Cargando…

Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling

Negatively regulating signaling by targeting key effectors for ubiquitina­tion/destruction is essential for development and oncogenesis. The tumor suppressor adenomatous polyposis coli (APC), an essential negative regulator of Wnt signaling, provides a paradigm. APC mutations occur in most colon can...

Descripción completa

Detalles Bibliográficos
Autores principales: Roberts, David M., Pronobis, Mira I., Poulton, John S., Waldmann, Jon D., Stephenson, Elise M., Hanna, Shahnaz, Peifer, Mark
Formato: Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103401/
https://www.ncbi.nlm.nih.gov/pubmed/21471006
http://dx.doi.org/10.1091/mbc.E10-11-0871
_version_ 1782204505849331712
author Roberts, David M.
Pronobis, Mira I.
Poulton, John S.
Waldmann, Jon D.
Stephenson, Elise M.
Hanna, Shahnaz
Peifer, Mark
author_facet Roberts, David M.
Pronobis, Mira I.
Poulton, John S.
Waldmann, Jon D.
Stephenson, Elise M.
Hanna, Shahnaz
Peifer, Mark
author_sort Roberts, David M.
collection PubMed
description Negatively regulating signaling by targeting key effectors for ubiquitina­tion/destruction is essential for development and oncogenesis. The tumor suppressor adenomatous polyposis coli (APC), an essential negative regulator of Wnt signaling, provides a paradigm. APC mutations occur in most colon cancers. Acting in the “destruction complex” with Axin, glycogen synthase kinase 3, and casein kinase, APC targets ßcatenin (ßcat) for phosphorylation and recognition by an E3 ubiquitin-ligase. Despite 20 years of work, the internal workings of the destruction complex and APC's role remain largely mysterious. We use both Drosophila and colon cancer cells to test hypotheses for APC's mechanism of action. Our data are inconsistent with current models suggesting that high-affinity ßcat-binding sites on APC play key roles. Instead, they suggest that multiple ßcat-binding sites act additively to fine-tune signaling via cytoplasmic retention. We identify essential roles for two putative binding sites for new partners—20-amino-acid repeat 2 and conserved sequence B—in destruction complex action. Finally, we demonstrate that APC interacts with Axin by two different modes and provide evidence that conserved sequence B helps ensure release of APC from Axin, with disassembly critical in regulating ßcat levels. Using these data, we suggest a new model for destruction complex action in development, which also provides new insights into functions of truncated APC proteins in cancer.
format Text
id pubmed-3103401
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher The American Society for Cell Biology
record_format MEDLINE/PubMed
spelling pubmed-31034012011-08-16 Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling Roberts, David M. Pronobis, Mira I. Poulton, John S. Waldmann, Jon D. Stephenson, Elise M. Hanna, Shahnaz Peifer, Mark Mol Biol Cell Articles Negatively regulating signaling by targeting key effectors for ubiquitina­tion/destruction is essential for development and oncogenesis. The tumor suppressor adenomatous polyposis coli (APC), an essential negative regulator of Wnt signaling, provides a paradigm. APC mutations occur in most colon cancers. Acting in the “destruction complex” with Axin, glycogen synthase kinase 3, and casein kinase, APC targets ßcatenin (ßcat) for phosphorylation and recognition by an E3 ubiquitin-ligase. Despite 20 years of work, the internal workings of the destruction complex and APC's role remain largely mysterious. We use both Drosophila and colon cancer cells to test hypotheses for APC's mechanism of action. Our data are inconsistent with current models suggesting that high-affinity ßcat-binding sites on APC play key roles. Instead, they suggest that multiple ßcat-binding sites act additively to fine-tune signaling via cytoplasmic retention. We identify essential roles for two putative binding sites for new partners—20-amino-acid repeat 2 and conserved sequence B—in destruction complex action. Finally, we demonstrate that APC interacts with Axin by two different modes and provide evidence that conserved sequence B helps ensure release of APC from Axin, with disassembly critical in regulating ßcat levels. Using these data, we suggest a new model for destruction complex action in development, which also provides new insights into functions of truncated APC proteins in cancer. The American Society for Cell Biology 2011-06-01 /pmc/articles/PMC3103401/ /pubmed/21471006 http://dx.doi.org/10.1091/mbc.E10-11-0871 Text en © 2011 Roberts et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB”, “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Roberts, David M.
Pronobis, Mira I.
Poulton, John S.
Waldmann, Jon D.
Stephenson, Elise M.
Hanna, Shahnaz
Peifer, Mark
Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling
title Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling
title_full Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling
title_fullStr Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling
title_full_unstemmed Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling
title_short Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling
title_sort deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor apc in regulating wnt signaling
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103401/
https://www.ncbi.nlm.nih.gov/pubmed/21471006
http://dx.doi.org/10.1091/mbc.E10-11-0871
work_keys_str_mv AT robertsdavidm deconstructingtheßcatenindestructioncomplexmechanisticrolesforthetumorsuppressorapcinregulatingwntsignaling
AT pronobismirai deconstructingtheßcatenindestructioncomplexmechanisticrolesforthetumorsuppressorapcinregulatingwntsignaling
AT poultonjohns deconstructingtheßcatenindestructioncomplexmechanisticrolesforthetumorsuppressorapcinregulatingwntsignaling
AT waldmannjond deconstructingtheßcatenindestructioncomplexmechanisticrolesforthetumorsuppressorapcinregulatingwntsignaling
AT stephensonelisem deconstructingtheßcatenindestructioncomplexmechanisticrolesforthetumorsuppressorapcinregulatingwntsignaling
AT hannashahnaz deconstructingtheßcatenindestructioncomplexmechanisticrolesforthetumorsuppressorapcinregulatingwntsignaling
AT peifermark deconstructingtheßcatenindestructioncomplexmechanisticrolesforthetumorsuppressorapcinregulatingwntsignaling