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First published online 13 October 2009
doi: 10.1242/jcs.044537

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Differential VASP phosphorylation controls remodeling of the actin cytoskeleton

Peter M. Benz^1,*,, Constanze Blume^1,*, Stefanie Seifert², Sabine Wilhelm¹, Jens Waschke³, Kai Schuh⁴, Frank Gertler⁵, Thomas Münzel⁶ and Thomas Renné^2,

¹ Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Würzburg, Germany
³ Institute of Anatomy, University of Würzburg, Würzburg, Germany
⁴ Institute of Physiology, University of Würzburg, Würzburg, Germany
² Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
⁵ Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
⁶ Second Medical Clinic, Department of Cardiology and Angiology, Johannes-Gutenberg-University, Mainz, Germany

Author for correspondence (thomas{at}renne.net)

Accepted 3 September 2009

Proteins of the Enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) family link signal transduction pathways to actin cytoskeleton dynamics. VASP is substrate of cAMP-dependent, cGMP-dependent and AMP-activated protein kinases that primarily phosphorylate the sites S157, S239 and T278, respectively. Here, we systematically analyzed functions of VASP phosphorylation patterns for actin assembly and subcellular targeting in vivo and compared the phosphorylation effects of Ena/VASP family members. Methods used were the reconstitution of VASP-null cells with `locked' phosphomimetic VASP mutants, actin polymerization of VASP mutants in vitro and in living cells, site-specific kinase-mediated VASP phosphorylation, and analysis of the endogenous protein with phosphorylation-status-specific antibodies. Phosphorylation at S157 influenced VASP localization, but had a minor impact on F-actin assembly. Phosphorylation of the S157-equivalent site in the Ena/VASP family members Mena and EVL had no effect on the ratio of cellular F-actin to G-actin. By contrast, VASP phosphorylation at S239 (and the equivalent site in Mena) or T278 impaired VASP-driven actin filament formation. The data show that VASP functions are precisely regulated by differential phosphorylation and provide new insights into cytoskeletal control by serine/threonine kinase-dependent signaling pathways.

Key words: Vasodilator-stimulated phosphoprotein (VASP), Ena/VASP family, Serine/threonine kinase, Actin turnover

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