GFRalpha-mediated Localization of RET to Lipid Rafts Is Required for Effective Downstream Signaling, Differentiation, and Neuronal Survival

Neuron. 2000 Mar;25(3):611-23. doi: 10.1016/s0896-6273(00)81064-8.

Abstract

The GDNF family ligands (GFLs: GDNF, neurturin, persephin, and artemin) signal through RET and a gly-cosyl-phosphatidylinositol (GPI)-anchored coreceptor (GFRalpha1-alpha4) 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 GFRalpha1 recruits RET to lipid rafts after GDNF stimulation and results in RET/Src association. Disruption of RET localization using either transmembrane-anchored or soluble GFRalpha1 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cell Fractionation
  • Cell Membrane / chemistry
  • Cell Survival / physiology
  • Cerebellum / cytology
  • Detergents
  • Drosophila Proteins*
  • Genetic Complementation Test
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Green Fluorescent Proteins
  • Indicators and Reagents
  • Ligands
  • Lipid Metabolism
  • Lipids / analysis*
  • Luminescent Proteins
  • Nerve Growth Factors*
  • Nerve Tissue Proteins / pharmacology
  • Neuroblastoma
  • Neurons / chemistry*
  • Neurons / cytology
  • Neurons / enzymology*
  • Neuroprotective Agents / pharmacology
  • Proto-Oncogene Proteins / analysis*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-ret
  • Rats
  • Receptor Protein-Tyrosine Kinases / analysis*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, trkA / metabolism
  • Recombinant Fusion Proteins / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Solubility
  • Tumor Cells, Cultured
  • src-Family Kinases / metabolism*

Substances

  • Detergents
  • Drosophila Proteins
  • Gdnf protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Indicators and Reagents
  • Ligands
  • Lipids
  • Luminescent Proteins
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Receptor, trkA
  • Ret protein, Drosophila
  • Ret protein, rat
  • src-Family Kinases