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Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wnt/β-Catenin Signaling

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 prot...

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Autores principales: Piao, Shunfu, Lee, Sun-Hye, Kim, Hyunjoon, Yum, Soohwan, Stamos, Jennifer L., Xu, Yongbin, Lee, Su-Jin, Lee, Jaewon, Oh, Sangtaek, Han, Jin-Kwan, Park, Bum-Joon, Weis, William I., Ha, Nam-Chul
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603313/
https://www.ncbi.nlm.nih.gov/pubmed/19107203
http://dx.doi.org/10.1371/journal.pone.0004046
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author Piao, Shunfu
Lee, Sun-Hye
Kim, Hyunjoon
Yum, Soohwan
Stamos, Jennifer L.
Xu, Yongbin
Lee, Su-Jin
Lee, Jaewon
Oh, Sangtaek
Han, Jin-Kwan
Park, Bum-Joon
Weis, William I.
Ha, Nam-Chul
author_facet Piao, Shunfu
Lee, Sun-Hye
Kim, Hyunjoon
Yum, Soohwan
Stamos, Jennifer L.
Xu, Yongbin
Lee, Su-Jin
Lee, Jaewon
Oh, Sangtaek
Han, Jin-Kwan
Park, Bum-Joon
Weis, William I.
Ha, Nam-Chul
author_sort Piao, Shunfu
collection PubMed
description 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.
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spelling pubmed-26033132008-12-24 Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wnt/β-Catenin Signaling Piao, Shunfu Lee, Sun-Hye Kim, Hyunjoon Yum, Soohwan Stamos, Jennifer L. Xu, Yongbin Lee, Su-Jin Lee, Jaewon Oh, Sangtaek Han, Jin-Kwan Park, Bum-Joon Weis, William I. Ha, Nam-Chul PLoS One Research Article 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. Public Library of Science 2008-12-24 /pmc/articles/PMC2603313/ /pubmed/19107203 http://dx.doi.org/10.1371/journal.pone.0004046 Text en Piao et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Piao, Shunfu
Lee, Sun-Hye
Kim, Hyunjoon
Yum, Soohwan
Stamos, Jennifer L.
Xu, Yongbin
Lee, Su-Jin
Lee, Jaewon
Oh, Sangtaek
Han, Jin-Kwan
Park, Bum-Joon
Weis, William I.
Ha, Nam-Chul
Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wnt/β-Catenin Signaling
title Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wnt/β-Catenin Signaling
title_full Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wnt/β-Catenin Signaling
title_fullStr Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wnt/β-Catenin Signaling
title_full_unstemmed Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wnt/β-Catenin Signaling
title_short Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wnt/β-Catenin Signaling
title_sort direct inhibition of gsk3β by the phosphorylated cytoplasmic domain of lrp6 in wnt/β-catenin signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603313/
https://www.ncbi.nlm.nih.gov/pubmed/19107203
http://dx.doi.org/10.1371/journal.pone.0004046
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