Cargando…
Tailored tetravalent antibodies potently and specifically activate Wnt/Frizzled pathways in cells, organoids and mice
Secreted Wnt proteins regulate development and adult tissue homeostasis by binding and activating cell-surface Frizzled receptors and co-receptors including LRP5/6. The hydrophobicity of Wnt proteins has complicated their purification and limited their use in basic research and as therapeutics. We d...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711705/ https://www.ncbi.nlm.nih.gov/pubmed/31452509 http://dx.doi.org/10.7554/eLife.46134 |
_version_ | 1783446556200927232 |
---|---|
author | Tao, Yuyong Mis, Monika Blazer, Levi Ustav, Mart Steinhart, Zachary Chidiac, Rony Kubarakos, Elli O'Brien, Siobhan Wang, Xiaomei Jarvik, Nick Patel, Nish Adams, Jarrett Moffat, Jason Angers, Stephane Sidhu, Sachdev S |
author_facet | Tao, Yuyong Mis, Monika Blazer, Levi Ustav, Mart Steinhart, Zachary Chidiac, Rony Kubarakos, Elli O'Brien, Siobhan Wang, Xiaomei Jarvik, Nick Patel, Nish Adams, Jarrett Moffat, Jason Angers, Stephane Sidhu, Sachdev S |
author_sort | Tao, Yuyong |
collection | PubMed |
description | Secreted Wnt proteins regulate development and adult tissue homeostasis by binding and activating cell-surface Frizzled receptors and co-receptors including LRP5/6. The hydrophobicity of Wnt proteins has complicated their purification and limited their use in basic research and as therapeutics. We describe modular tetravalent antibodies that can recruit Frizzled and LRP5/6 in a manner that phenocopies the activities of Wnts both in vitro and in vivo. The modular nature of these synthetic Frizzled and LRP5/6 Agonists, called FLAgs, enables tailored engineering of specificity for one, two or multiple members of the Frizzled family. We show that FLAgs underlie differentiation of pluripotent stem cells, sustain organoid growth, and activate stem cells in vivo. Activation of Wnt signaling circuits with tailored FLAgs will enable precise delineation of functional outcomes directed by distinct receptor combinations and could provide a new class of therapeutics to unlock the promise of regenerative medicine. |
format | Online Article Text |
id | pubmed-6711705 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-67117052019-08-30 Tailored tetravalent antibodies potently and specifically activate Wnt/Frizzled pathways in cells, organoids and mice Tao, Yuyong Mis, Monika Blazer, Levi Ustav, Mart Steinhart, Zachary Chidiac, Rony Kubarakos, Elli O'Brien, Siobhan Wang, Xiaomei Jarvik, Nick Patel, Nish Adams, Jarrett Moffat, Jason Angers, Stephane Sidhu, Sachdev S eLife Biochemistry and Chemical Biology Secreted Wnt proteins regulate development and adult tissue homeostasis by binding and activating cell-surface Frizzled receptors and co-receptors including LRP5/6. The hydrophobicity of Wnt proteins has complicated their purification and limited their use in basic research and as therapeutics. We describe modular tetravalent antibodies that can recruit Frizzled and LRP5/6 in a manner that phenocopies the activities of Wnts both in vitro and in vivo. The modular nature of these synthetic Frizzled and LRP5/6 Agonists, called FLAgs, enables tailored engineering of specificity for one, two or multiple members of the Frizzled family. We show that FLAgs underlie differentiation of pluripotent stem cells, sustain organoid growth, and activate stem cells in vivo. Activation of Wnt signaling circuits with tailored FLAgs will enable precise delineation of functional outcomes directed by distinct receptor combinations and could provide a new class of therapeutics to unlock the promise of regenerative medicine. eLife Sciences Publications, Ltd 2019-08-27 /pmc/articles/PMC6711705/ /pubmed/31452509 http://dx.doi.org/10.7554/eLife.46134 Text en © 2019, Tao 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 | Biochemistry and Chemical Biology Tao, Yuyong Mis, Monika Blazer, Levi Ustav, Mart Steinhart, Zachary Chidiac, Rony Kubarakos, Elli O'Brien, Siobhan Wang, Xiaomei Jarvik, Nick Patel, Nish Adams, Jarrett Moffat, Jason Angers, Stephane Sidhu, Sachdev S Tailored tetravalent antibodies potently and specifically activate Wnt/Frizzled pathways in cells, organoids and mice |
title | Tailored tetravalent antibodies potently and specifically activate Wnt/Frizzled pathways in cells, organoids and mice |
title_full | Tailored tetravalent antibodies potently and specifically activate Wnt/Frizzled pathways in cells, organoids and mice |
title_fullStr | Tailored tetravalent antibodies potently and specifically activate Wnt/Frizzled pathways in cells, organoids and mice |
title_full_unstemmed | Tailored tetravalent antibodies potently and specifically activate Wnt/Frizzled pathways in cells, organoids and mice |
title_short | Tailored tetravalent antibodies potently and specifically activate Wnt/Frizzled pathways in cells, organoids and mice |
title_sort | tailored tetravalent antibodies potently and specifically activate wnt/frizzled pathways in cells, organoids and mice |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711705/ https://www.ncbi.nlm.nih.gov/pubmed/31452509 http://dx.doi.org/10.7554/eLife.46134 |
work_keys_str_mv | AT taoyuyong tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT mismonika tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT blazerlevi tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT ustavmart tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT steinhartzachary tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT chidiacrony tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT kubarakoselli tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT obriensiobhan tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT wangxiaomei tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT jarviknick tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT patelnish tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT adamsjarrett tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT moffatjason tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT angersstephane tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice AT sidhusachdevs tailoredtetravalentantibodiespotentlyandspecificallyactivatewntfrizzledpathwaysincellsorganoidsandmice |