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Introduction
Ena/VASP protein family contributes cell motility and cell adhesion through the regulation of actin dynamics and consists of three members in mammals: Vasodilator-stimulated phosphoprotein (VASP), Mena (mammalian enabled), and the Ena-VASP-like protein Evl. They contain three domains: N-terminal Ena/Vasp like homology domain 1 (EVH1) with an optimal core consensus motif of “FPPPP”, central proline-rich region and C-terminal EVH2 domain. Ena/VASP proteins associate with actin filaments and localize in the hot spots of actin reassembly such as tips of lamellipodia and filopodia.
Sequence annotation
Ena/VASP proteins differ in size of proline-rich region and Mena contains a 91-residue region between the EVH1 domain and proline-rich core with 13 repeats of a 5-residue “LERER" motif [1].
VASP uniprot
Mena (Protein enabled homolog) uniprot
Evl uniprot
Structure
1egx NMR Structure of EVH1 domain of human VASP
1usd 1use Crystal structure of C-terminal coil -coiled part of EVH2 domain of human VASP
1evh Crystal structure of EVH1 domain of Mena (Mus Musculus) in complex with FPPP peptide
Function and interaction
EVH1 domain of Mena/VASP binds to the cytoskeleton proteins containing FPPPP motif, such as vinculin [2], lamellipodin [3], zyxin [4], palladin [5] and Xin [6]. The Pro-rich region of Mena/VASP binds profilin and the SH3 and WW domains of various signaling and scaffolding proteins. EVH2 domain comprises F- ang G-Actin binding sites and C-terminal coiled coil region, also known as tetramerization domain [7]. It was shown recently that Mena binds with fibronectin receptor α5β1 integrin via “LERER" motif [8]. Regulation of VASP protein activity occurs through phosphorylation at Ser-157, Ser-239, and Thr-278 by cAMP and cGMP induced protein kinases (PCA/PCG) by unknown mechanisms. The first two phosphorylation sites are conserved in Mena and EVL contains only the first one [9] [10].
It is suggested that Mena/VASP bind to the barbed end of actin filaments and prevent their capping by CapZ [11].
Ena/VASP proteins contribute to the nucleation and elongation of actin filaments: Ena/VASP deficiency in lamellipodia results in abnormally short and highly branched filaments and their excess, in contrast, results in longer, sparsely branched filaments [12].
Pathology
It was shown that delocalization of Mena/VASP proteins from intercalated discs at the interface of myocytes causes the severe cardiomyopathy [13]. Mena invasive isoform has been detected in breast cancer patients with invasive ductal carcinomas [14].
References
- ↑ 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 Oct 18;87(2):227-39. PMID:8861907
- ↑ Reinhard M, Rudiger M, Jockusch BM, Walter U. VASP interaction with vinculin: a recurring theme of interactions with proline-rich motifs. FEBS Lett. 1996 Dec 9;399(1-2):103-7. PMID:8980130
- ↑ Krause M, Leslie JD, Stewart M, Lafuente EM, Valderrama F, Jagannathan R, Strasser GA, Rubinson DA, Liu H, Way M, Yaffe MB, Boussiotis VA, Gertler FB. Lamellipodin, an Ena/VASP ligand, is implicated in the regulation of lamellipodial dynamics. Dev Cell. 2004 Oct;7(4):571-83. PMID:15469845 doi:S1534580704003302
- ↑ Drees B, Friederich E, Fradelizi J, Louvard D, Beckerle MC, Golsteyn RM. Characterization of the interaction between zyxin and members of the Ena/vasodilator-stimulated phosphoprotein family of proteins. J Biol Chem. 2000 Jul 21;275(29):22503-11. PMID:10801818 doi:10.1074/jbc.M001698200
- ↑ Boukhelifa M, Parast MM, Bear JE, Gertler FB, Otey CA. Palladin is a novel binding partner for Ena/VASP family members. Cell Motil Cytoskeleton. 2004 May;58(1):17-29. PMID:14983521 doi:10.1002/cm.10173
- ↑ van der Ven PF, Ehler E, Vakeel P, Eulitz S, Schenk JA, Milting H, Micheel B, Furst DO. Unusual splicing events result in distinct Xin isoforms that associate differentially with filamin c and Mena/VASP. Exp Cell Res. 2006 Jul 1;312(11):2154-67. Epub 2006 Apr 24. PMID:16631741 doi:S0014-4827(06)00110-8
- ↑ Bachmann C, Fischer L, Walter U, Reinhard M. The EVH2 domain of the vasodilator-stimulated phosphoprotein mediates tetramerization, F-actin binding, and actin bundle formation. J Biol Chem. 1999 Aug 13;274(33):23549-57. PMID:10438535
- ↑ Gupton SL, Riquelme D, Hughes-Alford SK, Tadros J, Rudina SS, O Hynes R, Lauffenburger D, Gertler FB. Mena binds alpha5 integrin directly and modulates alpha5beta1 function. J Cell Biol. 2012 Aug 20;198(4):657-76. PMID:22908313 doi:10.1083/jcb.201202079
- ↑ Benz PM, Blume C, Seifert S, Wilhelm S, Waschke J, Schuh K, Gertler F, Munzel T, Renne T. Differential VASP phosphorylation controls remodeling of the actin cytoskeleton. J Cell Sci. 2009 Nov 1;122(Pt 21):3954-65. Epub 2009 Oct 13. PMID:19825941 doi:10.1242/jcs.044537
- ↑ Blume C, Benz PM, Walter U, Ha J, Kemp BE, Renne T. AMP-activated protein kinase impairs endothelial actin cytoskeleton assembly by phosphorylating vasodilator-stimulated phosphoprotein. J Biol Chem. 2007 Feb 16;282(7):4601-12. Epub 2006 Nov 2. PMID:17082196 doi:10.1074/jbc.M608866200
- ↑ Bachmann C, Fischer L, Walter U, Reinhard M. The EVH2 domain of the vasodilator-stimulated phosphoprotein mediates tetramerization, F-actin binding, and actin bundle formation. J Biol Chem. 1999 Aug 13;274(33):23549-57. PMID:10438535
- ↑ 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 May 17;109(4):509-21. PMID:12086607
- ↑ Eigenthaler M, Engelhardt S, Schinke B, Kobsar A, Schmitteckert E, Gambaryan S, Engelhardt CM, Krenn V, Eliava M, Jarchau T, Lohse MJ, Walter U, Hein L. Disruption of cardiac Ena-VASP protein localization in intercalated disks causes dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2003 Dec;285(6):H2471-81. Epub 2003 Aug, 21. PMID:12933343 doi:http://dx.doi.org/10.1152/ajpheart.00362.2003
- ↑ Roussos ET, Balsamo M, Alford SK, Wyckoff JB, Gligorijevic B, Wang Y, Pozzuto M, Stobezki R, Goswami S, Segall JE, Lauffenburger DA, Bresnick AR, Gertler FB, Condeelis JS. Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer. J Cell Sci. 2011 Jul 1;124(Pt 13):2120-31. PMID:21670198 doi:10.1242/jcs.086231
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