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VCL  -  vinculin

Homo sapiens

 
 
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Disease relevance of VCL

  • A novel missense mutation, L277M-VCL, involving a conserved residue was identified in a patient with severely obstructive, mid-ventricular hypertrophy [1].
  • Vinculin proteolysis unmasks an ActA homolog for actin-based Shigella motility [2].
  • To characterize the ligand recruitment ability of the different vinculin domains in a cellular environment, we used a novel approach of comprising chimeric proteins of either the vinculin head, hinge or tail regions, fused to the membrane anchor sequence of ActA, a surface protein of the intracellular bacterial pathogen Listeria monocytogenes [3].
  • The R975W mutation, in the alternatively spliced exon 19 of vinculin (VCL) which yields the isoform metavinculin, was associated previously with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), and shown to alter in vivo organization of intercalated discs [1].
  • Six myotonic dystrophy cases and 4 inflammatory myopathy cases with regenerating fibers were also studied: dystrophin and the membrane cytoskeletal proteins were normally expressed in the former; and dystrophin, spectrin, and vinculin were reduced in the latter [4].
 

High impact information on VCL

 

Chemical compound and disease context of VCL

 

Biological context of VCL

  • Complementary physical and genetic techniques map the vinculin (VCL) gene on chromosome 10q [13].
  • Despite its ubiquitous expression, the HCM-associated VCL mutation clinically yielded a cardiac-specific phenotype [1].
  • Two new crystal structures reveal that vinculin exhibits a high degree of structural plasticity upon ligand binding that might promote rapid changes in cell adhesion [14].
  • Using a Forster resonance energy transfer probe that reports on changes in vinculin's conformation, we find that vinculin is in the actin-binding conformation in a peripheral band of adhesive puncta in spreading cells [15].
  • We have mapped the binding site for the Arp2/3 complex to the hinge region of vinculin, and a point mutation in this region selectively blocks binding to the Arp2/3 complex [16].
 

Anatomical context of VCL

  • Time-lapse imaging reveals a gradient of conformational change that precedes loss of vinculin from focal adhesions in retracting regions [15].
  • alpha-Catenin-vinculin interaction functions to organize the apical junctional complex in epithelial cells [17].
  • In platelets with tangentially radiating microfilaments, vinculin patches are aligned on the branches of a two-armed spiral [18].
  • It is suggested that the distribution of vinculin is due to competitive aggregation of vinculin close to the inner leaflet of the ventral plasma membrane and that sites of cytoskeleton-membrane linkage are important for generating supramolecular asymmetries of biological systems [18].
  • We have determined the complete sequence of human vinculin, a cytoskeletal protein associated with cell-cell and cell-matrix junctions [19].
 

Associations of VCL with chemical compounds

  • The recruitment of the Arp2/3 complex to vinculin may be one mechanism through which actin polymerization and membrane protrusion are coupled to integrin-mediated adhesion [16].
  • When an NH2-terminal alphaE-catenin fragment, which is by itself unable to organize the TJ, was fused with the vinculin tail, this chimeric molecule could induce TJ assembly in the alphaE-catenin-deficient cells [17].
  • Vinculin has one proline-rich region where two proline-rich sequences are located [20].
  • The tyrosine phosphorylation sites in vinculin were mapped to residues 100 and 1065 [21].
  • We propose that PIP2-dependent signalling modulates microfilament organization at cellular adhesion sites by regulating vinculin-VASP complexes [22].
 

