Ret-dependent and -independent mechanisms of glial cell line-derived neurotrophic factor signaling in neuronal cells
- PMID: 10409632
- DOI: 10.1074/jbc.274.30.20885
Ret-dependent and -independent mechanisms of glial cell line-derived neurotrophic factor signaling in neuronal cells
Abstract
Glial cell line-derived neurotrophic factor (GDNF) has been shown to signal through a multicomponent receptor complex consisting of the Ret receptor tyrosine kinase and a member of the GFRalpha family of glycosylphosphatidylinositol-anchored receptors. In the current model of GDNF signaling, Ret delivers the intracellular signal but cannot bind ligand on its own, while GFRalphas bind ligand but are thought not to signal in the absence of Ret. We have compared signaling pathways activated by GDNF in two neuronal cell lines expressing different complements of GDNF receptors. In a motorneuron-derived cell line expressing Ret and GFRalphas, GDNF stimulated sustained activation of the Ras/ERK and phosphatidylinositol 3-kinase/Akt pathways, cAMP response element-binding protein phosphorylation, and increased c-fos expression. Unexpectedly, GDNF also promoted biochemical and biological responses in a line of conditionally immortalized neuronal precursors that express high levels of GFRalphas but not Ret. GDNF treatment did not activate the Ras/ERK pathway in these cells, but stimulated a GFRalpha1-associated Src-like kinase activity in detergent-insoluble membrane compartments, rapid phosphorylation of cAMP response element-binding protein, up-regulation of c-fos mRNA, and cell survival. Together, these results offer new insights into the dynamics of GDNF signaling in neuronal cells, and indicate the existence of novel signaling mechanisms directly or indirectly mediated by GFRalpha receptors acting in a cell-autonomous manner independently of Ret.
Similar articles
-
Evidence for a ligand-specific signaling through GFRalpha-1, but not GFRalpha-2, in the absence of Ret.J Neurosci Res. 2001 Nov 1;66(3):390-5. doi: 10.1002/jnr.1231. J Neurosci Res. 2001. PMID: 11746356
-
Receptors of the glial cell line-derived neurotrophic factor family of neurotrophic factors signal cell survival through the phosphatidylinositol 3-kinase pathway in spinal cord motoneurons.J Neurosci. 1999 Nov 1;19(21):9160-9. doi: 10.1523/JNEUROSCI.19-21-09160.1999. J Neurosci. 1999. PMID: 10531419 Free PMC article.
-
Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons.Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):7018-23. doi: 10.1073/pnas.94.13.7018. Proc Natl Acad Sci U S A. 1997. PMID: 9192684 Free PMC article.
-
The GDNF/RET signaling pathway and human diseases.Cytokine Growth Factor Rev. 2001 Dec;12(4):361-73. doi: 10.1016/s1359-6101(01)00012-0. Cytokine Growth Factor Rev. 2001. PMID: 11544105 Review.
-
Signal transduction by the receptor tyrosine kinase Ret.Recent Results Cancer Res. 1998;154:271-81. doi: 10.1007/978-3-642-46870-4_18. Recent Results Cancer Res. 1998. PMID: 10027007 Review.
Cited by
-
GDNF synthesis, signaling, and retrograde transport in motor neurons.Cell Tissue Res. 2020 Oct;382(1):47-56. doi: 10.1007/s00441-020-03287-6. Epub 2020 Sep 8. Cell Tissue Res. 2020. PMID: 32897420 Free PMC article. Review.
-
Actions of neurotrophic factors and their signaling pathways in neuronal survival and axonal regeneration.Mol Neurobiol. 2006 Apr;33(2):155-79. doi: 10.1385/MN:33:2:155. Mol Neurobiol. 2006. PMID: 16603794 Review.
-
Glial cell line-derived neurotrophic factor and neurturin inhibit neurite outgrowth and activate RhoA through GFR alpha 2b, an alternatively spliced isoform of GFR alpha 2.J Neurosci. 2007 May 23;27(21):5603-14. doi: 10.1523/JNEUROSCI.4552-06.2007. J Neurosci. 2007. PMID: 17522305 Free PMC article.
-
Glial cell line-derived neurotrophic factor alters axon schwann cell units and promotes myelination in unmyelinated nerve fibers.J Neurosci. 2003 Jan 15;23(2):561-7. doi: 10.1523/JNEUROSCI.23-02-00561.2003. J Neurosci. 2003. PMID: 12533616 Free PMC article.
-
Cellular localization of GDNF and its GFRalpha1/RET receptor complex in the developing pancreas of cat.J Anat. 2008 Nov;213(5):565-72. doi: 10.1111/j.1469-7580.2008.00976.x. J Anat. 2008. PMID: 19014364 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous
