Cytoskeleton assembly at endothelial cell-cell contacts is regulated by alphaII-spectrin-VASP complexes
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Cytoskeleton assembly at endothelial cell-cell contacts is regulated by alphaII-spectrin-VASP complexes. / Benz, Peter M; Blume, Constanze; Moebius, Jan; Oschatz, Chris; Schuh, Kai; Sickmann, Albert; Walter, Ulrich; Feller, Stephan M; Renné, Thomas.
in: J CELL BIOL, Jahrgang 180, Nr. 1, 14.01.2008, S. 205-19.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Cytoskeleton assembly at endothelial cell-cell contacts is regulated by alphaII-spectrin-VASP complexes
AU - Benz, Peter M
AU - Blume, Constanze
AU - Moebius, Jan
AU - Oschatz, Chris
AU - Schuh, Kai
AU - Sickmann, Albert
AU - Walter, Ulrich
AU - Feller, Stephan M
AU - Renné, Thomas
PY - 2008/1/14
Y1 - 2008/1/14
N2 - 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 alphaII-spectrin as such a VASP-interacting protein. alphaII-Spectrin binds to the VASP triple GP(5)-motif via its SH3 domain. cAMP-dependent protein kinase-mediated VASP phosphorylation at Ser157 inhibits alphaII-spectrin-VASP binding. VASP is dephosphorylated upon formation of cell-cell contacts and in confluent, but not in sparse cells, alphaII-spectrin colocalizes with nonphosphorylated VASP at cell-cell junctions. Ectopic expression of the alphaII-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 alphaII-spectrin binding-deficient VASP mutants fail to restore elevated permeability. We propose that alphaII-spectrin-VASP complexes regulate cortical actin cytoskeleton assembly with implications for vascular permeability.
AB - 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 alphaII-spectrin as such a VASP-interacting protein. alphaII-Spectrin binds to the VASP triple GP(5)-motif via its SH3 domain. cAMP-dependent protein kinase-mediated VASP phosphorylation at Ser157 inhibits alphaII-spectrin-VASP binding. VASP is dephosphorylated upon formation of cell-cell contacts and in confluent, but not in sparse cells, alphaII-spectrin colocalizes with nonphosphorylated VASP at cell-cell junctions. Ectopic expression of the alphaII-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 alphaII-spectrin binding-deficient VASP mutants fail to restore elevated permeability. We propose that alphaII-spectrin-VASP complexes regulate cortical actin cytoskeleton assembly with implications for vascular permeability.
KW - Actin Cytoskeleton
KW - Amino Acid Sequence
KW - Animals
KW - Binding Sites
KW - Carrier Proteins
KW - Cell Adhesion
KW - Cell Adhesion Molecules
KW - Endothelial Cells
KW - Intercellular Junctions
KW - Mice
KW - Microfilament Proteins
KW - Molecular Sequence Data
KW - Phosphoproteins
KW - Phosphorylation
KW - Protein Interaction Domains and Motifs
KW - Protein Interaction Mapping
U2 - 10.1083/jcb.200709181
DO - 10.1083/jcb.200709181
M3 - SCORING: Journal article
C2 - 18195108
VL - 180
SP - 205
EP - 219
JO - J CELL BIOL
JF - J CELL BIOL
SN - 0021-9525
IS - 1
ER -