The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase

Netrin‐1 receptors UNC5H (UNC5H1–4) were originally proposed to mediate the chemorepulsive activity of netrin‐1 during axonal guidance processes. However, UNC5H receptors were more recently described as dependence receptors and, as such, able to trigger apoptosis in the absence of netrin‐1. They wer...

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Bibliographic Details
Published in:The EMBO journal 2005-03, Vol.24 (6), p.1192-1201
Main Authors: Llambi, Fabien, Lourenço, Filipe Calheiros, Gozuacik, Devrim, Guix, Catherine, Pays, Laurent, Del Rio, Gabriel, Kimchi, Adi, Mehlen, Patrick
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
apoptosis
Apoptosis - physiology
Apoptosis Regulatory Proteins
Brain - cytology
Calcium-Calmodulin-Dependent Protein Kinases - genetics
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Caspases - metabolism
Catalysis
Cells, Cultured
DAPK
Death-Associated Protein Kinases
dependence receptor
Fibroblasts - drug effects
Fibroblasts - metabolism
Immunoprecipitation
Mice
Molecular Sequence Data
Nerve Growth Factors - metabolism
Nerve Growth Factors - pharmacology
Nerve Growth Factors - physiology
Netrin Receptors
Netrin-1
Phosphorylation - drug effects
Protein Structure, Tertiary
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Receptors, Cell Surface - physiology
Transcriptional Activation
Tumor Suppressor Proteins - metabolism
Tumor Suppressor Proteins - pharmacology
Tumor Suppressor Proteins - physiology
UNC5H2
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Summary:Netrin‐1 receptors UNC5H (UNC5H1–4) were originally proposed to mediate the chemorepulsive activity of netrin‐1 during axonal guidance processes. However, UNC5H receptors were more recently described as dependence receptors and, as such, able to trigger apoptosis in the absence of netrin‐1. They were also proposed as putative tumor suppressors. Here, we show that UNC5H2 physically interacts with the serine/threonine kinase death‐associated protein kinase (DAP‐kinase) both in cell culture and in embryonic mouse brains. This interaction occurs in part through the respective death domains of UNC5H2 and DAP‐kinase. Moreover, part of UNC5H2 proapoptotic activity occurs through this interaction because UNC5H2‐induced cell death is partly impaired in the presence of dominant‐negative mutants of DAP‐kinase or in DAP‐kinase mutant murine embryonic fibroblast cells. In the absence of netrin‐1, UNC5H2 reduces DAP‐kinase autophosphorylation on Ser308 and increases the catalytic activity of the kinase while netrin‐1 blocks UNC5H2‐dependent DAP‐kinase activation. Thus, the pair netrin‐1/UNC5H2 may regulate cell fate by controlling the proapoptotic kinase activity of DAP‐kinase.
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7600584