Glial Cell Line-derived Neurotrophic Factor Signals through the RET Receptor and Activates Mitogen-activated Protein Kinase

Worby, Carolyn A.; Vega, Quinn; Zhao, Yi; Chao, Hanna H.-J.; Seasholtz, Audrey F.; Dixon, Jack E.

doi:10.1074/jbc.271.39.23619

Cited by 146 publications

(74 citation statements)

References 33 publications

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“…GDNF binding to RET receptor lead to tyrosine kinase autophosphorylation at a set of 16 cytoplasmic tyrosine residues, in the RET short and middle isoforms, and two additional tyrosines in the carboxy-terminal tail, in the RET long isoform. RET receptor tyrosine kinase autophosphorylation can activate various signaling pathways including RAS/ERK, PI3K/AKT and p38MAPK (Worby et al, 1996;Xing et al, 1998;Chiariello et al, 1998;Trupp et al, 1999;Soler et al, 1999;Hayashi et al, 2000;Takahashi, 2001;Sariola and Saarma, 2003). Particularly, it has been demonstrated that Tyr1062 is involved in the activation of Ras/Erk or PI3K/Akt pathways (Besset et al, 2000;Hayashi et al, 2000Hayashi et al, , 2001Murakami et al, 1999aMurakami et al, , 1999b and is required for GDNF-mediated neurons differentiation and survival (Coulpier et al, 2002;Califano et al, 2000;De Vita et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…RET short and middle isoforms contain 16 tyrosine residues in their intracellular domains and RET long isoform has two additional tyrosines in the carboxy-terminal tail. Like other receptor tyrosine kinases, RET can activate different signaling pathways including Ras/Erk, PI3K/Akt, p38/MAPK, PLCg and c-Jun N-terminal kinase (JNK) (Worby et al, 1996;Xing et al, 1998;Chiariello et al, 1998;Trupp et al, 1999;Soler et al, 1999;Hayashi et al, 2000;Takahashi, 2001;Sariola and Saarma, 2003). Among the various tyrosine kinase of RET, it has been demonstrated that Tyr1062 is involved in the activation of Ras/Erk or PI3K/Akt pathways (Besset et al, 2000;Hayashi et al, 2000Hayashi et al, , 2001Murakami et al, 1999aMurakami et al, , 1999b and it is required for GDNF-mediated differentiation and survival of neurons (Coulpier et al, 2002;Califano et al, 2000;De Vita et al, 2000;Asai et al, 1996;Besset et al, 2000) As extension of previous work (Battaglia et al, 2009), in the present study we aimed to verify if the enhancement of GDNF production in mouse striatum following treatment with LY379268 may also induce in the nigrostriatal system a time-related activation of RET receptor and its specific intracellular signaling.…”

Section: Introductionmentioning

confidence: 99%

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mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum

Liberto¹,

Mudò²,

Belluardo³

2011

Neuropharmacology

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Keywords:GDNF RET mGluR2/3 LY379268 Erk1/2 TrK phosphorylation a b s t r a c tIn the present study we aimed to verify if the enhancement of glial cell line-derived neurotrophic factor (GDNF) production in mouse striatum following treatment with LY379268 may also induce in the nigrostriatal system a time-related activation of RET receptor and its specific intracellular signaling. For this purpose, we have investigated the effects of LY379268 treatment on RET phosphorylation at the Tyr1062 and on downstream signaling Erk1/2, Akt and PLCg1 pathway activation. The results showed that treatment with LY379268 (3 mg/kg) induces a significant increase of GDNF levels and time-related RET and Erk1/2 phosphorylation in the striatum. These increases were detected at 24 h and 48 h following LY379268 treatment. No changes were observed in the Akt and PLCg1 phosphorylation levels. Similar results for p-Erk1/2 were observed in the substantia nigra. A complete block of LY379268 effect on striatal RET and p-Erk1/2 phosphorylation was observed in mice intrastriatal injected with anti-GDNF antibodies, suggesting a correlation between GDNF upregulation and RET activation. Overall, with present data we have shown that activation of mGluR2/3 receptors by LY379268 may be particularly promising for nigrostriatal dopaminergic system protection by enhancing striatal levels of GDNF/RET trophic system activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum

