Abstract
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 NCI 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 co-expression. 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. Agonism is selective for cells expressing RET. The RET binding and the agonistic activities are independent of a co-receptor GFRα which is required by the natural growth factor GDNF. The lead agent protects neurons from death, and in vivo it is effective under conditions where the natural growth factor GDNF is ineffective. This work validates RET receptor as a druggable therapeutic target, and provides for potential leads to evaluate in neurodegenerative states. In addition, we report the potential problems that arise when screening chemical libraries, as a matter of education to the readership.
- Drug development
- Drug discovery
- Neurodegeneration
- Neuroprotection
- Neurotrophic factors
- Receptor tyrosine kinases (RTKs)
- Retina
- Signal transduction networks
- The American Society for Pharmacology and Experimental Therapeutics
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Small-molecule ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by co-receptor GFRα1
