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 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.
Mesh Terms:
Amino Acid Sequence, Animals, Apoptosis, Apoptosis Regulatory Proteins, Brain, Calcium-Calmodulin-Dependent Protein Kinases, Caspases, Catalysis, Cells, Cultured, Death-Associated Protein Kinases, Fibroblasts, Immunoprecipitation, Mice, Molecular Sequence Data, Nerve Growth Factors, Phosphorylation, Protein Structure, Tertiary, Receptors, Cell Surface, Transcriptional Activation, Tumor Suppressor Proteins
EMBO J.
Date: Mar. 23, 2005
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