The dependence receptor UNC5H2 mediates apoptosis through DAP‐kinase
Open accessAbstract
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.
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In absence of ligands, UNC5B enables PP2A-mediated activating dephosphorylation of DAPK1, which promotes p53-dependent RCD.
“(3) UNC5B enables the protein phosphatase 2 (PP2A)-mediated activating dephosphorylation of death associated protein kinase 1 (DAPK1), which is known to promote p53-dependent RCD [355–357]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [355]
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- Authors
- Llambi, F., Lourenço, F. C., Gozuacik, D., Guix, C., Pays, L., Del Rio, G., Kimchi, A., & Mehlen, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Weizmann Institute of Science (IL)
- Corresponding author
- Mehlen, Patrick
- Venue
- The EMBO Journal
- Published
- 2005-02-24
- Volume
- 24
- Issue
- 6
- Pages
- 1192-1201
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC556396
- OpenAlex
- W1981720385
- Cited by
- 173
- References
- 31
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 11 · 2023: 7 · 2022: 1 · 2021: 4 · 2020: 14 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 11 · 2015: 4 · 2014: 7 · 2013: 14 · 2012: 14
- FWCI
- 4.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Israel Academy of Sciences and Humanities
- Israel Science Foundation
- Ligue Contre le Cancer
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- DAP kinase, dependence receptors, netrin-1, apoptosis, DAPK, death domain, kinase autophosphorylation, tumor suppression, axon guidance, cell fate regulation, embryonic fibroblasts
- MeSH terms
- Netrin Receptors, Netrin-1, Amino Acid Sequence, Animals, Brain, Catalysis, Cells, Cultured, Fibroblasts, Molecular Sequence Data, Nerve Growth Factors, Phosphorylation, Receptors, Cell Surface, Transcriptional Activation, Apoptosis, Protein Structure, Tertiary, Calcium-Calmodulin-Dependent Protein Kinases, Caspases, Tumor Suppressor Proteins, Immunoprecipitation, Apoptosis Regulatory Proteins, Mice, Death-Associated Protein Kinases
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