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Published online January 14, 2008
doi:10.1083/jcb.200709181
The Journal of Cell Biology, Vol. 180, No. 1, 205-219
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Benz et al.
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Article

 Cytoskeleton assembly at endothelial cell–cell contacts is regulated by {alpha}II-spectrin–VASP complexes

Peter M. Benz1, Constanze Blume1, Jan Moebius2, Chris Oschatz1, Kai Schuh1, Albert Sickmann2, Ulrich Walter1, Stephan M. Feller3, and Thomas Renné1

1 Institute of Clinical Biochemistry and Pathobiochemistry and 2 Rudolf-Virchow-Center for Experimental Biomedicine, University of Würzburg, D-97080 Würzburg, Germany
3 Cell Signalling Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, England, UK

Correspondence to Thomas Renné: thomas{at}renne.net

Directed cortical actin assembly is the driving force for intercellular adhesion. Regulated by phosphorylation, vasodilator-stimulated phosphoprotein (VASP) participates in actin fiber formation. We screened for endothelial proteins, which bind to VASP, dependent on its phosphorylation status. Differential proteomics identified {alpha}II-spectrin as such a VASP-interacting protein. {alpha}II-Spectrin binds to the VASP triple GP5-motif via its SH3 domain. cAMP-dependent protein kinase–mediated VASP phosphorylation at Ser157 inhibits {alpha}II-spectrin–VASP binding. VASP is dephosphorylated upon formation of cell–cell contacts and in confluent, but not in sparse cells, {alpha}II-spectrin colocalizes with nonphosphorylated VASP at cell–cell junctions. Ectopic expression of the {alpha}II-spectrin SH3 domain at cell–cell contacts translocates VASP, initiates cortical actin cytoskeleton formation, stabilizes cell–cell contacts, and decreases endothelial permeability. Conversely, the permeability of VASP-deficient endothelial cells (ECs) and microvessels of VASP-null mice increases. Reconstitution of VASP-deficient ECs rescues barrier function, whereas {alpha}II-spectrin binding-deficient VASP mutants fail to restore elevated permeability. We propose that {alpha}II-spectrin–VASP complexes regulate cortical actin cytoskeleton assembly with implications for vascular permeability.

Abbreviations: AMPK, AMP-activated protein kinase; EC, endothelial cell; EVH, Ena/VASP homology; EVL, Ena-VASP–like; IEJ, interendothelial junction; MALDI-TOF, matrix-assisted laser desorption ionization time-of-flight; PMF, peptide mass fingerprinting; PRR, proline-rich region; VASP, vasodilator-stimulated phosphoprotein.


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