Tyrosine 981, a Novel Ret Autophosphorylation Site, Binds c-Src to Mediate Neuronal Survival
The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are neurotrophic factors that influence several aspects of the developing and injured nervous system. GFLs signal through a common receptor tyrosine kinase (Ret) and one of the four ligand-binding co-receptors (GFRα1 to 4)...
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Published in | The Journal of biological chemistry Vol. 279; no. 18; pp. 18262 - 18269 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
30.04.2004
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Subjects | |
Online Access | Get full text |
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Summary: | The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are neurotrophic factors that influence several
aspects of the developing and injured nervous system. GFLs signal through a common receptor tyrosine kinase (Ret) and one
of the four ligand-binding co-receptors (GFRα1 to 4). Ligand-induced translocation of Ret to lipid rafts, where it interacts
with the nonreceptor tyrosine kinase Src, is a prerequisite for full biological activity of these neurotrophic factors. This
interaction and subsequent activation of Src are required for GFL-mediated neuronal survival, neurite outgrowth, or cell proliferation.
Here we show by multiple approaches that Ret tyrosine 981 constitutes the major binding site of the Src homology 2 domain
of Src and therefore the primary residue responsible for Src activation upon Ret engagement. Other tyrosines such as 1015
and 1029 may contribute to the overall interaction between Ret and Src, as judged by overexpression experiments. By generating
a phosphospecific antibody, we demonstrate that tyrosine 981 is a novel autophosphorylation site in Ret. Importantly, we also
show that this tyrosine becomes phosphorylated in dissociated sympathetic neurons after ligand stimulation. Mutation of tyrosine
981 to phenylalanine reduces GDNF-mediated survival in a transfected cerebellar granule neuron paradigm. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M400505200 |