Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors

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Jmaeff , S , Sidorova , Y , Nedev , H , Saarma , M & Saragovi , H U 2020 , ' Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors ' , Journal of Biological Chemistry , vol. 295 , no. 19 , pp. 6532-6542 . https://doi.org/10.1074/jbc.RA119.011802

Title: Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors
Author: Jmaeff, Sean; Sidorova, Yulia; Nedev, Hinyu; Saarma, Mart; Saragovi, H. Uri
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
Date: 2020-05-08
Language: eng
Number of pages: 11
Belongs to series: Journal of Biological Chemistry
ISSN: 0021-9258
URI: http://hdl.handle.net/10138/327047
Abstract: Glial cell line?derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor ?1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET?GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development.
Subject: receptor tyrosine kinase
signal transduction
small molecule
ligand-binding protein
retinal degeneration
structure?function
biased agonist
naphthoquinone
neuroprotection
RET receptor
retinitis pigmentosa
NEUROTROPHIC FACTOR
NEURONAL SURVIVAL
GDNF
GFR-ALPHA-1
EXPRESSION
RHODOPSIN
MECHANISM
BINDING
MICE
1182 Biochemistry, cell and molecular biology
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