Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1

Autores
Jmaeff, Sean; Sidorova, Yulia; Lippiatt, Hayley; Barcelona, Pablo Federico; Nedev, Hinyu; Saragovi, Lucia M.; Hancock, Mark A.; Saarma, Mart; Saragovi, H. Uri
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Glial cell line-derived neurotrophic factor (GDNF) binds the GFRα1 receptor, and the GDNF-GFRα1 complex binds to and activates the transmembrane RET tyrosine kinase to signal through intracellular Akt/Erk pathways. To dissect the GDNF-GFRα1-RET signaling complex, agents that bind and activate RET directly and independently of GFRα1 expression are valuable tools. In a focused naphthalenesulfonic acid library from the National Cancer Institute database, we identified small molecules that are genuine ligands binding to the RET extracellular domain. These ligands activate RET tyrosine kinase and afford trophic signals irrespective of GFRα1 coexpression. However, RET activation by these ligands is constrained by GFRα1, likely via an allosteric mechanism that can be overcome by increasing RET ligand concentration. In a mouse model of retinitis pigmentosa, monotherapy with a small-molecule RET agonist activates survival signals and reduces neuronal death significantly better than GDNF, suggesting therapeutic potential. SIGNIFICANCE STATEMENT: A genuine ligand of RET receptor ectodomain was identified, which acts as an agonist. Binding and agonism are independent of a coreceptor glial cell line-derived neurotrophic factor family receptor α, which is required by the natural growth factor glial cell line-derived neurotrophic factor, and are selective for cells expressing RET. The lead agent protects neurons from death in vivo. This work validates RET receptor as a druggable therapeutic target and provides for potential leads to evaluate in neurodegenerative states. We also report problems that arise when screening chemical libraries.
Fil: Jmaeff, Sean. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Sidorova, Yulia. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Lippiatt, Hayley. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Nedev, Hinyu. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Saragovi, Lucia M.. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Hancock, Mark A.. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Saarma, Mart. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; Canadá
Materia
GFR α 1
RET Receptor Activate Neuroprotective
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/158914
Acceder
id CONICETDig_5760f42b5cea7449aa2278b5df4477bd
oai_identifier_str oai:ri.conicet.gov.ar:11336/158914
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1Jmaeff, SeanSidorova, YuliaLippiatt, HayleyBarcelona, Pablo FedericoNedev, HinyuSaragovi, Lucia M.Hancock, Mark A.Saarma, MartSaragovi, H. UriGFR α 1RET Receptor Activate Neuroprotectivehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Glial cell line-derived neurotrophic factor (GDNF) binds the GFRα1 receptor, and the GDNF-GFRα1 complex binds to and activates the transmembrane RET tyrosine kinase to signal through intracellular Akt/Erk pathways. To dissect the GDNF-GFRα1-RET signaling complex, agents that bind and activate RET directly and independently of GFRα1 expression are valuable tools. In a focused naphthalenesulfonic acid library from the National Cancer Institute database, we identified small molecules that are genuine ligands binding to the RET extracellular domain. These ligands activate RET tyrosine kinase and afford trophic signals irrespective of GFRα1 coexpression. However, RET activation by these ligands is constrained by GFRα1, likely via an allosteric mechanism that can be overcome by increasing RET ligand concentration. In a mouse model of retinitis pigmentosa, monotherapy with a small-molecule RET agonist activates survival signals and reduces neuronal death significantly better than GDNF, suggesting therapeutic potential. SIGNIFICANCE STATEMENT: A genuine ligand of RET receptor ectodomain was identified, which acts as an agonist. Binding and agonism are independent of a coreceptor glial cell line-derived neurotrophic factor family receptor α, which is required by the natural growth factor glial cell line-derived neurotrophic factor, and are selective for cells expressing RET. The lead agent protects neurons from death in vivo. This work validates RET receptor as a druggable therapeutic target and provides for potential leads to evaluate in neurodegenerative states. We also report problems that arise when screening chemical libraries.Fil: Jmaeff, Sean. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Sidorova, Yulia. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Lippiatt, Hayley. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Nedev, Hinyu. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Saragovi, Lucia M.. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Hancock, Mark A.. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Saarma, Mart. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; CanadáAmerican Society for Pharmacology and Experimental Therapeutics2020-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/158914Jmaeff, Sean; Sidorova, Yulia; Lippiatt, Hayley; Barcelona, Pablo Federico; Nedev, Hinyu; et al.; Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 98; 1; 8-2020; 1-120026-895X1521-0111CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1124/mol.119.118950info:eu-repo/semantics/altIdentifier/url/https://molpharm.aspetjournals.org/content/98/1/1info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:50:23Zoai:ri.conicet.gov.ar:11336/158914instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:50:24.458CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1
title Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1
spellingShingle Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1
Jmaeff, Sean
GFR α 1
RET Receptor Activate Neuroprotective
title_short Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1
title_full Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1
title_fullStr Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1
title_full_unstemmed Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1
title_sort Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1
dc.creator.none.fl_str_mv Jmaeff, Sean
Sidorova, Yulia
Lippiatt, Hayley
Barcelona, Pablo Federico
Nedev, Hinyu
Saragovi, Lucia M.
