RET Receptor

The REarranged during Transfection (RET) receptor protein is a single-pass transmembrane receptor tyrosine kinase that is encoded by RET proto-oncogene. RET can transduce signalling by ligands of the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophins which currently comprises GDNF, neuturin (NTN) , artemin (ART) and persephin (PSP). GDNF, NRTN, ARTN and PSP can bind to and specifically activate RET through their cognate co-receptors GFRα1-4, respectively. The signal transduction by RET activates several second messenger systems including the Raf/Mek/ERK1/2, PI3K/Akt, PLCY, Ras, JNK and inositol phosphate pathways. The RET protein is composed of three domains: an extracellular ligand-binding domain, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. The extracellular domain contains four cadherin-like repeats as well as a highly conserved cysteine-rich region. The cysteine-rich region is important for tertiary structure and dimerization through disulfide bond formation. 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. 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.