The RET proto-oncogene on human chromosome 10q11.2, encodes a receptor tyrosine kinase (RTK) activated by members of the glial cell line-derived neurotrophic factor (GDNF) ligand family (GDNF, neurturin, artemin, and persephin) in conjunction with a ligand-specific coreceptor (GFRα1-4)¹. RET belongs to the cadherin superfamily, and it has been suggested that the ret gene is the result of a recombination between a gene encoding a tyrosine kinase receptor and a gene encoding an ancestral cadherin at an early stage of evolution². The extracellular domain of RET comprises, as observed for other tyrosine kinase receptors, a cysteine-rich domain, but also four cadherin-like domains³.

RET signaling 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. Outside the nervous system, RET is crucial for development of the kidney and plays a key role in spermatogenesis⁴.

RET has attracted considerable clinical interest because of the range of mutations found in diverse conditions that include Hirschsprung disease and a variety of cancers involving the thyroid gland. RET-related cancers with thyroid involvement include sporadic and familial medullary thyroid carcinoma (MTC), multiple endocrine neoplasia 2 (MEN2) syndromes MEN2A and MEN2B, and papillary thyroid carcinoma (PTC)⁵.