title: Prostaglandin-induced VASP phosphorylation controls alpha II-spectrin breakdown in apoptotic cells.
abstract: In pathological conditions, the inflammatory mediator prostaglandin E2 (PGE2) has been shown to induce apoptosis through a cAMP-dependent pathway. However, underlying mechanisms have remained illusive. Irrespective whether apoptosis is induced by the intrinsic or extrinsic pathway, the cysteine protease caspase-3 becomes activated and cleaves many key proteins including spectrins. Cleavage of the plasma membrane-associated spectrins leads to cell shrinkage, membrane blebbing, the formation of apoptotic bodies, and irreversible cell death. Recently, we identified a novel interaction between alpha II-spectrin and vasodilator-stimulated phosphoprotein (VASP), which is abrogated by the cAMP-dependent protein kinase (PKA)-mediated phosphorylation of VASP. In the present study we investigated whether VASP binding to alpha II-spectrin affects spectrin breakdown in PGE2-induced apoptosis. PGE2 dose- and time-dependently triggered VASP phosphorylation. Following induction of apoptosis, caspase-3-mediated alpha II-spectrin breakdown and membrane blebbing were markedly delayed in wild-type as compared to VASP-deficient endothelial cells. This suggests that VASP binding to alpha II-spectrin attenuates alpha II-spectrin cleavage in apoptotic cells and that PGE2-induced VASP phosphorylation regulates this process. Our findings may therefore provide the molecular basis for PGE2-induced apoptosis in pathological events.
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Benz
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Feller
authors.forename: Albert
authors.initials: A
authors.lastname: Sickmann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D013049:Spectrin / Q000378:metabolism*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D013049:Spectrin; D053148:Caspase 3; D015232:Dinoprostone