Liberto¹,

Mudò²,

Belluardo³

2011

Neuropharmacology

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“…These residues can serve as intracellular docking sites to many different SH2 domain-containing proteins, including Src. While Src interacts with Ret at Tyr 981 (Encinas et al, 2004), Tyr 1062 serves as a docking site to most other effectors and triggers the activation of the Ras signaling pathway in the developing enteric nervous system, the developing kidney, and also in neuroblastoma (Worby et al, 1996;Jijiwa et al, 2004;Hayashi et al, 2000). Therefore, we examined whether Gdnf can activate Ras signaling in SSCs (He et al, 2008).…”

Section: Ras Signaling Pathwaymentioning

confidence: 99%

Gdnf signaling pathways within the mammalian spermatogonial stem cell niche

Hofmann

2008

Molecular and Cellular Endocrinology

204

178

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SummaryMammalian spermatogenesis is a complex process in which male germ-line stem cells develop to ultimately form spermatozoa. Spermatogonial stem cells, or SSCs, are found in the basal compartment of the seminiferous epithelium. They self-renew to maintain the pool of stem cells throughout life, or they differentiate to generate a large number of germ cells. A balance between SSC self-renewal and differentiation in the adult testis is therefore essential to maintain normal spermatogenesis and fertility. Maintenance and self-renewal are tightly regulated by extrinsic signals from the surrounding microenvironment, called the spermatogonial stem cell niche. By physically supporting the SSCs and providing them with growth factors, the Sertoli cell is the main component of the niche. In addition, adhesion molecules that connect the SSCs to the basement membrane and cellular components of the interstitium between the seminiferous tubules are important regulators of the niche function. This review mainly focuses on glial cell line-derived neurotrophic factor (Gdnf), which is produced by Sertoli cells to maintain SSCs self-renewal, and the downstream signaling pathways induced by this crucial growth factor. Interactions between Gdnf and other signaling pathways that maintain self-renewal, as well as the role of novel SSC-and Sertoli cell-specific transcription factors, are also discussed.

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“…Recently, however, the Ret tyrosine kinase protein was identified as the signal transducing component of the GDNF receptor complex (2)(3)(4)(5)(6). The association between Ret and GDNF was deduced in part from the phenotypic similarities of mice with null mutations for either the ligand or the receptor.…”

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confidence: 99%

Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons

Creedon

Tansey

Baloh

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

204

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Neurturin (NTN) is a neurotrophic factor that shares homology with glial cell line-derived neurotrophic factor (GDNF). Recently, a receptor complex has been identified for GDNF that includes the Ret tyrosine kinase receptor and a glycosylphosphatidylinositol-linked protein termed ''GDNFR␣.'' However, differences in the phenotype of Ret and GDNF knockout animals suggest that Ret has at least one additional ligand. In this report, we demonstrate that NTN induces Ret phosphorylation in primary cultures of rat superior cervical ganglion (SCG) neurons. NTN also caused Ret phosphorylation in fibroblasts that were transfected stably with Ret and GDNFR␣ but not in cells expressing Ret alone. A glycosylphosphatidylinositol-linked protein also was important for NTN and GDNF signaling in SCG neurons; phosphatidylinositol-specific phospholipase C treatment of SCG cultures reduced the ability of NTN to phosphorylate Ret and the ability of NTN or GDNF to activate the mitogen-activated protein kinase pathway. NTN and GDNF also caused sustained activation of Ret and the mitogen-activated protein kinase pathway in SCG neurons. Finally, both NTN and GDNF activated the phosphatidylinositol 3-kinase pathway in SCG neurons, which may be important for the ability of NTN and GDNF to promote neuronal survival. These data indicate that NTN is a physiologically relevant ligand for the Ret receptor and suggest that NTN may have a critical role in the development of many neuronal populations.

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Glial Cell Line-derived Neurotrophic Factor Signals through the RET Receptor and Activates Mitogen-activated Protein Kinase

Cited by 146 publications

References 33 publications

mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum

mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum

Gdnf signaling pathways within the mammalian spermatogonial stem cell niche

Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons

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