1999,
Pubmed
Tada,
Xwnt11 is a target of Xenopus Brachyury: regulation of gastrulation movements via Dishevelled, but not through the canonical Wnt pathway.
2000,
Pubmed
,
Xenbase
Tamai,
LDL-receptor-related proteins in Wnt signal transduction.
2000,
Pubmed
,
Xenbase
Tamai,
A mechanism for Wnt coreceptor activation.
2004,
Pubmed
,
Xenbase
Tolwinski,
Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/Gsk3beta activity.
2003,
Pubmed
Umbhauer,
The C-terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/beta-catenin signalling.
2000,
Pubmed
,
Xenbase
van de Water,
Ectopic Wnt signal determines the eyeless phenotype of zebrafish masterblind mutant.
2001,
Pubmed
Wallingford,
The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity.
2005,
Pubmed
Wang,
Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation.
2006,
Pubmed
,
Xenbase
Wehrli,
arrow encodes an LDL-receptor-related protein essential for Wingless signalling.
2000,
Pubmed
Wei,
R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling.
2007,
Pubmed
,
Xenbase
Wharton,
Runnin' with the Dvl: proteins that associate with Dsh/Dvl and their significance to Wnt signal transduction.
2003,
Pubmed
Wong,
Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled.
2003,
Pubmed
,
Xenbase
Yamamoto,
Caveolin is necessary for Wnt-3a-dependent internalization of LRP6 and accumulation of beta-catenin.
2006,
Pubmed
Yamamoto,
Shisa promotes head formation through the inhibition of receptor protein maturation for the caudalizing factors, Wnt and FGF.
2005,
Pubmed
,
Xenbase
Yang-Snyder,
A frizzled homolog functions in a vertebrate Wnt signaling pathway.
1996,
Pubmed
,
Xenbase
Zeng,
A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation.
2005,
Pubmed
,
Xenbase
Zeng,
The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation.
1997,
Pubmed
,
Xenbase
Zhang,
Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3.
2003,
Pubmed
