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.
Llambi
Fabien
F
Apoptosis, Cancer and Development Laboratory, Equipe labellisée La Ligue, CNRS FRE2870, Centre Leon Berard, Lyon, France.
Lourenço
Filipe Calheiros
FC
Gozuacik
Devrim
D
Guix
Catherine
C
Pays
Laurent
L
Del Rio
Gabriel
G
Kimchi
Adi
A
Mehlen
Patrick
P
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001921:Brain / Q000166:cytology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002384:Catalysis; D002478:Cells, Cultured; D064550:Death-Associated Protein Kinases; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020169:Caspases; D064550:Death-Associated Protein Kinases; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D000075388:Netrin-1; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C000617353:Ntn1 protein, mouse; C000617308:Unc5A protein, mouse; C000617307:Unc5b protein, mouse
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