The Dependence Receptor UNC5H2/B Triggers Apoptosis via PP2A-Mediated Dephosphorylation of DAP Kinase
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The UNC5H dependence receptors promote apoptosis in the absence of their ligand, netrin-1, and this is important for neuronal and vascular development and for limitation of cancer progression. UNC5H2 (also called UNC5B) triggers cell death through the activation of the serine-threonine protein kinase DAPk. While performing a siRNA screen to identify genes implicated in UNC5H-induced apoptosis, we identified the structural subunit PR65β of the holoenzyme protein phosphatase 2A (PP2A). We show that UNC5H2/B recruits a protein complex that includes PR65β and DAPk and retains PP2A activity. PP2A activity is required for UNC5H2/B-induced apoptosis, since it activates DAPk by triggering its dephosphorylation. Moreover, netrin-1 binding to UNC5H2/B prevents this effect through interaction of the PP2A inhibitor CIP2A to UNC5H2/B. Thus we show here that, in the absence of netrin-1, recruitment of PP2A to UNC5H2/B allows the activation of DAPk via a PP2A-mediated dephosphorylation and that this mechanism is involved in angiogenesis regulation.
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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 [356]
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- Authors
- Guenebeaud, C., Goldschneider, D., Castets, M., Guix, C., Chazot, G., Delloye-Bourgeois, C., Eisenberg-Lerner, A., Shohat, G., Zhang, M., Laudet, V., Kimchi, A., Bernet, A., & Mehlen, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Hong Kong University of Science and Technology (HK)
- École Normale Supérieure de Lyon (FR)
- Weizmann Institute of Science (IL)
- Corresponding author
- Mehlen, Patrick
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 40
- Issue
- 6
- Pages
- 863-876
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2142296555
- Cited by
- 137
- References
- 62
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 9 · 2021: 4 · 2020: 13 · 2019: 6 · 2018: 9 · 2017: 8 · 2016: 10 · 2015: 9 · 2014: 10 · 2013: 14 · 2012: 17
- FWCI
- 5.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 995 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- 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
- UNC5B, dependence receptors, DAP kinase, protein phosphatase 2A, PP2A dephosphorylation, CIP2A, netrin-1, apoptosis, angiogenesis, siRNA screen
- MeSH terms
- Netrin Receptors, Humans, Phosphorylation, Receptors, Cell Surface, Tumor Cells, Cultured, Apoptosis, Calcium-Calmodulin-Dependent Protein Kinases, Apoptosis Regulatory Proteins, Protein Phosphatase 2, Death-Associated Protein Kinases
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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