Prostaglandin-induced VASP phosphorylation controls alpha II-spectrin breakdown in apoptotic cells
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Prostaglandin-induced VASP phosphorylation controls alpha II-spectrin breakdown in apoptotic cells. / Benz, Peter M; Feller, Stephan M; Sickmann, Albert; Walter, Ulrich; Renné, Thomas.
In: INT IMMUNOPHARMACOL, Vol. 8, No. 2, 01.02.2008, p. 319-24.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Prostaglandin-induced VASP phosphorylation controls alpha II-spectrin breakdown in apoptotic cells
AU - Benz, Peter M
AU - Feller, Stephan M
AU - Sickmann, Albert
AU - Walter, Ulrich
AU - Renné, Thomas
PY - 2008/2/1
Y1 - 2008/2/1
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis
KW - Caspase 3
KW - Cell Adhesion Molecules
KW - Dinoprostone
KW - Dose-Response Relationship, Drug
KW - Mice
KW - Microfilament Proteins
KW - Phosphoproteins
KW - Phosphorylation
KW - Spectrin
U2 - 10.1016/j.intimp.2007.10.004
DO - 10.1016/j.intimp.2007.10.004
M3 - SCORING: Journal article
C2 - 18182247
VL - 8
SP - 319
EP - 324
JO - INT IMMUNOPHARMACOL
JF - INT IMMUNOPHARMACOL
SN - 1567-5769
IS - 2
ER -