RET receptor tyrosine kinase architecture, assemblies, and activation

Among the 58 human receptor tyrosine kinases that are known, only the RET (REarrangement during Transfection) receptor contains cadherin-like domains in its extracellular portion. This multidomain extracellular module contains a binding site for a family of five related heterodimeric ligands. Each heterodimer comprises a secreted glial cell line-derived neurotrophic factor (GDNF) family ligand (GFL) and a membrane-anchored co-receptor GFR⍺ (GDNF family receptor alpha). Once a GFL-GFR⍺ ligand is bound to RET, this stimulates the activation of the receptor through tyrosine-based autophosphorylation. This mini review explores how the shape and architecture of RET encode a flexible GFL-GFR⍺-binding site, summarising recent progress in understanding RET structure. It then discusses current views on how distinct assemblies of GFL-GFR⍺-RET receptor complexes are able to activate the intrinsic RET tyrosine kinase function to relay intracellular signals.