GFR alpha-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survival

The GDNF family ligands (GFLs: GDNF, neurturin, persephin, and artemin) sig nal through RET and a glycosyl-phosphatidylinositol (GPI)-anchored corecept or (GFR alpha 1-alpha 4) that binds ligand with high affinity and provides specificity. The importance of the GPI anchor is not fully understood; howe ver, GPI-linked proteins cluster into lipid rafts, structures that may repr esent highly specialized signaling organelles. Here, we report that GPI-anc hored GFR alpha 1 recruits RET to lipid rafts after GDNF stimulation and re sults in RET/Src association. Disruption of RET localization using either t ransmembrane-anchored or soluble GFR alpha 1 results in RET phosphorylation , but GDNF-induced intracellular signaling events are markedly attenuated a s are neuronal differentiation and survival responses. Therefore, proper me mbrane localization of RET via interaction with a raft-localized, GPI-linke d coreceptor is of fundamental importance in GFL signaling.