Physical interactions of VCL

 

Co-localisations of VCL

 

Regulatory relationships of VCL

 

Other interactions of VCL

  • Tyrosine kinase inhibition also failed to block the ability of ligand occupancy plus integrin aggregation to trigger transmembrane accumulation of the three cytoskeletal molecules talin, alpha-actinin, and vinculin; these molecules accumulated even in the presence of cytochalasin D [38].
  • Coimmunoprecipitation studies confirm that the ability of pp125(FAK) to associate with paxillin, vinculin, and p130cas is significantly reduced in SMC treated with degraded collagen fragments [39].
  • This motif is also present and functional in at least two cellular proteins, zyxin and vinculin, which are in this respect major eukaryotic analogs of ActA [40].
  • Earlier findings demonstrated that vinculin p90 binds to IcsA (Suzuki, T.A., S. Saga, and C. Sasakawa. 1996. J. Biol. Chem. 271:21878-21885) and to vasodilator-stimulated phosphoprotein (VASP) (Brindle, N.P.J., M. R. Hold, J.E. Davies, C.J. Price, and D.R. Critchley. 1996. Biochem. J. 318:753-757) [2].
  • By screening a yeast two-hybrid library with COOH-terminal fragments of vinculin/metavinculin as the bait, we identified a new protein termed raver1 [41].
 

