RET receptor tyrosine kinase (RET)

The RET receptor tyrosine kinase is a single-pass transmembrane protein composed of an extracellular ligand-binding domain with cadherin-like repeats and a cysteine-rich region; a single hydrophobic transmembrane segment; and an intracellular split tyrosine kinase domain followed by a carboxy-terminal tail that exists in alternative splice forms. It functions primarily as the high-affinity cell surface receptor for glial cell line-derived neurotrophic factor family ligands via co-receptors from the GDNF receptor-alpha family. Upon ligand binding and dimerization/oligomerization at the plasma membrane, it undergoes autophosphorylation on specific intracellular tyrosines—initiating multiple signal transduction cascades regulating cellular proliferation, differentiation, migration, survival/apoptosis balance, metabolism control, neuronal development/maintenance throughout life stages. RET plays essential roles during embryogenesis—especially in nervous system development—and remains important postnatally for neuronal maintenance and metabolic regulation. Oncogenic activation occurs through point mutations or chromosomal rearrangements leading to constitutive activity; this underlies several aggressive cancers including medullary thyroid carcinoma (MTC) via germline/somatic mutation or papillary thyroid carcinoma via gene fusion/rearrangement. Therapeutic targeting of aberrant RET signaling has led to approval/use of both selective small-molecule inhibitors and broader-spectrum multikinase agents across various malignancies; however clinical benefit can be limited by resistance mechanisms or toxicity from off-target inhibition.

Other names

Proto-oncogene tyrosine-protein kinase receptor RetRearranged during transfection (RET)RET proto-oncogeneReceptor tyrosine-protein kinase Ret

Drugs targeting RET typically act as small-molecule inhibitors that block the ATP-binding site of the intracellular tyrosine kinase domain. This inhibits autophosphorylation and downstream signaling pathways involved in cell growth and survival. Some drugs are multikinase inhibitors affecting other kinases such as VEGFR2 in addition to RET.