Glial cell line-derived neurotrophic factor family receptor alpha-2–Ret proto-oncogene receptor complex (GFRα2-RET receptor complex)

The GFRα2-RET receptor complex is a membrane-bound multi-protein assembly required for signaling by specific members of the glial cell line-derived neurotrophic factor (GDNF) ligand family, notably neurturin (NRTN). In this complex, GFRα2 acts as a glycosylphosphatidylinositol (GPI)-anchored co-receptor, binding to its ligand (neurturin) and presenting it to the RET proto-oncogene protein, a receptor tyrosine kinase. The extracellular RET region consists of four cadherin-like domains (CLD1-4) and a cysteine-rich domain (CRD), which, together with GFRα2, is essential for ligand-induced activation. Ligand binding induces assembly into a higher-order structure (heterohexamer), leading to dimerization and activation of the intracellular RET kinase domains and subsequent signal transduction involved in neuronal development, survival, and disease. Pathologically, aberrant RET signaling (often via mutation or gene fusion) is implicated in multiple cancers and some neurodevelopmental and neurodegenerative disorders. Selective RET kinase inhibitors are approved therapeutics for certain RET-driven cancers, but careful consideration of neurological and developmental side effects is necessary due to the physiological roles of this pathway[1][2][3][5][6].

Other names

RET–GFRα2 complexGDNF family receptor alpha-2–RET complexNeurturin–GFRα2–RET complex

Inhibition of RET kinase activity (for RET inhibitors); Blockade of RET dimerization/activation (experimental approaches); Modulation of neurotrophic signaling pathways