Released GFRα1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts

Gustavo Paratcha; Fernanda Ledda; Louise Baars; Muriel Coulpier; Valerie Besset; Jonas Anders; Rizaldy Scott; Carlos F. Ibáñez

doi:10.1016/S0896-6273(01)00188-X

Released GFRα1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts

Gustavo Paratcha, Fernanda Ledda, Louise Baars, Muriel Coulpier, Valerie Besset, Jonas Anders, Rizaldy Scott, Carlos F. Ibáñez

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

250 Scopus citations

Abstract

Although both c-Ret and GFRα1 are required for responsiveness to GDNF, GFRα1 is widely expressed in the absence of c-Ret, suggesting alternative roles for "ectopic" sites of GFRα1 expression. We show that GFRα1 is released by neuronal cells, Schwann cells, and injured sciatic nerve, c-Ret stimulation in trans by soluble or immobilized GFRα1 potentiates downstream signaling, neurite outgrowth, and neuronal survival, and elicits dramatic localized expansions of axons and growth cones. Soluble GFRα1 mediates robust recruitment of c-Ret to lipid rafts via a novel mechanism requiring the c-Ret tyrosine kinase. Activated c-Ret associates with different adaptor proteins inside and outside lipid rafts. These results provide an explanation for the tissue distribution of GFRα1, supporting the physiological importance of c-Ret activation in trans as a novel mechanism to potentiate and diversify the biological responses to GDNF.

Original language	English (US)
Pages (from-to)	171-184
Number of pages	14
Journal	Neuron
Volume	29
Issue number	1
DOIs	https://doi.org/10.1016/S0896-6273(01)00188-X
State	Published - 2001

Funding

We thank Kai Simons and Derek Toomre for their support and for advice on lipid rafts, Michele Sanicola for anti-GFRα1 antibodies, Susan Meakin for anti-FRS2 antibodies used in confirmatory immunoprecipitation experiments, Bengt Fundin for help with confocal microscopy, Ann-Sofie Nilsson for help with protein and plasmid purification, Annika Ahlsén for additional technical assistance, and Xiaoli Li-Hellström for secretarial help. Financial support was obtained from the Swedish Medical Research Council (K99-33X-10908-06C), the Biomed2 Program of the European Commission (BMH4-97-2157), the Swedish Cancer Society (3474-B97-05XBC), the Göran Gustafssons Stiftelse, and the Karolinska Institute. J. A. was supported by a grant (An 338/1-1) from the Deutsche Forschungsgemeinschoft, Bonn, Germany, and V. B. by a fellowship from the Wenner Gren Foundations.

ASJC Scopus subject areas

General Neuroscience

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10.1016/S0896-6273(01)00188-X

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title = "Released GFRα1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts",

abstract = "Although both c-Ret and GFRα1 are required for responsiveness to GDNF, GFRα1 is widely expressed in the absence of c-Ret, suggesting alternative roles for {"}ectopic{"} sites of GFRα1 expression. We show that GFRα1 is released by neuronal cells, Schwann cells, and injured sciatic nerve, c-Ret stimulation in trans by soluble or immobilized GFRα1 potentiates downstream signaling, neurite outgrowth, and neuronal survival, and elicits dramatic localized expansions of axons and growth cones. Soluble GFRα1 mediates robust recruitment of c-Ret to lipid rafts via a novel mechanism requiring the c-Ret tyrosine kinase. Activated c-Ret associates with different adaptor proteins inside and outside lipid rafts. These results provide an explanation for the tissue distribution of GFRα1, supporting the physiological importance of c-Ret activation in trans as a novel mechanism to potentiate and diversify the biological responses to GDNF.",

author = "Gustavo Paratcha and Fernanda Ledda and Louise Baars and Muriel Coulpier and Valerie Besset and Jonas Anders and Rizaldy Scott and Ib{\'a}{\~n}ez, {Carlos F.}",

