Small-Molecule Ligands that Bind the RET Receptor Activate Neuroprotective Signals Independent of but Modulated by Coreceptor GFR alpha 1

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dc.contributor.author Jmaeff, Sean
dc.contributor.author Sidorova, Yulia
dc.contributor.author Lippiatt, Hayley
dc.contributor.author Barcelona, Pablo F.
dc.contributor.author Nedev, Hinyu
dc.contributor.author Saragovi, Lucia M.
dc.contributor.author Hancock, Mark A.
dc.contributor.author Saarma, Mart
dc.contributor.author Saragovi, H. Uri
dc.date.accessioned 2021-06-30T22:23:55Z
dc.date.available 2021-12-18T03:45:52Z
dc.date.issued 2020-07-01
dc.identifier.citation Jmaeff , S , Sidorova , Y , Lippiatt , H , Barcelona , P F , Nedev , H , Saragovi , L M , Hancock , M A , Saarma , M & Saragovi , H U 2020 , ' Small-Molecule Ligands that Bind the RET Receptor Activate Neuroprotective Signals Independent of but Modulated by Coreceptor GFR alpha 1 ' , Molecular pharmacology : an international journal , vol. 98 , no. 1 , pp. 1-12 . https://doi.org/10.1124/mol.119.118950
dc.identifier.other PURE: 151245102
dc.identifier.other PURE UUID: 70f7c297-e01c-429f-8678-5edc970c950e
dc.identifier.other WOS: 000571818000001
dc.identifier.other ORCID: /0000-0001-5543-7160/work/83843658
dc.identifier.uri http://hdl.handle.net/10138/332075
dc.description.abstract Glial cell line-derived neurotrophic factor (GDNF) binds the GFR alpha 1 receptor, and the GDNF-GFR alpha 1 complex binds to and activates the transmembrane RET tyrosine kinase to signal through intracellular Akt/Erk pathways. To dissect the GDNF-GFR alpha 1-RET signaling complex, agents that bind and activate RET directly and independently of GFR alpha 1 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 GFR alpha 1 coexpression. However, RET activation by these ligands is constrained by GFR alpha 1, 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 a, 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. en
dc.format.extent 12
dc.language.iso eng
dc.relation.ispartof Molecular pharmacology : an international journal
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject NEUROTROPHIC FACTOR GDNF
dc.subject TYROSINE KINASE
dc.subject RAT MODEL
dc.subject FAMILY
dc.subject TRKA
dc.subject GROWTH
dc.subject DEGENERATION
dc.subject NEUROPATHY
dc.subject MECHANISM
dc.subject NEURTURIN
dc.subject 1182 Biochemistry, cell and molecular biology
dc.title Small-Molecule Ligands that Bind the RET Receptor Activate Neuroprotective Signals Independent of but Modulated by Coreceptor GFR alpha 1 en
dc.type Article
dc.contributor.organization Institute of Biotechnology
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1124/mol.119.118950
dc.relation.issn 0026-895X
dc.rights.accesslevel openAccess
dc.type.version acceptedVersion

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