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Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development

The molecular basis of Wnt-Frizzled specificity is a central question in developmental biology. Reck, a multi-domain and multi-functional glycosylphosphatidylinositol-anchored protein, specifically enhances beta-catenin signaling by Wnt7a and Wnt7b in cooperation with the 7-transmembrane protein Gpr...

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Autores principales: Cho, Chris, Wang, Yanshu, Smallwood, Philip M, Williams, John, Nathans, Jeremy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588345/
https://www.ncbi.nlm.nih.gov/pubmed/31225798
http://dx.doi.org/10.7554/eLife.47300
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author Cho, Chris
Wang, Yanshu
Smallwood, Philip M
Williams, John
Nathans, Jeremy
author_facet Cho, Chris
Wang, Yanshu
Smallwood, Philip M
Williams, John
Nathans, Jeremy
author_sort Cho, Chris
collection PubMed
description The molecular basis of Wnt-Frizzled specificity is a central question in developmental biology. Reck, a multi-domain and multi-functional glycosylphosphatidylinositol-anchored protein, specifically enhances beta-catenin signaling by Wnt7a and Wnt7b in cooperation with the 7-transmembrane protein Gpr124. Among amino acids that distinguish Wnt7a and Wnt7b from other Wnts, two clusters are essential for signaling in a Reck- and Gpr124-dependent manner. Both clusters are far from the site of Frizzled binding: one resides at the amino terminus and the second resides in a protruding loop. Within Reck, the fourth of five tandem repeats of an unusual domain with six-cysteines (the CC domain) is essential for Wnt7a stimulation: substitutions P256A and W261A in CC4 eliminate this activity without changing protein abundance or surface localization. Mouse embryos carrying Reck(P256A,W261A) have severe defects in forebrain angiogenesis, providing the strongest evidence to date that Reck promotes CNS angiogenesis by specifically stimulating Wnt7a and Wnt7b signaling.
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spelling pubmed-65883452019-06-24 Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development Cho, Chris Wang, Yanshu Smallwood, Philip M Williams, John Nathans, Jeremy eLife Developmental Biology The molecular basis of Wnt-Frizzled specificity is a central question in developmental biology. Reck, a multi-domain and multi-functional glycosylphosphatidylinositol-anchored protein, specifically enhances beta-catenin signaling by Wnt7a and Wnt7b in cooperation with the 7-transmembrane protein Gpr124. Among amino acids that distinguish Wnt7a and Wnt7b from other Wnts, two clusters are essential for signaling in a Reck- and Gpr124-dependent manner. Both clusters are far from the site of Frizzled binding: one resides at the amino terminus and the second resides in a protruding loop. Within Reck, the fourth of five tandem repeats of an unusual domain with six-cysteines (the CC domain) is essential for Wnt7a stimulation: substitutions P256A and W261A in CC4 eliminate this activity without changing protein abundance or surface localization. Mouse embryos carrying Reck(P256A,W261A) have severe defects in forebrain angiogenesis, providing the strongest evidence to date that Reck promotes CNS angiogenesis by specifically stimulating Wnt7a and Wnt7b signaling. eLife Sciences Publications, Ltd 2019-06-21 /pmc/articles/PMC6588345/ /pubmed/31225798 http://dx.doi.org/10.7554/eLife.47300 Text en © 2019, Cho et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Developmental Biology
Cho, Chris
Wang, Yanshu
Smallwood, Philip M
Williams, John
Nathans, Jeremy
Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development
title Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development
title_full Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development
title_fullStr Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development
title_full_unstemmed Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development
title_short Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development
title_sort molecular determinants in frizzled, reck, and wnt7a for ligand-specific signaling in neurovascular development
topic Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588345/
https://www.ncbi.nlm.nih.gov/pubmed/31225798
http://dx.doi.org/10.7554/eLife.47300
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