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Ena/VASP family

Glossary Term: Ena/VASP


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Ena/VASP is essential in the Functional Module: Arp2/3 Mediated Nucleation where it is involved in Filopodia formation

It is also involved in Cell-Matrix Adhesion formation.

Protein Structure

Ena/VASP (vasodilator-stimulated phophoprotein) belongs to a group of highly related multifunctional actin-binding proteins that includes Drosophila Enabled (Ena), its mammalian homologue Mena (mammalian Enabled), the murine homologue Evl (Enabled/vasodilator-stimulated phosphoprotein-like), and the C. elegans homologue unc34. Proteins of the Ena/VASP family share a common structural organization composed of highly conserved amino and carboxy terminal domains (called Ena-VASP homology 1 and 2 [EVH1 and EVH2]); these domains mediate binding to actin filament nucleation factors (e.g. bacterial ActA, formins) and focal adhesion proteins (e.g. zyxin, vinculin) (reviewed in [1]). Members of the Ena/VASP family are thought to oligomerize in solution and be active as a tetramer in cells (see Figure below) [2, 3]. Phosphorylation of VASP proteins alters their ability to bind to actin filaments but not their ability to form a tetramer or interact with known ligands (e.g. profilin, vinculin, zyxin) [4].


Figure: Ena/VASP family. This schematic diagram illustrates the molecular organization of the Ena/VASP protein family and provides examples for how the Ena/VASP proteins are represented in figures throughout this resource. Relevant domains believed to be important for binding to actin and for protein-protein interactions are highlighted (reviewed in [1]).

Ena/VASP localization

Proteins of the Ena/VASP family contribute to cell movement, axon guidance, neural tube closure and shape change in vertebrate cells by modulating actin filament organization and dynamics; these effects are achieved in part by regulating the morphology and behavior of actin-based structures such as lamellipodia and filopodia (reviewed in [1]). Ena/VASP proteins also modulate actin dynamics at sites of cell-ECM and cell-cell interactions and they are concentrated to the proximal portion of phosphotyrosine-rich domains at the ends of F-actin stress fibers [5].

Ena/VASP function

Ena/VASP proteins promote actin filament elongation by tethering the filaments to sites of active actin assembly [6, 7, 8]. Ena/VASP proteins recruit actin nucleation and initiation factors (e.g. Arp2/3 complex, formins) and they promote G-actin assembly through profilin-binding (reviewed in [9]). The rate of actin filament elongation by Ena/VASP proteins is determined in by the recruitment of G-actin via teh G-actin binding site (GAB) that lies within the EVH2 domain and shares close sequence homology to WASP homology 2 motifs [10]. Ena/VASP proteins are also thought to accumulate at the plasma membrane where they alter actin polymerization by antagonizing barbed (+) end capping proteins, thereby enabling the incorporation of actin into longer filaments [6, 7]; however, controversy over their exact mechanism still exists (reviewed in [1]). In addition, Ena/VASP may promote actin assembly by an unknown mechanism that is independent of initiation factors, however, this has not been demonstrated in intact cells [11]

Ena/VASP activity in filopodia:

The Ena/VASP family promotes filopodia formation through cooperation with formins and by modulating actin filament assembly [12] (reviewed in [13]). Ena/VASP protects actin filaments from capping, thereby enhancing filament elongation and promoting F-actin bundling, which together help stimulate filopodium protrusion [8, 14, 15, 16, 17]. VASP sustains filopodia protrusion and extension through its localization at the filopodia tips [18]; myosin X is responsible for this transport of VASP to the tip [19]. Formins are found at adhesion junctions and formin-mediated actin assembly may play a part in extending the contact area after cell-cell adhesion of filopodia on apposed cells [20]. Knowing that VASP tethers growing actin filaments to the filopodium tip [7], implies that VASP may couple actin assembly and actin rearward movement to membrane protrusion, thereby expanding the region of cell-cell contact.

Ena/VASP activity at adhesions:

Ena/VASP proteins associate with components of the Arp2/3-mediated actin assembly module and they are required for actin dynamics at sites of cadherin-cadherin binding [21]. The association of Mena and VASP may be modulated by signal-mediated phosphorylation (reviewed in [22]); VASP phosphorylation prevents it from interacting with other cadherin-complex proteins (e.g. zyxin) [23].

