Proto-oncogene tyrosine-protein kinase receptor Ret (RET)

RET kinase, formally known as Proto-oncogene tyrosine-protein kinase receptor Ret, is a receptor tyrosine kinase encoded by the RET proto-oncogene involved in cellular processes like proliferation, neuronal navigation, and migration. It has a multi-domain structure including extracellular cadherin-like and cysteine-rich regions, a transmembrane domain, and an intracellular kinase domain with alternative C-terminal isoforms (RET9/RET51). Activation involves GDNF-family ligands binding to GFRα co-receptors, inducing RET dimerization and trans-autophosphorylation at specific tyrosine residues (e.g., Tyr900, Tyr905, Tyr981, Tyr1015, Tyr1062, Tyr1096) to initiate signaling. Unusually, the kinase domain shows an active conformation even when non-phosphorylated, with only modest activity increase upon phosphorylation. RET is implicated in diseases: loss-of-function mutations cause Hirschsprung disease, while activating mutations drive various cancers including familial medullary thyroid carcinoma, multiple endocrine neoplasias 2A/2B, and specific RET-altered thyroid and lung cancers. It is a therapeutic target for these cancers with selective inhibitors like selpercatinib and pralsetinib, although resistance mutations (G810C/S, Y806C/N) can occur.

Other names

RET proto-oncogeneRET kinase

RET inhibitors target the kinase domain to block downstream signaling. Clinically relevant inhibitors bind RET in an unconventional mode.