note = "Funding Information: We thank Kai Simons and Derek Toomre for their support and for advice on lipid rafts, Michele Sanicola for anti-GFRα1 antibodies, Susan Meakin for anti-FRS2 antibodies used in confirmatory immunoprecipitation experiments, Bengt Fundin for help with confocal microscopy, Ann-Sofie Nilsson for help with protein and plasmid purification, Annika Ahls{\'e}n for additional technical assistance, and Xiaoli Li-Hellstr{\"o}m for secretarial help. Financial support was obtained from the Swedish Medical Research Council (K99-33X-10908-06C), the Biomed2 Program of the European Commission (BMH4-97-2157), the Swedish Cancer Society (3474-B97-05XBC), the G{\"o}ran Gustafssons Stiftelse, and the Karolinska Institute. J. A. was supported by a grant (An 338/1-1) from the Deutsche Forschungsgemeinschoft, Bonn, Germany, and V. B. by a fellowship from the Wenner Gren Foundations. ",

year = "2001",

doi = "10.1016/S0896-6273(01)00188-X",

language = "English (US)",

volume = "29",

pages = "171--184",

journal = "Neuron",

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T1 - Released GFRα1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts

AU - Paratcha, Gustavo

AU - Ledda, Fernanda

AU - Baars, Louise

AU - Coulpier, Muriel

AU - Besset, Valerie

AU - Anders, Jonas

AU - Scott, Rizaldy

AU - Ibáñez, Carlos F.

N1 - Funding Information: We thank Kai Simons and Derek Toomre for their support and for advice on lipid rafts, Michele Sanicola for anti-GFRα1 antibodies, Susan Meakin for anti-FRS2 antibodies used in confirmatory immunoprecipitation experiments, Bengt Fundin for help with confocal microscopy, Ann-Sofie Nilsson for help with protein and plasmid purification, Annika Ahlsén for additional technical assistance, and Xiaoli Li-Hellström for secretarial help. Financial support was obtained from the Swedish Medical Research Council (K99-33X-10908-06C), the Biomed2 Program of the European Commission (BMH4-97-2157), the Swedish Cancer Society (3474-B97-05XBC), the Göran Gustafssons Stiftelse, and the Karolinska Institute. J. A. was supported by a grant (An 338/1-1) from the Deutsche Forschungsgemeinschoft, Bonn, Germany, and V. B. by a fellowship from the Wenner Gren Foundations.

PY - 2001

Y1 - 2001

N2 - Although both c-Ret and GFRα1 are required for responsiveness to GDNF, GFRα1 is widely expressed in the absence of c-Ret, suggesting alternative roles for "ectopic" sites of GFRα1 expression. We show that GFRα1 is released by neuronal cells, Schwann cells, and injured sciatic nerve, c-Ret stimulation in trans by soluble or immobilized GFRα1 potentiates downstream signaling, neurite outgrowth, and neuronal survival, and elicits dramatic localized expansions of axons and growth cones. Soluble GFRα1 mediates robust recruitment of c-Ret to lipid rafts via a novel mechanism requiring the c-Ret tyrosine kinase. Activated c-Ret associates with different adaptor proteins inside and outside lipid rafts. These results provide an explanation for the tissue distribution of GFRα1, supporting the physiological importance of c-Ret activation in trans as a novel mechanism to potentiate and diversify the biological responses to GDNF.

AB - Although both c-Ret and GFRα1 are required for responsiveness to GDNF, GFRα1 is widely expressed in the absence of c-Ret, suggesting alternative roles for "ectopic" sites of GFRα1 expression. We show that GFRα1 is released by neuronal cells, Schwann cells, and injured sciatic nerve, c-Ret stimulation in trans by soluble or immobilized GFRα1 potentiates downstream signaling, neurite outgrowth, and neuronal survival, and elicits dramatic localized expansions of axons and growth cones. Soluble GFRα1 mediates robust recruitment of c-Ret to lipid rafts via a novel mechanism requiring the c-Ret tyrosine kinase. Activated c-Ret associates with different adaptor proteins inside and outside lipid rafts. These results provide an explanation for the tissue distribution of GFRα1, supporting the physiological importance of c-Ret activation in trans as a novel mechanism to potentiate and diversify the biological responses to GDNF.

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ER -

Released GFRα1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts

Abstract

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