Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Brain / cytology
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Caspases / metabolism
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Catalysis
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Cells, Cultured
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Death-Associated Protein Kinases
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Immunoprecipitation
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Mice
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Molecular Sequence Data
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Nerve Growth Factors / metabolism
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Nerve Growth Factors / pharmacology
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Nerve Growth Factors / physiology*
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Netrin Receptors
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Netrin-1
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Phosphorylation / drug effects
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Protein Structure, Tertiary
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Receptors, Cell Surface / physiology*
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Transcriptional Activation
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Tumor Suppressor Proteins / metabolism
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Tumor Suppressor Proteins / pharmacology
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Tumor Suppressor Proteins / physiology*
Substances
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Apoptosis Regulatory Proteins
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Nerve Growth Factors
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Netrin Receptors
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Ntn1 protein, mouse
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Receptors, Cell Surface
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Tumor Suppressor Proteins
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Unc5A protein, mouse
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Unc5h2 protein, mouse
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Netrin-1
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Death-Associated Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Caspases