Prostaglandin-induced VASP phosphorylation controls αII-spectrin breakdown in apoptotic cells

In pathological conditions, the inflammatory mediator prostaglandin E2 (PGE(2)) 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 (A-spectrin affects spectrin breakdown in PGE(2)-induced apoptosis. PGE(2) 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 all-spectrin attenuates all-spectrin cleavage in apoptotic cells and that PGE(2)-induced VASP phosphorylation regulates this process. Our findings may therefore provide the molecular basis for PGE(2)-induced apoptosis in pathological events. (c) 2007 Elsevier B.V. All rights reserved.