The Dependence Receptor UNC5H2/B Triggers Apoptosis via PP2A-Mediated Dephosphorylation of DAP Kinase

Céline Guenebeaud, David Goldschneider, Marie Castets, Catherine Guix, Guillaume Chazot, Céline Delloye-Bourgeois, Avital Eisenberg-Lerner, Galit Shohat, Mingjie Zhang, Vincent Laudet, Adi Kimchi, Agnès Bernet, Patrick Mehlen

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)863-876
Number of pages14
JournalMolecular Cell
Volume40
Issue number6
DOIs
StatePublished - 22 Dec 2010
Externally publishedYes

Bibliographical note

Funding Information:
We wish to thank SW Jang, K. Ye, F. Llambi and C. Maisse for technical advice, J. Westermarck and MR Juntilla for the CIP2A construct. We are grateful to D.E. Bredesen and O.Meurette for suggestion and critical reading and editing of the manuscript. This work was supported by institutional grant from CNRS (PM), Centre Léon Bérard (PM), Université de Lyon (PM) and from the Ligue Contre le Cancer (PM), INCa (PM), ANR blanche (PM), STREP Hermione (PM) and APO-SYS (PM and AK). AK is the incumbent of Helena Rubinstein Chair of Cancer Research.

Funding

We wish to thank SW Jang, K. Ye, F. Llambi and C. Maisse for technical advice, J. Westermarck and MR Juntilla for the CIP2A construct. We are grateful to D.E. Bredesen and O.Meurette for suggestion and critical reading and editing of the manuscript. This work was supported by institutional grant from CNRS (PM), Centre Léon Bérard (PM), Université de Lyon (PM) and from the Ligue Contre le Cancer (PM), INCa (PM), ANR blanche (PM), STREP Hermione (PM) and APO-SYS (PM and AK). AK is the incumbent of Helena Rubinstein Chair of Cancer Research.

FundersFunder number
Centre Léon Bérard
Seventh Framework Programme200767
Agence Nationale de la Recherche
Ligue Contre le Cancer
Centre National de la Recherche Scientifique
Institut National du Cancer
Université de Lyon

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