Ret proto-oncogene receptor tyrosine kinase (RET) (RET)

RET is a membrane-spanning receptor tyrosine kinase with a large extracellular domain containing four cadherin-like repeats and a cysteine-rich region, a single-pass transmembrane segment, and an intracellular tyrosine kinase domain. Activation requires binding of glial cell line-derived neurotrophic factor (GDNF) family ligands to GFRα co-receptors, which recruit and dimerize RET in lipid rafts, leading to kinase activation and autophosphorylation. Phosphorylated tyrosines (notably Tyr1062; Tyr1096 in RET51) serve as docking sites to propagate signaling through MAPK/ERK, PI3K/AKT, PLCγ, and other pathways controlling growth, survival, and differentiation. Alternative splicing produces major isoforms RET9 and RET51 with distinct C-termini and signaling features. Germline activating mutations drive MEN2A/2B, while somatic RET fusions act as oncogenic drivers in several cancers; conversely, loss-of-function mutations cause Hirschsprung’s disease.

Other names

Rearranged during transfection (RET)Proto-oncogene protein c-RETRET proto-oncogene receptor tyrosine kinase

ATP-competitive inhibition of the RET intracellular tyrosine kinase domain, blocking autophosphorylation and downstream signaling (e.g., MAPK and PI3K/AKT)