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The VASP family

Originally isolated from platelets as a substrate for both cGMP-dependent and cAMP-dependent kinases (Halbrugge & Walter, 1989). VASP (Vasodilator-Stimulated Phosphoprotein) is also expressed in other cells and is localized to focal adhesion in many cell types (Reinhard et al, 1995).  VASP binds actin (Hüttelmaier et al, 1999) through the EVH2 domain (Bachmann et al, 1999). Several similar proteins proteins have now come to light (see below).

Figure 1. The structure of Ena, EVL and VASP. Two domains are named after the VASP family EVH1 (orange) and EVH2 (Cyan). There are three SH3 binding sites (blue) and 4 profilin binding sites (light blue).

VASP forms complexes with a number of other proteins, mainly those that also are enriched at the focal adhesion (table 1).

Protein Function References
Profilin An actin binding protein that both sequesters actin monomers and (under certain conditions) activates actin polymerization. Reinhard et al, 1995; Jonckheere et al, 1999
Vinculin A component of the focal adhesion, binds VASP in a PIP2 sensitive manner. Huttelmaier et al, 1998; Bubeck et al, 1997
ActA A protein secreted by the bacteria Listeria monocytogenes that causes "rocketing" of the bacteria through the host cell. Niebuhr et al, 1997
Actin Main constituent of the cytoskeleton in most cells. Pistor et al, 1995; Huttelmaier et al, 1999; Harbeck et al, 2000.
Table 1   VASP-Binding proteins

Surprisingly, the VASP knock out is not lethal but show platelet hypersensitivity to activation and have more megakaryocytes than wild-type mice (Hauser et al, 1999), whereas MENA (a VASP relative) shows defects in neurulation ( Lanier et al, 1999).

Other members of the VASP family

The structure of VASP reveals that it belongs to a large family of proteins including WASP, and Homer

Figure 2. WASP
Figure 3. Homer

References:-

Bachmann, C., Fischer, L., Walter, U. & Reinhard, M. (1999) The EVH2 domain of the vasodilator-stimulated phosphoprotein mediates tetramerization, F-actin binding, and actin bundle formation. J.Biol.Chem. 274, 23549-23557.

Comerford, K. M., Lawrence, D. W., Synnestvedt, K., Levi, B. P. & Colgan, S. P. (2002) Role of vasodilator-stimulated phosphoprotein in PKA-induced changes in endothelial junctional permeability.  FASEB J. 16, 583-585.

Reinhard, M., Giehl, K., Abel, K., Haffner, C., Jarchau, T., Hoppe, V., Jockusch, B. M. & Walter, U. (1995) The proline-rich focal adhesion and microfilament protein VASP is a ligand for profilins, EMBO J. 14, 1583-1589.

Niebuhr, K., Ebel, F., Frank, R., Reinhard, M., Domann, E., Carl, U. D., Walter, U., Gertler, F. B., Wehland, J. & Chakraborty, T. (1997) A novel proline-rich motif present in ActA of Listeria monocytogenes and cytoskeletal proteins is the ligand for the EVH1 domain, a protein module present in the Ena/VASP family, EMBO J. 16, 5433-5444.

Halbrugge, M. & Walter, U. (1989) Purification of a vasodilator-regulated phosphoproten from human platelets., Eur. J. Biochem. 185, 41-50.

Hauser, W., Knobeloch, K. P., Eigenthaler, M., Gambayan, S., Krenn, V., Geiger, J., Glaszova, M., Rohde, E., Horak, I. & Walter, U. (1999) Megakarycyte hyperplasia and enhanced agonist-induced platelet activation in vasodilator-stimulated phosphoprotein knockout mice., PNAS. 96, 8120-8125.

Hüttelmaier, S., Mayboroda, O., Harbeck, B., Jarchau, T., Jockusch, B. M. & Rüdiger, M. (1998) The interaction of cell-contact proteins VASP and vinculin is regulated by phosphatidylinositol-4,5-bisphosphate, Current Biol. 8, 479-488.

Hüttelmaier, S., Harbeck, B., Steffens, N. O., Meberschmidt, T., Illenberger, S. & Jockusch, B. M. (1999) Characterization of the actin binding properties of the vasodilator-stimulated phosphoprotein VASP., FEBS letters. 451, 68-74.

Jonckheere, V., Lambrechts, A., Vanderkerckhove, J. & Ampe, C. (1999) Dimerization of profilin II upon binding the (GP5)3 peptide from VASP overcomes the inhibition of actin nucelation by profilin II and thymosin., FEBS letters. 447, 257-263.

Rottner, K., Behrendt, B., Small, J. V. & Wehland, J. (1999) VASP dynamics during lamellipodia protrusion., Nature Cell Biol. 1, 321-322.

Bearer, E. L., Prakash, J. M., Manchester, R. D. & Allen, P. G. (2000) VASP protects actin filaments from gelsolin: An in vitro study with implications for platelet actin reorganizations., Cell Motility Cytoskeleton. 47, 351-364.

Smith, G. A., Theriot, J. A. & Portnoy, D. A. (1996) The tandem repeat domain in the Listeria monocytogenes ActA protein controls the rate of actin-based motility, the percentage of moving bacteria, and the localization of Vasodilator-stimulated phosphoprotein and profilin, J.Cell Biol. 135, 647-660.

Bubeck, P., Pistor, S., Wehland, J. & Jockusch, B. M. (1997) Ligand recruitment by vinculin domains in transfected cells, J.Cell Sci. 110, 1361-1371.

Pistor, S., Chakroborty, T., Walter, U. & Wehland, J. (1995) The bacterial actin nucleator protein ActA of Listeria monocytogenes contain multiple binding sites for host microfilament proteins, Current Biol. 5, 517-525.

Salazar, R., Bell, S. E. & Davis, G. E. (1999) Coordinate induction of the actin cytoskeletal regulatory proteins gelsolin, Vasodilator-stimulated phosphoprotein, and profilin during capillary morphogenesis in vitro., Exp.Cell Res. 249, 22-32.

Machesky, L. M. (1999) Rocket-based motility: a universal mechanism?, Nature Cell Biol. 1, E29-E31.

 Lanier, L. M., Gates, M. A., Witke, W., Menzies, A. S., Wehman, A. M., Macklis, J. D., Kwiatkowski, D., Soriano, P. & Gertler, F. B. (1999) Mena is required for neurulation and commissure formation., Neuron. 22, 313-325.

Wills, Z., Bateman, J., Korey, C. A., Comer, A. & Van Vactor, D. (1999) The tyrosine kinase Abl and its substrate enabled collaborate with the receptor phosphase Dlar to control motor axon guidance., Neuron. 22, 301-312.

Harbeck, B., Huttelmaier, S., Schluter, K., Jockusch, B. M. & Illenberger, S. (2000) Phosphorylation of the vasodilator-stimulated phosphoprotein regulates its interaction with actin., J.Biol.Chem. 275, 30817-30825.

 
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