References

  1. Bear JE. & Gertler FB. Ena/VASP: towards resolving a pointed controversy at the barbed end. J. Cell. Sci. 2009; 122(Pt 12):1947-53. [PMID: 19494122]
  2. Zimmermann J., Labudde D., Jarchau T., Walter U., Oschkinat H. & Ball LJ. Relaxation, equilibrium oligomerization, and molecular symmetry of the VASP (336-380) EVH2 tetramer. Biochemistry 2002; 41(37):11143-51. [PMID: 12220179]
  3. Haffner C., Jarchau T., Reinhard M., Hoppe J., Lohmann SM. & Walter U. Molecular cloning, structural analysis and functional expression of the proline-rich focal adhesion and microfilament-associated protein VASP. EMBO J. 1995; 14(1):19-27. [PMID: 7828592]
  4. Harbeck B., Hüttelmaier S., Schluter K., Jockusch BM. & Illenberger S. Phosphorylation of the vasodilator-stimulated phosphoprotein regulates its interaction with actin. J. Biol. Chem. 2000; 275(40):30817-25. [PMID: 10882740]
  5. Gertler FB., Niebuhr K., Reinhard M., Wehland J. & Soriano P. Mena, a relative of VASP and Drosophila Enabled, is implicated in the control of microfilament dynamics. Cell 1996; 87(2):227-39. [PMID: 8861907]
  6. Bear JE., Svitkina TM., Krause M., Schafer DA., Loureiro JJ., Strasser GA., Maly IV., Chaga OY., Cooper JA., Borisy GG. & Gertler FB. Antagonism between Ena/VASP proteins and actin filament capping regulates fibroblast motility. Cell 2002; 109(4):509-21. [PMID: 12086607]
  7. Breitsprecher D., Kiesewetter AK., Linkner J., Urbanke C., Resch GP., Small JV. & Faix J. Clustering of VASP actively drives processive, WH2 domain-mediated actin filament elongation. EMBO J. 2008; 27(22):2943-54. [PMID: 18923426]
  8. Lebrand C., Dent EW., Strasser GA., Lanier LM., Krause M., Svitkina TM., Borisy GG. & Gertler FB. Critical role of Ena/VASP proteins for filopodia formation in neurons and in function downstream of netrin-1. Neuron 2004; 42(1):37-49. [PMID: 15066263]
  9. Chesarone MA. & Goode BL. Actin nucleation and elongation factors: mechanisms and interplay. Curr. Opin. Cell Biol. 2009; 21(1):28-37. [PMID: 19168341]
  10. Breitsprecher D., Kiesewetter AK., Linkner J., Vinzenz M., Stradal TE., Small JV., Curth U., Dickinson RB. & Faix J. Molecular mechanism of Ena/VASP-mediated actin-filament elongation. EMBO J. 2011; 30(3):456-67. [PMID: 21217643]
  11. Fradelizi J., Noireaux V., Plastino J., Menichi B., Louvard D., Sykes C., Golsteyn RM. & Friederich E. ActA and human zyxin harbour Arp2/3-independent actin-polymerization activity. Nat. Cell Biol. 2001; 3(8):699-707. [PMID: 11483954]
  12. Schirenbeck A., Arasada R., Bretschneider T., Schleicher M. & Faix J. Formins and VASPs may co-operate in the formation of filopodia. Biochem. Soc. Trans. 2005; 33(Pt 6):1256-9. [PMID: 16246092]
  13. Mattila PK. & Lappalainen P. Filopodia: molecular architecture and cellular functions. Nat. Rev. Mol. Cell Biol. 2008; 9(6):446-54. [PMID: 18464790]
  14. Svitkina TM., Bulanova EA., Chaga OY., Vignjevic DM., Kojima S., Vasiliev JM. & Borisy GG. Mechanism of filopodia initiation by reorganization of a dendritic network. J. Cell Biol. 2003; 160(3):409-21. [PMID: 12566431]
  15. Schirenbeck A., Arasada R., Bretschneider T., Stradal TE., Schleicher M. & Faix J. The bundling activity of vasodilator-stimulated phosphoprotein is required for filopodium formation. Proc. Natl. Acad. Sci. U.S.A. 2006; 103(20):7694-9. [PMID: 16675552]
  16. Han YH., Chung CY., Wessels D., Stephens S., Titus MA., Soll DR. & Firtel RA. Requirement of a vasodilator-stimulated phosphoprotein family member for cell adhesion, the formation of filopodia, and chemotaxis in dictyostelium. J. Biol. Chem. 2002; 277(51):49877-87. [PMID: 12388544]
  17. Mogilner A. & Rubinstein B. The physics of filopodial protrusion. Biophys. J. 2005; 89(2):782-95. [PMID: 15879474]
  18. Rottner K., Behrendt B., Small JV. & Wehland J. VASP dynamics during lamellipodia protrusion. Nat. Cell Biol. 1999; 1(5):321-2. [PMID: 10559946]
  19. Tokuo H. & Ikebe M. Myosin X transports Mena/VASP to the tip of filopodia. Biochem. Biophys. Res. Commun. 2004; 319(1):214-20. [PMID: 15158464]
  20. Kobielak A., Pasolli HA. & Fuchs E. Mammalian formin-1 participates in adherens junctions and polymerization of linear actin cables. Nat. Cell Biol. 2004; 6(1):21-30. [PMID: 14647292]
  21. Vasioukhin V., Bauer C., Yin M. & Fuchs E. Directed actin polymerization is the driving force for epithelial cell-cell adhesion. Cell 2000; 100(2):209-19. [PMID: 10660044]
  22. Butt E., Abel K., Krieger M., Palm D., Hoppe V., Hoppe J. & Walter U. cAMP- and cGMP-dependent protein kinase phosphorylation sites of the focal adhesion vasodilator-stimulated phosphoprotein (VASP) in vitro and in intact human platelets. J. Biol. Chem. 1994; 269(20):14509-17. [PMID: 8182057]
  23. Moody JD., Grange J., Ascione MP., Boothe D., Bushnell E. & Hansen MD. A zyxin head-tail interaction regulates zyxin-VASP complex formation. Biochem. Biophys. Res. Commun. 2009; 378(3):625-8. [PMID: 19061869]
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