{"id":4455,"date":"2020-04-27T18:27:14","date_gmt":"2020-04-27T22:27:14","guid":{"rendered":"https:\/\/ccna-ccnv.ca\/ccna_publication\/small-molecule-agonists-of-the-ret-receptor-tyrosine-kinase-activate-biased-trophic-signals-that-are-influenced-by-the-presence-of-gfra1-co-receptors-2\/"},"modified":"2024-12-03T14:56:43","modified_gmt":"2024-12-03T19:56:43","slug":"small-molecule-agonists-of-the-ret-receptor-tyrosine-kinase-activate-biased-trophic-signals-that-are-influenced-by-the-presence-of-gfra1-co-receptors-2","status":"publish","type":"ccna_publication","link":"https:\/\/ccna-ccnv.ca\/fr\/ccna_publication\/small-molecule-agonists-of-the-ret-receptor-tyrosine-kinase-activate-biased-trophic-signals-that-are-influenced-by-the-presence-of-gfra1-co-receptors-2\/","title":{"rendered":"Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors"},"content":{"rendered":"<h3>Abstract<\/h3>\n<div>\n<p>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 alpha 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. \u00a0Here using biochemical techniques, TUNEL 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 (AKT) or extracellular signal-regulated kinase (ERK) 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.<\/p>\n<\/div>\n","protected":false},"author":19,"featured_media":0,"template":"","meta":{"_acf_changed":false},"studies-relation":[],"class_list":["post-4455","ccna_publication","type-ccna_publication","status-publish","hentry"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v28.2 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors - CCNA - CCNV<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/ccna-ccnv.ca\/fr\/ccna_publication\/small-molecule-agonists-of-the-ret-receptor-tyrosine-kinase-activate-biased-trophic-signals-that-are-influenced-by-the-presence-of-gfra1-co-receptors-2\/\" \/>\n<meta property=\"og:locale\" content=\"fr_CA\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"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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