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

Malú G. Tansey, Robert H. Baloh, Jeffrey Milbrandt, Eugene M. Johnson

Research output: Contribution to journalArticlepeer-review

232 Scopus citations

Abstract

The GDNF family ligands (GFLs: GDNF, neurturin, persephin, and artemin) signal through RET and a glycosyl-phosphatidylinositol (GPI)-anchored coreceptor (GFRα1-α4) that binds ligand with high affinity and provides specificity. The importance of the GPI anchor is not fully understood; however, GPI-linked proteins cluster into lipid rafts, structures that may represent highly specialized signaling organelles. Here, we report that GPI-anchored GFRα1 recruits RET to lipid rafts after GDNF stimulation and results in RET/Src association. Disruption of RET localization using either transmembrane-anchored or soluble GFRα1 results in RET phosphorylation, but GDNF-induced intracellular signaling events are markedly attenuated as are neuronal differentiation and survival responses. Therefore, proper membrane localization of RET via interaction with a raft-localized, GPI-linked coreceptor is of fundamental importance in GFL signaling.

Original languageEnglish
Pages (from-to)611-623
Number of pages13
JournalNeuron
Volume25
Issue number3
DOIs
StatePublished - Jan 1 2000

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