Analytical, diagnostic and therapeutic context of VCL

References

  1. A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy. Vasile, V.C., Ommen, S.R., Edwards, W.D., Ackerman, M.J. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  2. Vinculin proteolysis unmasks an ActA homolog for actin-based Shigella motility. Laine, R.O., Zeile, W., Kang, F., Purich, D.L., Southwick, F.S. J. Cell Biol. (1997) [Pubmed]
  3. Ligand recruitment by vinculin domains in transfected cells. Bubeck, P., Pistor, S., Wehland, J., Jockusch, B.M. J. Cell. Sci. (1997) [Pubmed]
  4. Fetus-like dystrophin expression and other cytoskeletal protein abnormalities in centronuclear myopathies. Mora, M., Morandi, L., Merlini, L., Vita, G., Baradello, A., Barresi, R., Di Blasi, C., Blasevich, F., Gebbia, M., Daniel, S. Muscle Nerve (1994) [Pubmed]
  5. Phosphorylation of vinculin by pp60src: what might it mean? Hynes, R. Cell (1982) [Pubmed]
  6. A transmembrane relationship between fibronectin and vinculin (130 kd protein): serum modulation in normal and transformed hamster fibroblasts. Singer, I.I., Paradiso, P.R. Cell (1981) [Pubmed]
  7. Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Ling, K., Doughman, R.L., Firestone, A.J., Bunce, M.W., Anderson, R.A. Nature (2002) [Pubmed]
  8. Apoptotic cells overexpress vinculin and induce vinculin-specific cytotoxic T-cell cross-priming. Propato, A., Cutrona, G., Francavilla, V., Ulivi, M., Schiaffella, E., Landt, O., Dunbar, R., Cerundolo, V., Ferrarini, M., Barnaba, V. Nat. Med. (2001) [Pubmed]
  9. Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Avizienyte, E., Wyke, A.W., Jones, R.J., McLean, G.W., Westhoff, M.A., Brunton, V.G., Frame, M.C. Nat. Cell Biol. (2002) [Pubmed]
  10. A novel bacterial virulence gene in Listeria monocytogenes required for host cell microfilament interaction with homology to the proline-rich region of vinculin. Domann, E., Wehland, J., Rohde, M., Pistor, S., Hartl, M., Goebel, W., Leimeister-Wächter, M., Wuenscher, M., Chakraborty, T. EMBO J. (1992) [Pubmed]
  11. Increased phosphorylation of tyrosine in vinculin does not occur upon transformation by some avian sarcoma viruses. Antler, A.M., Greenberg, M.E., Edelman, G.M., Hanafusa, H. Mol. Cell. Biol. (1985) [Pubmed]
  12. Formation of vinculin plaques precedes other cytoskeletal changes during retinoic acid-induced teratocarcinoma cell differentiation. Lehtonen, E., Lehto, V.P., Badley, R.A., Virtanen, I. Exp. Cell Res. (1983) [Pubmed]
  13. Complementary physical and genetic techniques map the vinculin (VCL) gene on chromosome 10q. Mulligan, L.M., Gardner, E., Telenius, H., Ponder, B.A. Genomics (1992) [Pubmed]
  14. Vinculin--a dynamic regulator of cell adhesion. Demali, K.A. Trends Biochem. Sci. (2004) [Pubmed]
  15. Spatial distribution and functional significance of activated vinculin in living cells. Chen, H., Cohen, D.M., Choudhury, D.M., Kioka, N., Craig, S.W. J. Cell Biol. (2005) [Pubmed]
  16. Recruitment of the Arp2/3 complex to vinculin: coupling membrane protrusion to matrix adhesion. DeMali, K.A., Barlow, C.A., Burridge, K. J. Cell Biol. (2002) [Pubmed]
  17. alpha-Catenin-vinculin interaction functions to organize the apical junctional complex in epithelial cells. Watabe-Uchida, M., Uchida, N., Imamura, Y., Nagafuchi, A., Fujimoto, K., Uemura, T., Vermeulen, S., van Roy, F., Adamson, E.D., Takeichi, M. J. Cell Biol. (1998) [Pubmed]
  18. Pattern formation and handedness in the cytoskeleton of human platelets. Hagmann, J. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  19. Complete sequence of human vinculin and assignment of the gene to chromosome 10. Weller, P.A., Ogryzko, E.P., Corben, E.B., Zhidkova, N.I., Patel, B., Price, G.J., Spurr, N.K., Koteliansky, V.E., Critchley, D.R. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  20. Ponsin/SH3P12: an l-afadin- and vinculin-binding protein localized at cell-cell and cell-matrix adherens junctions. Mandai, K., Nakanishi, H., Satoh, A., Takahashi, K., Satoh, K., Nishioka, H., Mizoguchi, A., Takai, Y. J. Cell Biol. (1999) [Pubmed]
  21. The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreading. Zhang, Z., Izaguirre, G., Lin, S.Y., Lee, H.Y., Schaefer, E., Haimovich, B. Mol. Biol. Cell (2004) [Pubmed]
  22. The interaction of the cell-contact proteins VASP and vinculin is regulated by phosphatidylinositol-4,5-bisphosphate. Hüttelmaier, S., Mayboroda, O., Harbeck, B., Jarchau, T., Jockusch, B.M., Rüdiger, M. Curr. Biol. (1998) [Pubmed]
  23. Two distinct head-tail interfaces cooperate to suppress activation of vinculin by talin. Cohen, D.M., Chen, H., Johnson, R.P., Choudhury, B., Craig, S.W. J. Biol. Chem. (2005) [Pubmed]
