RET receptor tyrosine kinase (complexed with GDNF family receptor alpha-like co-receptor) (RET (when referring to the receptor); GFRAL or GFRα1-4 for co-receptors)

The RET receptor tyrosine kinase, when associated with glial cell line-derived neurotrophic factor (GDNF) family ligands bound by their respective glycosylphosphatidylinositol-linked co-receptors (GDNF family receptors α1–4, or alpha-like/GFRAL) forms a multimeric cell-surface signaling complex. Ligand binding occurs first at the extracellular domain of a specific co-receptor; this ligand-co-receptor dimer then recruits two monomers of membrane-spanning RET, leading to autophosphorylation within its intracellular kinase domains. This triggers multiple downstream pathways critical for neuronal survival/differentiation as well as organogenesis such as kidney formation. Aberrant activation—by mutation or gene fusion—of this pathway is implicated in several cancers including medullary thyroid carcinoma and non-small-cell lung cancer. The same axis is under investigation for therapeutic modulation in neurodegenerative diseases like Parkinson’s disease but has shown mixed results so far. Targeting can involve either inhibition (for oncology indications) or stimulation/agonism (for regenerative neurology).

Other names

RETRearranged during transfection proto-oncogeneProto-oncogene c-RetReceptor tyrosine kinase RetGlial cell line-derived neurotrophic factor family receptors: GFRα1, GFRα2, GFRα3, GFRα4; also includes "GDNF family receptor alpha-like" (GFRAL)

For inhibitors: Inhibit ATP binding site of the intracellular tyrosine kinase domain of RET to block downstream oncogenic signaling pathways. For agonists: Mimic natural ligands or activate the extracellular domain/co-receptor interface to promote neuronal survival signaling.