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

doi:10.1016/j.molcel.2010.11.021

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 journal › Article › peer-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 language	English
Pages (from-to)	863-876
Number of pages	14
Journal	Molecular Cell
Volume	40
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2010.11.021
State	Published - 22 Dec 2010
Externally published	Yes

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.

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10.1016/j.molcel.2010.11.021

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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. (2010). The Dependence Receptor UNC5H2/B Triggers Apoptosis via PP2A-Mediated Dephosphorylation of DAP Kinase. Molecular Cell, 40(6), 863-876. https://doi.org/10.1016/j.molcel.2010.11.021

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

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.",

author = "C{\'e}line Guenebeaud and David Goldschneider and Marie Castets and Catherine Guix and Guillaume Chazot and C{\'e}line Delloye-Bourgeois and Avital Eisenberg-Lerner and Galit Shohat and Mingjie Zhang and Vincent Laudet and Adi Kimchi and Agn{\`e}s Bernet and Patrick Mehlen",

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 L{\'e}on B{\'e}rard (PM), Universit{\'e} 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. ",

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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 2010, 'The Dependence Receptor UNC5H2/B Triggers Apoptosis via PP2A-Mediated Dephosphorylation of DAP Kinase', Molecular Cell, vol. 40, no. 6, pp. 863-876. https://doi.org/10.1016/j.molcel.2010.11.021

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AU - Guenebeaud, Céline

AU - Goldschneider, David

AU - Castets, Marie

AU - Guix, Catherine

AU - Chazot, Guillaume

AU - Delloye-Bourgeois, Céline

AU - Eisenberg-Lerner, Avital

AU - Shohat, Galit

AU - Zhang, Mingjie

AU - Laudet, Vincent

AU - Kimchi, Adi

AU - Bernet, Agnès

AU - Mehlen, Patrick

N1 - 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.

PY - 2010/12/22

Y1 - 2010/12/22

N2 - 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.

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

Abstract

Bibliographical note

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