Neurotrophic factor receptor RET: structure, cell biology, and inherited diseases

RET (REarranged during Transfection) is a transmembrane receptor tyrosine kinase that is activated by a complex consisting of a soluble glial cell line-derived neurotrophic factor (GDNF) family ligand (GFL) and a glycosyl phosphatidylinositol-anchored co-receptor, GDNF family receptors alpha (GFR alpha). RET signalling is crucial for the development of the enteric nervous system. RET also regulates the development of sympathetic, parasympathetic, motor, and sensory neurons, and is necessary for the postnatal maintenance of dopaminergic neurons. The effect of GFLs on sensory, motor, and dopaminergic neurons has raised clinical interest towards these ligands. Outside the nervous system, RET is crucial for development of the kidney and plays a key role in spermatogenesis. Inactivating mutations in RET cause the Hirschsprung's disease characterized by megacolon aganglionosis. In contrast, activating mutations give rise to different types of cancer, multiple endocrine neoplasia type 2A and type 2B, familial medullary thyroid carcinoma, and papillary thyroid carcinoma. The multiple disease phenotypes correlate with differences in the molecular and cell biological functions of different oncogenic RET proteins. In this review we summarize how the different domains of the RET protein contribute to its normal function and how mutations in these domains affect the function of the receptor.