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Updated: May 10, 2026

Investigating von Willebrand Factor Pathophysiology Using a Flow Chamber Model of von Willebrand Factor-platelet String Formation
08:30

Investigating von Willebrand Factor Pathophysiology Using a Flow Chamber Model of von Willebrand Factor-platelet String Formation

Published on: August 14, 2017

cAMP-induced secretion of endothelial von Willebrand factor is regulated by a phosphorylation/dephosphorylation

Ines Brandherm1, Jennifer Disse, Dagmar Zeuschner

  • 1Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Muenster, Von-Esmarch-Strasse 56, Muenster, Germany.

Blood
|June 13, 2013
PubMed

The large multimeric glyocoprotein von Willebrand factor (VWF) is a crucial component of both primary and secondary hemostasis. It is stored in secretory granules of vascular endothelial cells, the Weibel-Palade bodies (WPBs), and is released following stimulation by agonists that raise intracellular Ca(2+) or cyclic adenosine monophosphate (cAMP) levels. cAMP-induced exocytosis of WPBs requires protein kinase A activity, but downstream factors that are regulated by phosphorylation/dephosphorylation are not known. Here we identify the complex consisting of the lipid-binding protein annexin A2 (AnxA2) and S100A10 as such a factor. Knockdown and specific rescue approaches reveal that a functional AnxA2-S100A10 complex is required for the forskolin-induced, cAMP-dependent release of VWF. Forskolin triggers dephosphorylation of AnxA2 that is mediated by a calcineurin-like phosphatase and stabilizes the AnxA2-S100A10 complex, thereby promoting VWF release. Serine 11 of AnxA2 was identified as the target residue of this phosphorylation switch because a phosphomimicking mutation at this site prevents complex formation with S100A10 and, in contrast to wild-type or S11A-AnxA2, is unable to restore cAMP-dependent VWF secretion in AnxA2-depleted cells. Thus, complex formation of AnxA2 with S100A10 is a central regulatory mechanism in the acute release of VWF in response to cAMP-elevating agonists.

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