Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wnt/β-Catenin Signaling
Shunfu Piao,Sun-Hye Lee,Hyunjoon Kim,Soohwan Yum,Jennifer L. Stamos,Yongbin Xu,Su-Jin Lee,Jaewon Lee,Sangtaek Oh,Jin-Kwan Han,Bum-Joon Park,William I. Weis,Nam-Chul Ha +12 more
TLDR
It is demonstrated that phosphorylated LRP6/5 both recruits and directly inhibits GSK3β using two distinct portions of its cytoplasmic sequence, and this observation is suggested to suggest a novel mechanism of activation in this signaling pathway.Abstract:
Wnt/β-catenin signaling plays a central role in development and is also involved in a diverse array of diseases. Binding of Wnts to the coreceptors Frizzled and LRP6/5 leads to phosphorylation of PPPSPxS motifs in the LRP6/5 intracellular region and the inhibition of GSK3β bound to the scaffold protein Axin. However, it remains unknown how GSK3β is specifically inhibited upon Wnt stimulation. Here, we show that overexpression of the intracellular region of LRP6 containing a Ser/Thr rich cluster and a PPPSPxS motif impairs the activity of GSK3β in cells. Synthetic peptides containing the PPPSPxS motif strongly inhibit GSK3β in vitro only when they are phosphorylated. Microinjection of these peptides into Xenopus embryos confirms that the phosphorylated PPPSPxS motif potentiates Wnt-induced second body axis formation. In addition, we show that the Ser/Thr rich cluster of LRP6 plays an important role in LRP6 binding to GSK3β. These observations demonstrate that phosphorylated LRP6/5 both recruits and directly inhibits GSK3β using two distinct portions of its cytoplasmic sequence, and suggest a novel mechanism of activation in this signaling pathway.read more
Citations
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Journal ArticleDOI
Wnt/β-catenin signaling: components, mechanisms, and diseases
TL;DR: Some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis are highlighted, and potential therapeutic implications are discussed.
Journal ArticleDOI
The complex world of WNT receptor signalling
TL;DR: What emerges is an intricate network of receptors that form higher-order ligand–receptor complexes routing downstream signalling that is regulated both extracellularly by agonists such as R-spondin and intracellulary by post-translational modifications such as phosphorylation, proteolytic processing and endocytosis.
Journal ArticleDOI
The many faces and functions of β‐catenin
TL;DR: One focus will be the interaction of β‐catenin with different transcription factors and the potential implications of these interactions for direct cross‐talk between β‐ catenin and non‐Wnt signalling pathways.
Journal ArticleDOI
Wnt Signaling through Inhibition of β-Catenin Degradation in an Intact Axin1 Complex
Vivian S. W. Li,Ser Sue Ng,Paul J. Boersema,Teck Yew Low,Wouter R. Karthaus,Jan P. Gerlach,Shabaz Mohammed,Albert J. R. Heck,Madelon M. Maurice,Tokameh Mahmoudi,Tokameh Mahmoudi,Hans Clevers +11 more
TL;DR: The results demonstrate that β-catenin is not only phosphorylated inside the Axin1 complex, but also ubiquinated and degraded via the proteasome, all within an intact Axin 1 complex.
Journal ArticleDOI
GSK3 signalling in neural development
Eun Mi Hur,Feng Quan Zhou +1 more
TL;DR: The mechanisms by which GSK3 activity is regulated in the nervous system are discussed and an overview of the recent advances in the understanding of how G SK3 signalling controls neurogenesis, neuronal polarization and axon growth during brain development is provided.
References
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β‐catenin is a target for the ubiquitin–proteasome pathway
TL;DR: It is shown that ubiquitination of β‐catenin is greatly reduced in Wnt‐expressing cells, providing the first evidence that the ubiquitin–proteasome degradation pathway may act downstream of GSK3β in the regulation ofβ‐ catenin.
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Mechanisms of wnt signaling in development
Andreas Wodarz,Roel Nusse +1 more
TL;DR: Over the past two years the understanding of Wnt signaling has been substantially improved by the identification of Frizzled proteins as cell surface receptors for Wnts and by the finding that beta-catenin, a component downstream of the receptor, can translocate to the nucleus and function as a transcriptional activator.
Journal ArticleDOI
A major developmental transition in early xenopus embryos: I. characterization and timing of cellular changes at the midblastula stage
TL;DR: The Xenopus embryo undergoes 12 rapid synchronous cleavages followed by a period of slower asynchronous divisions more typical of somatic cells, termed the midblastula transition (MBT), which shows that at the MBT the blastomeres become motile and transcriptionally active for the first time.