TY - JOUR
T1 - GFRα-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survival
AU - Tansey, Malú G.
AU - Baloh, Robert H.
AU - Milbrandt, Jeffrey
AU - Johnson, Eugene M.
N1 - Funding Information:
We thank Krista Moulder for teaching us the dissection and primary culture of cerebellar granule cells and K. Moulder, B. Tsui-Pierchala and H. Enomoto for helpful scientific discussions. We thank D. Lublin for the DAF-HLA-B44 cDNA and P. Osborne for assistance with the preparation of the manuscript. This work was supported by the National Parkinson Foundation (M. G. T.) and National Institutes of Health Grants AG-13729 (E. M. J.) and AG-13730 (J. M.). Washington University, J. M., and E. M. J. may receive income based on a license to Genentech.
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0033625038&partnerID=8YFLogxK
U2 - 10.1016/S0896-6273(00)81064-8
DO - 10.1016/S0896-6273(00)81064-8
M3 - Article
C2 - 10774729
AN - SCOPUS:0033625038
SN - 0896-6273
VL - 25
SP - 611
EP - 623
JO - Neuron
JF - Neuron
IS - 3
ER -