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.
authors.affiliation: Apoptosis, Cancer and Development Laboratory-Equipe Labellisée "La Ligue," CNRS UMR5238, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Guenebeaud
authors.forename: David
authors.initials: D
authors.lastname: Goldschneider
authors.forename: Marie
authors.initials: M
authors.lastname: Castets
authors.forename: Catherine
authors.initials: C
authors.lastname: Guix
authors.forename: Guillaume
authors.initials: G
authors.lastname: Chazot
authors.forename: Céline
authors.initials: C
authors.lastname: Delloye-Bourgeois
authors.forename: Avital
authors.initials: A
authors.lastname: Eisenberg-Lerner
authors.forename: Galit
authors.initials: G
authors.lastname: Shohat
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
authors.forename: Vincent
authors.initials: V
authors.lastname: Laudet
authors.forename: Adi
authors.initials: A
authors.lastname: Kimchi
authors.forename: Agnès
authors.initials: A
authors.lastname: Bernet
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D064550:Death-Associated Protein Kinases; D006801:Humans; D000075386:Netrin Receptors; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D051017:Apoptosis Regulatory Proteins; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; C532445:UNC5B protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D054648:Protein Phosphatase 2