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Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist
The development of MET receptor agonists is an important goal in regenerative medicine, but is limited by the complexity and incomplete understanding of its interaction with HGF/SF (Hepatocyte Growth Factor/Scatter Factor). NK1 is a natural occurring agonist comprising the N-terminal (N) and the fir...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496502/ https://www.ncbi.nlm.nih.gov/pubmed/28717459 http://dx.doi.org/10.1039/c4sc03856h |
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author | Simonneau, Claire Bérénice Leclercq, Mougel, Alexandra Adriaenssens, Eric Paquet, Charlotte Raibaut, Laurent Ollivier, Nathalie Drobecq, Hervé Marcoux, Julien Cianférani, Sarah Tulasne, David de Jonge, Hugo Melnyk, Oleg Vicogne, Jérôme |
author_facet | Simonneau, Claire Bérénice Leclercq, Mougel, Alexandra Adriaenssens, Eric Paquet, Charlotte Raibaut, Laurent Ollivier, Nathalie Drobecq, Hervé Marcoux, Julien Cianférani, Sarah Tulasne, David de Jonge, Hugo Melnyk, Oleg Vicogne, Jérôme |
author_sort | Simonneau, Claire |
collection | PubMed |
description | The development of MET receptor agonists is an important goal in regenerative medicine, but is limited by the complexity and incomplete understanding of its interaction with HGF/SF (Hepatocyte Growth Factor/Scatter Factor). NK1 is a natural occurring agonist comprising the N-terminal (N) and the first kringle (K1) domains of HGF/SF. In the presence of heparin, NK1 can self-associate into a “head to tail” dimer which is considered as the minimal structural module able to trigger MET dimerization and activation whereas isolated K1 and N domains showed a weak or a complete lack of agonistic activity respectively. Starting from these structural and biological observations, we investigated whether it was possible to recapitulate the biological properties of NK1 using a new molecular architecture of isolated N or K1 domains. Therefore, we engineered multivalent N or K1 scaffolds by combining synthetic and homogeneous site-specifically biotinylated N and K1 domains (NB and K1B) and streptavidin (S). NB alone or in complex failed to activate MET signaling and to trigger cellular phenotypes. Importantly and to the contrary of K1B alone, the semi-synthetic K1B/S complex mimicked NK1 MET agonist activity in cell scattering, morphogenesis and survival phenotypic assays. Impressively, K1B/S complex stimulated in vivo angiogenesis and, when injected in mice, protected the liver against fulminant hepatitis in a MET dependent manner whereas NK1 and HGF were substantially less potent. These data reveal that without N domain, proper multimerization of K1 domain is a promising strategy for the rational design of powerful MET agonists. |
format | Online Article Text |
id | pubmed-5496502 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-54965022017-07-17 Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist Simonneau, Claire Bérénice Leclercq, Mougel, Alexandra Adriaenssens, Eric Paquet, Charlotte Raibaut, Laurent Ollivier, Nathalie Drobecq, Hervé Marcoux, Julien Cianférani, Sarah Tulasne, David de Jonge, Hugo Melnyk, Oleg Vicogne, Jérôme Chem Sci Chemistry The development of MET receptor agonists is an important goal in regenerative medicine, but is limited by the complexity and incomplete understanding of its interaction with HGF/SF (Hepatocyte Growth Factor/Scatter Factor). NK1 is a natural occurring agonist comprising the N-terminal (N) and the first kringle (K1) domains of HGF/SF. In the presence of heparin, NK1 can self-associate into a “head to tail” dimer which is considered as the minimal structural module able to trigger MET dimerization and activation whereas isolated K1 and N domains showed a weak or a complete lack of agonistic activity respectively. Starting from these structural and biological observations, we investigated whether it was possible to recapitulate the biological properties of NK1 using a new molecular architecture of isolated N or K1 domains. Therefore, we engineered multivalent N or K1 scaffolds by combining synthetic and homogeneous site-specifically biotinylated N and K1 domains (NB and K1B) and streptavidin (S). NB alone or in complex failed to activate MET signaling and to trigger cellular phenotypes. Importantly and to the contrary of K1B alone, the semi-synthetic K1B/S complex mimicked NK1 MET agonist activity in cell scattering, morphogenesis and survival phenotypic assays. Impressively, K1B/S complex stimulated in vivo angiogenesis and, when injected in mice, protected the liver against fulminant hepatitis in a MET dependent manner whereas NK1 and HGF were substantially less potent. These data reveal that without N domain, proper multimerization of K1 domain is a promising strategy for the rational design of powerful MET agonists. Royal Society of Chemistry 2015-03-01 2015-01-29 /pmc/articles/PMC5496502/ /pubmed/28717459 http://dx.doi.org/10.1039/c4sc03856h Text en This journal is © The Royal Society of Chemistry 2015 http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Chemistry Simonneau, Claire Bérénice Leclercq, Mougel, Alexandra Adriaenssens, Eric Paquet, Charlotte Raibaut, Laurent Ollivier, Nathalie Drobecq, Hervé Marcoux, Julien Cianférani, Sarah Tulasne, David de Jonge, Hugo Melnyk, Oleg Vicogne, Jérôme Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist |
title | Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist
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title_full | Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist
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title_fullStr | Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist
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title_full_unstemmed | Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist
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title_short | Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist
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title_sort | semi-synthesis of a hgf/sf kringle one (k1) domain scaffold generates a potent in vivo met receptor agonist |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496502/ https://www.ncbi.nlm.nih.gov/pubmed/28717459 http://dx.doi.org/10.1039/c4sc03856h |
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