Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Biol. Chem. 280 (38): 32866-32876

© 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

A Novel Mechanism of G Protein-dependent Phosphorylation of Vasodilator-stimulated Phosphoprotein*

Jasmina Profirovic1, Matvey Gorovoy2, Jiaxin Niu, Sasa Pavlovic, , and Tatyana Voyno-Yasenetskaya¶, Established Investigator of the American Heart Association3

Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612

Abstract: Vasodilator-stimulated phosphoprotein (VASP) is a major substrate of protein kinase A (PKA). Here we described the novel mechanism of VASP phosphorylation via cAMP-independent PKA activation. We showed that in human umbilical vein endothelial cells (HUVECs) α-thrombin induced phosphorylation of VASP. Specific inhibition of Gα13 protein by the RGS domain of a guanine nucleotide exchange factor, p115RhoGEF, inhibited thrombin-dependent phosphorylation of VASP. More importantly, Gα13-induced VASP phosphorylation was dependent on activation of RhoA and mitogen-activated protein kinase kinase kinase, MEKK1, leading to the stimulation of the NF-{kappa}B signaling pathway. α-Thrombin-dependent VASP phosphorylation was inhibited by small interfering RNA-mediated knockdown of RhoA, whereas Gα13-dependent VASP phosphorylation was inhibited by a specific RhoA inhibitor botulinum toxin C3 and by a dominant negative mutant of MEKK1. We determined that Gα13-dependent VASP phosphorylation was also inhibited by specific PKA inhibitors, PKI and H-89. In addition, the expression of phosphorylation-deficient I{kappa}B and pretreatment with the proteasome inhibitor MG-132 abolished Gα13- and α-thrombin-induced VASP phosphorylation. In summary, we have described a novel pathway of Gα13-induced VASP phosphorylation that involves activation of RhoA and MEKK1, phosphorylation and degradation of I{kappa}B, release of PKA catalytic subunit from the complex with I{kappa}B and NF-{kappa}B, and subsequent phosphorylation of VASP.

Received for publication February 4, 2005. Revision received July 15, 2005.

3 To whom correspondence should be addressed: Dept. of Pharmacology (MC 868), University of Illinois, 835 S. Wolcott Ave., Chicago, IL 60612. Tel.: 312-996-9823; Fax: 312-996-1225; E-mail: tvy{at}

Sodium butyrate decreases the activation of NF-{kappa}B reducing inflammation and oxidative damage in the kidney of rats subjected to contrast-induced nephropathy.
R. A. Machado, L. d. S. Constantino, C. D. Tomasi, H. A. Rojas, F. S. Vuolo, M. F. Vitto, P. A. Cesconetto, C. T. de Souza, C. Ritter, and F. Dal-Pizzol (2012)
Nephrol. Dial. Transplant. 27, 3136-3140
   Abstract »    Full Text »    PDF »
The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Inhibits Vascular Smooth Muscle Growth through the cAMP-Dependent Protein Kinase and cGMP-Dependent Protein Kinase Pathways.
C. N. Joshi, D. N. Martin, J. C. Fox, N. N. Mendelev, T. A. Brown, and D. A. Tulis (2011)
J. Pharmacol. Exp. Ther. 339, 394-402
   Abstract »    Full Text »    PDF »
Nuclear Emancipation: A Platelet Tour de Force.
S. L. Spinelli, S. B. Maggirwar, N. Blumberg, and R. P. Phipps (2010)
Science Signaling 3, pe37
   Abstract »    Full Text »    PDF »
Thrombin and Collagen Induce a Feedback Inhibitory Signaling Pathway in Platelets Involving Dissociation of the Catalytic Subunit of Protein Kinase A from an NF{kappa}B-I{kappa}B Complex.
S. Gambaryan, A. Kobsar, N. Rukoyatkina, S. Herterich, J. Geiger, A. Smolenski, S. M. Lohmann, and U. Walter (2010)
J. Biol. Chem. 285, 18352-18363
   Abstract »    Full Text »    PDF »
Differential VASP phosphorylation controls remodeling of the actin cytoskeleton.
P. M. Benz, C. Blume, S. Seifert, S. Wilhelm, J. Waschke, K. Schuh, F. Gertler, T. Munzel, and T. Renne (2009)
J. Cell Sci. 122, 3954-3965
   Abstract »    Full Text »    PDF »
The role of VASP in regulation of cAMP- and Rac 1-mediated endothelial barrier stabilization.
N. Schlegel, S. Burger, N. Golenhofen, U. Walter, D. Drenckhahn, and J. Waschke (2008)
Am J Physiol Cell Physiol 294, C178-C188
   Abstract »    Full Text »    PDF »
CTL-Associated Antigen-4 Ligation Induces Rapid T Cell Polarization That Depends on Phosphatidylinositol 3-Kinase, Vav-1, Cdc42, and Myosin Light Chain Kinase.
B. Wei, S. da Rocha Dias, H. Wang, and C. E. Rudd (2007)
J. Immunol. 179, 400-408
   Abstract »    Full Text »    PDF »
AMP-activated Protein Kinase Impairs Endothelial Actin Cytoskeleton Assembly by Phosphorylating Vasodilator-stimulated Phosphoprotein.
C. Blume, P. M. Benz, U. Walter, J. Ha, B. E. Kemp, and T. Renne (2007)
J. Biol. Chem. 282, 4601-4612
   Abstract »    Full Text »    PDF »
PKC{delta} regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation.
G. Pula, K. Schuh, K. Nakayama, K. I. Nakayama, U. Walter, and A. W. Poole (2006)
Blood 108, 4035-4044
   Abstract »    Full Text »    PDF »
Role of Scavenger Receptor Class B Type I and Sphingosine 1-Phosphate Receptors in High Density Lipoprotein-induced Inhibition of Adhesion Molecule Expression in Endothelial Cells.
T. Kimura, H. Tomura, C. Mogi, A. Kuwabara, A. Damirin, T. Ishizuka, A. Sekiguchi, M. Ishiwara, D.-S. Im, K. Sato, et al. (2006)
J. Biol. Chem. 281, 37457-37467
   Abstract »    Full Text »    PDF »
Recent Evidence for an Involvement of Rho-Kinase in Cerebral Vascular Disease.
S. Chrissobolis and C. G. Sobey (2006)
Stroke 37, 2174-2180
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882