Development of Potent, Selective Surrogate WNT Molecules and Their Application in Defining Frizzled Requirements
| Autor: | Wen-Chen Yeh, Yang Li, Zhong Huang, Asmiti Sura, Darshini Shah, Diksha Bhatia, Haili Zhang, Sung-Jin Lee, Brian Ouyang, Chenggang Lu, Hui Chen |
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| Rok vydání: | 2020 |
| Předmět: |
Frizzled
Clinical Biochemistry Biology Ligands 01 natural sciences Biochemistry Mice Drug Discovery Organoid Animals Wnt Signaling Pathway Molecular Biology LDL-Receptor Related Proteins beta Catenin Tissue homeostasis Pharmacology 010405 organic chemistry Wnt signaling pathway Injury repair Frizzled Receptors 0104 chemical sciences Cell biology Intestines Organoids Wnt Proteins Molecular Medicine Stem cell Multivalent binding Function (biology) |
| Zdroj: | Cell Chemical Biology. 27:598-609.e4 |
| ISSN: | 2451-9456 |
| Popis: | WNTs regulate myriad biological processes during embryonic development and are key regulators of stem cell function, tissue homeostasis, and injury repair in adults. The creation of WNT-based therapies has been hampered by challenges in developing soluble, potent, and selective WNT molecules. Soluble WNT surrogates have been reported, but they demonstrate relatively weak WNT signaling activity. Here, we describe a platform for potent, selective WNT surrogate generation. We identify multivalent binding to Frizzleds (FZDs) and low-density lipoprotein receptor-related proteins (LRPs) to be a requirement for maximal WNT/β-catenin activation. Furthermore, we show that recruitment of two different FZDs together with LRP causes efficient signaling. Surrogate WNT targeting either FZD1,2,7 or FZD5,8 induces expansive growth of intestinal organoids. This flexible WNT surrogate platform yields potent agonists with any desired receptor specificity and will be useful for research and therapeutic applications for tissue regeneration. |
| Databáze: | OpenAIRE |
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