Role of EnaVASP Proteins in Homeostasis and Disease

Contents

1 Domain Structure and Functions of the Ena/VASP Proteins 40

1.1 EVH1 Domain Structure and Function 40

1.2 Structure and Function of the Proline-Rich Domain 41

1.3 EVH2 Domain Structure and Function 41

2 Protein Complexes Containing Ena/VASP Proteins 43

2.1 Listeria 43

2.2 Focal Adhesions and Stress Fibres 43

2.3 Lamellipodia and Filopodia 44

2.4 Cell-Cell Junctions (Endothelia/Epithelia) 45

2.5 Immunological Synapse 45

2.6 Phagosome 46

3 Regulation of Ena/VASP Proteins by Phosphorylation 46

3.1 PKA- and PKG-Dependent Phosphorylation of Ena/VASP Proteins 46

3.2 PKA- and PKG-Independent Phosphorylation of Ena/VASP Proteins 47

3.3 Regulation of Ena/VASP Protein Functions by Phosphorylation 48

4 Pathophysiologic Relevance of Ena/VASP Proteins 49

4.1 Thrombosis 49

4.2 Cancer 52

4.3 Arteriosclerosis 54

4.4 Cardiomyopathy 54

4.5 Nephritis 55

5 Ena/VASP Proteins and Drug Discovery 56

References 57

Abstract The actin cytoskeleton is required for many important processes during embryonic development. In later stages of life, important homeostatic processes depend on the actin cytoskeleton, such as immune response, haemostasis and blood vessel preservation. Therefore, the function of the actin cytoskeleton must be tightly regulated, and aberrant regulation may cause disease. A growing number of proteins

Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's

M. Krause

Randall Division of Cell and Molecular Bioph; House, Guy's Campus, London SE1 1UL, UK [email protected]

E. Klussmann, J. Scott (eds.) Protein-Protein Interactions as New Drug Targets. Handbook of Experimental Pharmacology 186, © Springer-Verlag Berlin Heidelberg 2008

have been described to bind and regulate the actin cytoskeleton. Amongst them, Ena/VASP proteins function as anti-capping proteins, thereby directly modulating the actin ultrastructure. Ena/VASP function is regulated by their recruitment into protein complexes downstream of plasma membrane receptors and by phosphorylation. As regulators of the actin ultrastructure, Ena/VASP proteins are involved in crucial cellular functions, such as shape change, adhesion, migration and cell-cell interaction and hence are important targets for therapeutic intervention. In this chapter, we will first describe the structure, function and regulation of Ena/VASP proteins. Then, we will review the involvement of Ena/VASP proteins in the development of human diseases. Growing evidence links Ena/VASP proteins to important human diseases, such as thrombosis, cancer, arteriosclerosis, cardiomyopathy and nephritis. Finally, present and future perspectives for the development of therapeutic molecules interfering with Ena/VASP-mediated protein-protein interactions are presented.

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