The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase

• 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; EMBO07; EMBO37; Fibroblasts - drug effects; Fibroblasts - metabolism; Immunoprecipitation; Mice; Molecular Sequence Data; Mortality; Mutants; 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
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/sj.emboj.7600584

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.