RET tyrosine kinase receptor (RET)

RET (Rearranged during Transfection) receptor tyrosine kinase is a cell surface receptor belonging to the receptor tyrosine kinase (RTK) family, crucial for development and cellular signaling. It comprises an extracellular domain with four cadherin-like repeats for ligand binding, a single transmembrane domain, and an intracellular domain containing a juxtamembrane portion, a split tyrosine kinase domain, and a C-terminal tail (RET9 and RET51 isoforms). RET is activated by GDNF family ligands (GFLs) complexed with GPI-anchored GFRα co-receptors (GFRα1-4). This complex induces RET dimerization and trans-autophosphorylation of specific tyrosine residues, notably Tyr900 and Tyr905 in the activation loop, which stabilizes the active conformation and promotes phosphorylation of other sites, especially in the C-terminus (e.g., Tyr981, Tyr1015, Tyr1062, Tyr1096). Activated RET initiates several downstream pathways including Ras/MAP kinase, PI3 kinase/AKT, and Phospholipase C-γ (PLCγ) by recruiting effectors via phosphorylated tyrosines. Beyond its roles in kidney and nervous system development, neural crest development, and mechanoreceptor differentiation, RET exhibits unique regulatory features: both phosphorylated and nonphosphorylated forms can adopt an active conformation, autophosphorylation has only a modest activity increase, and it lacks an intracellular cis-inhibitory mechanism, suggesting alternative regulatory modes.

Other names

Rearranged during TransfectionProto-oncogene RET