Hancock, Mark A.
Saarma, Mart
Saragovi, H. Uri
author Jmaeff, Sean
author_facet Jmaeff, Sean
Sidorova, Yulia
Lippiatt, Hayley
Barcelona, Pablo Federico
Nedev, Hinyu
Saragovi, Lucia M.
Hancock, Mark A.
Saarma, Mart
Saragovi, H. Uri
author_role author
author2 Sidorova, Yulia
Lippiatt, Hayley
Barcelona, Pablo Federico
Nedev, Hinyu
Saragovi, Lucia M.
Hancock, Mark A.
Saarma, Mart
Saragovi, H. Uri
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv GFR α 1
RET Receptor Activate Neuroprotective
topic GFR α 1
RET Receptor Activate Neuroprotective
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Glial cell line-derived neurotrophic factor (GDNF) binds the GFRα1 receptor, and the GDNF-GFRα1 complex binds to and activates the transmembrane RET tyrosine kinase to signal through intracellular Akt/Erk pathways. To dissect the GDNF-GFRα1-RET signaling complex, agents that bind and activate RET directly and independently of GFRα1 expression are valuable tools. In a focused naphthalenesulfonic acid library from the National Cancer Institute database, we identified small molecules that are genuine ligands binding to the RET extracellular domain. These ligands activate RET tyrosine kinase and afford trophic signals irrespective of GFRα1 coexpression. However, RET activation by these ligands is constrained by GFRα1, likely via an allosteric mechanism that can be overcome by increasing RET ligand concentration. In a mouse model of retinitis pigmentosa, monotherapy with a small-molecule RET agonist activates survival signals and reduces neuronal death significantly better than GDNF, suggesting therapeutic potential. SIGNIFICANCE STATEMENT: A genuine ligand of RET receptor ectodomain was identified, which acts as an agonist. Binding and agonism are independent of a coreceptor glial cell line-derived neurotrophic factor family receptor α, which is required by the natural growth factor glial cell line-derived neurotrophic factor, and are selective for cells expressing RET. The lead agent protects neurons from death in vivo. This work validates RET receptor as a druggable therapeutic target and provides for potential leads to evaluate in neurodegenerative states. We also report problems that arise when screening chemical libraries.
Fil: Jmaeff, Sean. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Sidorova, Yulia. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Lippiatt, Hayley. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Nedev, Hinyu. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Saragovi, Lucia M.. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Hancock, Mark A.. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Saarma, Mart. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; Canadá
description Glial cell line-derived neurotrophic factor (GDNF) binds the GFRα1 receptor, and the GDNF-GFRα1 complex binds to and activates the transmembrane RET tyrosine kinase to signal through intracellular Akt/Erk pathways. To dissect the GDNF-GFRα1-RET signaling complex, agents that bind and activate RET directly and independently of GFRα1 expression are valuable tools. In a focused naphthalenesulfonic acid library from the National Cancer Institute database, we identified small molecules that are genuine ligands binding to the RET extracellular domain. These ligands activate RET tyrosine kinase and afford trophic signals irrespective of GFRα1 coexpression. However, RET activation by these ligands is constrained by GFRα1, likely via an allosteric mechanism that can be overcome by increasing RET ligand concentration. In a mouse model of retinitis pigmentosa, monotherapy with a small-molecule RET agonist activates survival signals and reduces neuronal death significantly better than GDNF, suggesting therapeutic potential. SIGNIFICANCE STATEMENT: A genuine ligand of RET receptor ectodomain was identified, which acts as an agonist. Binding and agonism are independent of a coreceptor glial cell line-derived neurotrophic factor family receptor α, which is required by the natural growth factor glial cell line-derived neurotrophic factor, and are selective for cells expressing RET. The lead agent protects neurons from death in vivo. This work validates RET receptor as a druggable therapeutic target and provides for potential leads to evaluate in neurodegenerative states. We also report problems that arise when screening chemical libraries.
publishDate 2020
dc.date.none.fl_str_mv 2020-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/158914
Jmaeff, Sean; Sidorova, Yulia; Lippiatt, Hayley; Barcelona, Pablo Federico; Nedev, Hinyu; et al.; Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 98; 1; 8-2020; 1-12
0026-895X
1521-0111
CONICET Digital
CONICET
url http://hdl.handle.net/11336/158914
identifier_str_mv Jmaeff, Sean; Sidorova, Yulia; Lippiatt, Hayley; Barcelona, Pablo Federico; Nedev, Hinyu; et al.; Small-Molecule Ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by coreceptor GFR α 1; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 98; 1; 8-2020; 1-12
0026-895X
1521-0111
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1124/mol.119.118950
info:eu-repo/semantics/altIdentifier/url/https://molpharm.aspetjournals.org/content/98/1/1
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Pharmacology and Experimental Therapeutics
publisher.none.fl_str_mv American Society for Pharmacology and Experimental Therapeutics
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842269028264968192
score 13.13397

Publicaciones similares