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

SEAN JMAEFF; YULIA SIDOROVA; HAYLEY LIPPIATT; BARCELONA, PF; HINYU NEDEV; LUCIA M. SARAGOVI; MARK A. HANCOCK; MART SAARMA; H. URI SARAGOVI

MOLECULAR PHARMACOLOGY

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Lugar: Baltimore; Año: 2020

0026-895X

lial 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 signific