Molecules in focus The focal adhesion phosphoprotein, VASP

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Abstract

Vasodilator-stimulated phosphoprotein (VASP) is associated with focal adhesions and areas of dynamic membrane activity, where it is thought to have an important role in actin filament assembly and cell motility. VASP contains a central proline-rich sequence which recruits the G-actin binding protein profilin. Localization of VASP to the leading edge of a migrating cell can lead to local accumulation of profilin, which in turn can supply actin monomers to growing filament ends. VASP binds to the focal adhesion proteins vinculin and zyxin and this probably directs the phosphoprotein to focal adhesions and the leading edge of stimulated cells. VASP functions as a binding intermediate between profilin and focal adhesion proteins. Intracellular pathogens, including Listeria monocytogenes, have coat proteins which bind VASP. This is one way in which these pathogens use VASP, and other proteins from the host cell, to assemble the actin filaments they require to move around the cytoplasm of infected cells and enter neighbouring cells. Understanding the role of VASP and other proteins in cell and bacterial motility is likely to lead to development of new therapeutic strategies for diseases including atherosclerosis and tumour growth, and for limiting the spread of intracellular pathogens.

Introduction

Vasodilator-stimulated phosphoprotein (VASP) is a 40 kDa protein associated with cell adhesion and areas of dynamic membrane activity. It was first characterized by Halbrugge and Walter (1989)as a major phosphorylated protein in platelets and endothelial cells, following stimulation with vasodilators such as prostaglandins and nitric oxide donors. Evidence is now emerging to suggest VASP, and related proteins, are important components in the cellular machinery responsible for actin filament assembly.

Section snippets

Structure

The human VASP cDNA was sequenced in 1995 by Haffner and co-workers (Haffner et al., 1995), and encodes a 380 residue polypeptide with a predicted molecular mass of 39.8 kDa. During SDS–PAGE, VASP migrates with an apparent molecular mass of 46 kDa. Three phosphorylation sites have been identified in the protein, serine-157, serine-239 and threonine-278. Phosphorylation of serine-157 results in a marked conformational change in VASP that decreases its mobility in SDS–PAGE.

Phosphorylation occurs in

Synthesis and degradation

VASP is known to have a wide tissue distribution and is expressed in a number of cell types, including vascular endothelial and smooth muscle cells, platelets, and fibroblasts (Haffner et al., 1995). As yet, there is no information on synthesis and degradation of the protein.

Biological function

An important putative function of VASP is to promote actin filament assembly. This is dependent on the ability of VASP to recruit the G-actin binding protein profilin (Reinhard et al., 1995a). Profilin is a 14 kDa polypeptide found, with VASP, at sites of filament assembly. This small ubiquitous protein both binds G-actin and stimulates exchange of ADP for ATP on the monomer (Machesky and Pollard, 1993). Profilin binds to the GP5 motif within VASP (Reinhard et al., 1995a) and this can lead to

Role in disease processes

VASP has an important role in the motility of several intracellular pathogens including Listeria monocytogenes. This pathogen causes listeriosis and is associated with contaminated dairy products. Following entry into the cell, the bacterium assembles a “comet tail” of F-actin at its rear pole and this results in bacterial movement which is dependent on the continuous polymerization of actin from the rear of the bacterium. A number of host proteins are found in comet tails such as α-actinin,

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