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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...

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Autores principales: 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
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
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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.
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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
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