The RET Receptor Family

Abstract

The RET (REarranged during Transfection) gene encodes the tyrosine kinase membrane receptor (RET) for glial cell line-derived neurotrophic factor (GDNF) family ligands (GFL). The human RET gene is located on the long arm of chromosome 10 (10q11.2). RET protein contains an N-terminal glycosylated extracellular portion, with four cadherin-like and one cysteine-rich domain, a central hydrophobic transmembrane segment, and a cytosolic domain that has the tyrosine kinase (TK) activity. RET activation is achieved through the formation of a ternary complex with GFLs and glycosylphosphatidylinositol (GPI)-anchored co-receptors of the GDNF receptor-α (GFRα) family. Upon binding to GFL-GFRα, RET protein undergoes dimerization and activation. RET loss-of-function mutations are found in developmental disorders such as Hirschsprung’s disease, characterized by the congenital absence of the enteric innervation, and congenital anomalies of the kidney or lower urinary tract. Gain-of-function mutations in RET are the driver events of the hereditary cancer syndromes named multiple endocrine neoplasia (MEN) type 2A and 2B. Gene rearrangements fusing the tyrosine kinase domain of RET with the N-terminal portion of heterologous proteins lead to the formation of chimeric oncoproteins endowed with constitutive catalytic activity in papillary thyroid carcinoma and other human malignancies. Finally, altered RET expression has been linked to several additional human neoplasms, including breast carcinoma.