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Internalization of Glial Cell-Derived Neurotrophic Factor Receptor GFRα1 in the Absence of the Ret Tyrosine Kinase Coreceptor

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Abstract

1. Glial cell-derived neurothrophic factor (GDNF) interacts with a cell surface receptor, GFRα1, that is linked via a glycosyl-phosphatidylinositol (GPI) lipid to the cell membrane. The neurotrophic activities of GDNF are mediated by binding to GFRα1 and further interaction of the GDN–GFRα1 complex with a coreceptor tyrosine kinase encoded by the c-Ret protooncogene. There is also evidence for the existence of cell signaling by GDNF and GFRα1 in the absence of Ret.

2. To further delineate the Ret-dependent and -independent functions of GDNF, cellular internalization of GDNF and GFRα1 was examined in cells lines and primary neurons.

3. Relative to other GPI-anchored receptors, efficient endocytosis ( 30–40% of total surface-bound ligand internalized after 2 min) of GNDF and GFRα1 was observed in neuroblastoma and transfected-fibroblast cell lines that lack Ret. Primary hippocampal neurons from transgenic mice that express a wild-type GFRα1 together with a mutant, tyrosine kinase-inactive Ret also internalized GDNF efficiently ( 20% of total surface-bound ligand internalized after 2 min). We also observed a ligand dependence for GFRα1 internalization in the cell lines that lack Ret. Furthermore, a comparison in the presence and absence of Ret indicates that this coreceptor tyrosine kinase slows internalization at early time points.

4. The data suggest different mechanisms of internalization for GDNF–GFRα1 in the absence and presence of the Ret coreceptor.

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  1. Laboratory for Metabolic and Endocrine Research, Simon Fraser University, Burnaby, British Columbia, Canada

    P. Vieira, J. Thomas-Crusells & A. Vieira

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Vieira, P., Thomas-Crusells, J. & Vieira, A. Internalization of Glial Cell-Derived Neurotrophic Factor Receptor GFRα1 in the Absence of the Ret Tyrosine Kinase Coreceptor. Cell Mol Neurobiol 23, 43–55 (2003). https://doi.org/10.1023/A:1022593001155

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