  24. VASP interaction with vinculin: a recurring theme of interactions with proline-rich motifs. Reinhard, M., Rüdiger, M., Jockusch, B.M., Walter, U. FEBS Lett. (1996) [Pubmed]
  25. Identification of LIM3 as the principal determinant of paxillin focal adhesion localization and characterization of a novel motif on paxillin directing vinculin and focal adhesion kinase binding. Brown, M.C., Perrotta, J.A., Turner, C.E. J. Cell Biol. (1996) [Pubmed]
  26. Identification of integrin collagen receptors on human melanoma cells. Kramer, R.H., Marks, N. J. Biol. Chem. (1989) [Pubmed]
  27. Synemin may function to directly link muscle cell intermediate filaments to both myofibrillar Z-lines and costameres. Bellin, R.M., Huiatt, T.W., Critchley, D.R., Robson, R.M. J. Biol. Chem. (2001) [Pubmed]
  28. HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells. Natarajan, M., Stewart, J.E., Golemis, E.A., Pugacheva, E.N., Alexandropoulos, K., Cox, B.D., Wang, W., Grammer, J.R., Gladson, C.L. Oncogene (2006) [Pubmed]
  29. The protooncogene product, PEBP2beta/CBFbeta, is mainly located in the cytoplasm and has an affinity with cytoskeletal structures. Tanaka, Y., Watanabe, T., Chiba, N., Niki, M., Kuroiwa, Y., Nishihira, T., Satomi, S., Ito, Y., Satake, M. Oncogene (1997) [Pubmed]
  30. Localization of fibronectin matrix assembly sites on fibroblasts and endothelial cells. Christopher, R.A., Kowalczyk, A.P., McKeown-Longo, P.J. J. Cell. Sci. (1997) [Pubmed]
  31. Inhibitor of growth 4 suppresses cell spreading and cell migration by interacting with a novel binding partner, liprin alpha1. Shen, J.C., Unoki, M., Ythier, D., Duperray, A., Varticovski, L., Kumamoto, K., Pedeux, R., Harris, C.C. Cancer Res. (2007) [Pubmed]
  32. Adhesive properties of isolated chick osteocytes in vitro. Aarden, E.M., Nijweide, P.J., van der Plas, A., Alblas, M.J., Mackie, E.J., Horton, M.A., Helfrich, M.H. Bone (1996) [Pubmed]
  33. Structural basis for amplifying vinculin activation by talin. Izard, T., Vonrhein, C. J. Biol. Chem. (2004) [Pubmed]
  34. Coincidence of actin filaments and talin is required to activate vinculin. Chen, H., Choudhury, D.M., Craig, S.W. J. Biol. Chem. (2006) [Pubmed]
  35. MAGI-1 is required for Rap1 activation upon cell-cell contact and for enhancement of vascular endothelial cadherin-mediated cell adhesion. Sakurai, A., Fukuhara, S., Yamagishi, A., Sako, K., Kamioka, Y., Masuda, M., Nakaoka, Y., Mochizuki, N. Mol. Biol. Cell (2006) [Pubmed]
  36. The role of p42/44 MAPK and protein kinase B in connective tissue growth factor induced extracellular matrix protein production, cell migration, and actin cytoskeletal rearrangement in human mesangial cells. Crean, J.K., Finlay, D., Murphy, M., Moss, C., Godson, C., Martin, F., Brady, H.R. J. Biol. Chem. (2002) [Pubmed]
  37. TNF-alpha promotes a stop signal that inhibits neutrophil polarization and migration via a p38 MAPK pathway. Lokuta, M.A., Huttenlocher, A. J. Leukoc. Biol. (2005) [Pubmed]
  38. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. Miyamoto, S., Teramoto, H., Coso, O.A., Gutkind, J.S., Burbelo, P.D., Akiyama, S.K., Yamada, K.M. J. Cell Biol. (1995) [Pubmed]
  39. Degraded collagen fragments promote rapid disassembly of smooth muscle focal adhesions that correlates with cleavage of pp125(FAK), paxillin, and talin. Carragher, N.O., Levkau, B., Ross, R., Raines, E.W. J. Cell Biol. (1999) [Pubmed]
  40. 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. Niebuhr, K., Ebel, F., Frank, R., Reinhard, M., Domann, E., Carl, U.D., Walter, U., Gertler, F.B., Wehland, J., Chakraborty, T. EMBO J. (1997) [Pubmed]
  41. Raver1, a dual compartment protein, is a ligand for PTB/hnRNPI and microfilament attachment proteins. Hüttelmaier, S., Illenberger, S., Grosheva, I., Rüdiger, M., Singer, R.H., Jockusch, B.M. J. Cell Biol. (2001) [Pubmed]
  42. Dilated cardiomyopathy associated with deficiency of the cytoskeletal protein metavinculin. Maeda, M., Holder, E., Lowes, B., Valent, S., Bies, R.D. Circulation (1997) [Pubmed]
  43. Vinculin in relation to stress fibers in spread platelets. Nachmias, V.T., Golla, R. Cell Motil. Cytoskeleton (1991) [Pubmed]
  44. An additional exon in the human vinculin gene specifically encodes meta-vinculin-specific difference peptide. Cross-species comparison reveals variable and conserved motifs in the meta-vinculin insert. Koteliansky, V.E., Ogryzko, E.P., Zhidkova, N.I., Weller, P.A., Critchley, D.R., Vancompernolle, K., Vandekerckhove, J., Strasser, P., Way, M., Gimona, M. Eur. J. Biochem. (1992) [Pubmed]
 
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