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Functional role of cGMP-dependent VASP phosphorylation in vascular cells

This lecture will take a focussed look at key elements of the cGMP signalling cascade in vascular cells and recent advances in our knowledge of cGMP-dependent protein kinase (cGK or PKG) and its substrate VASP (Vasodilator-stimulated phosphoprotein) [1]. In particular, the role of this pathway for the regulation of platelet – vessel wall interactions will be examined [2, 3]. Vasodilator-stimulated phosphoprotein (VASP) belongs to the Ena/VASP family, which plays an important role in regulating cytoskeletal dynamics, cell migration and other complex cellular functions [1, 4]. Three VASP phosphorylation sites have been identified, serine157, serine239, and threonine278. Serine239 is the preferential phosphorylation site for PKG, whereas serine157 is the preferential phosphorylation site for PKA. Recently, we showed that VASP serine157 is also phosphorylated in vascular smooth muscle cells (SMCs) in response to growth factors mediated by PKC. Additional data suggest that VASP phosphorylation at serine157 is important for the growth-stimulatory effect of VASP in SMCs, whereas VASP phosphorylation at serine239 is involved in the growth inhibitory effects of NO on SMCs [5]. Overall, VASP appears to be a modulator of vascular cell functions by integrating positive and negative signals that target different phosphorylation sites of VASP.

References

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    Lohmann SM, Walter U: Tracking functions of cGMP-dependent protein kinases (cGK). Front Biosci. 2005, 10: 1313-1328.

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    Massberg S, Gruner S, Konrad I, Arguinzonis G, Eigenthaler MI, Hemler M, Kersting K, Schulz J, Muller C, Besta I, Nieswandt F, Heinzmann B, Walter U, Gawaz M: Enhanced in vivo platelet adhesion in vasodilator-stimulated phosphoprotein (VASP)-deficient mice. Blood. 2004, 103: 136-142. 10.1182/blood-2002-11-3417.

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    Gambaryan S, Geiger J, Schwarz UR, Butt E, Begonja A, Obergfell A, Walter U: Potent inhibition of human platelets by cGMP analogs independent of cGMP-dependent protein kinase. Blood. 2004, 103: 2593-2600. 10.1182/blood-2003-09-3349.

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    Zhuang S, Nguyen GT, Chen Y, Gudi T, Eigenthaler M, Jarchau T, Walter U, Boss GR, Pilz RB: Vasodilator-stimulated phosphoprotein activation of serum-response element-dependent transcription occurs downstream of RhoA and is inhibited by cGMP-dependent protein kinase phosphorylation. J Biol Chem. 2004, 279: 10397-10407. 10.1074/jbc.M313048200.

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    Chen L, Daum G, Chitaley K, Coats SA, Bowen-Pope DF, Eigenthaler M, Thumati NR, Walter U, Clowes AW: Vasodilator-stimulated phosphoprotein regulates proliferation and growth inhibition by nitric oxide in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2004, 24: 1-6. 10.1161/01.ATV.0000112102.28859.39.

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Correspondence to Ulrich Walter.

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Keywords

  • Protein Kinase
  • Smooth Muscle Cell
  • Cell Migration
  • Vessel Wall
  • Signalling Cascade