Group:MUZIC:Zyxin

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Contents

Introduction

Zyxin, meaning a joining[1], is a LIM domain protein of the zyxin/ajuba family, encoded by the gene ZYX [1], also known as ESP-2 and HED-2. Zyxin, is an important scaffolding protein that regulates actin dynamics in response to mechanical stress and shuttles between focal adhesions and the cell nucleus[2].

Sequence Annotation

The human gene encodes a 572-amino acid polypeptide with a molecular weight of 84kDa (Q15942). The polypeptide sequence displays 58% identity to chicken zyxin, having a proline-rich N-terminal region and 3 tandemly arranged LIM domains in the C-terminal region, which exhibits a characteristic arrangement of cysteine and histidine residues and represents a novel zinc binding sequence[3][4].

Function

Zyxin is a zinc-binding phosphoprotein that concentrates at cell-cell or cell-matrix adhesion sites, stress fiber bundles and along the actin cytoskeleton [5] [6]. Zyxin is specifically found in more mature adhesion sites (e.g. focal adhesions) [7], which are actin-rich structures that enable cells to adhere to the extracellular matrix[8] and its absence in early adhesions (e.g. focal complexes) is commonly used to distinguish the 'age' of an adhesion[9]. Zyxin exhibits a functional nuclear export signal that is required to keep zyxin concentrated in the cytoplasm and is sufficient to direct nuclear proteins to the cytosol. Furthermore, native zyxin shuttles between the nucleus and sites of cell adhesion in fibroblasts[10]. In cardiomyocytes, zyxin translocates to the nucleus in response to atrial natriuretic peptide/cGMP-dependent upstream signals, where it associates with AKT and enhances cell survival[11]. Zyxin play an important role in apoptosis as a critical regulator for the p53 Ser46 kinase HIPK2, which induces apoptosis in response to DNA damage[12]. It is postulate, that Zyxin may be a component of a signal transduction pathway that mediates adhesion-stimulated changes in gene expression [13]. The LIM domains of zyxin have been shown to bind to factors that control gene transcription[14] and they function as regulatory domains for controlling protein-protein interactions with components involved in cell-cell junction assembly [15] [16]. Zyxin is also thought to be autoregulated by an intramolecular interaction between the LIM domains and the VASP binding site [17]. The proline-rich domain may interact with SH3 domains of proteins involved in signal transduction pathways while the LIM domains are likely involved in protein-protein binding. Alternative splicing results in multiple transcript variants that encode the same isoform [18]. The main function of zyxin is to form a bridge between the adhesion components at the cell membrane and the internal cytoskeleton [19]. Zyxin is vital for coordinating matrix-dependent cues with actin dynamics; for example, within stress fibers and focal adhesions (FAs), zyxin acts as a mechanosensor that binds to areas where forces are applied[20][21] [22]. Not only is zyxin binding proportional to the mechanical force (e.g. decreased traction reduces zyxin-binding) but zyxin recruitment and stability at adhesion sites is tension-dependent[23][24]. Cellular adaptation to mechanical stress also involves redistribution of zyxin from FAs to stress fibers, which causes stress fiber thickening[25]. Mislocalization of zyxin leads to defects in cell migration and spreading[26][27] and its absence leads to increased cellular motility[28] preseumably through reduced adhesive strength[29]. Zyxin influences actin organization and assembly around FAs by recruiting Ena/VASP [30] [31] [32]. The initiation factor-independent mechanism, by which Ena/VASP may subsequently generate new actin filaments is still unknown[33].



300x

Interactions

Performing yeast two-hybrid analysis system, Yu and Luo found that zyxin interacts with myopodin with high affinity both in vitro and in vivo and that this interaction leads to slower migration of prostate cancer cells and reduced invasiveness [34]. The binding between zyxin and myopodin seems to be direct. Screening of a series of myopodin deletion mutants and peptide competition analyses revealed that myopodin is bound by zyxin at a site located within the sequence of the 19 amino acids at the myopodin COOH terminus. Importantly, this is the same region where the tumor suppressor activity of myopodin is located. The motility and invasion suppression activity of myopodin were significantly weakened in myopodin mutants lacking this sequence. Zyxin may be a critical functional regulator of myopodin. Zyxin interacts with the E6 Protein from Human Papillomavirus Type 6 and this interaction results in its nuclear translocation [35]. Furthermore Zyxin interact with h-warts/LATS1 tumor suppressor[36] forming a regulatory complex on mitotic apparatus and therefore is believed to play an important role in controlling mitosis progression. Zyxin has been shown also to interact with: Ena/VASP[37] [38] enhancing the production of actin-rich structures at the apical surface of cells, LASP1 (LIM and SH3 protein-1) [39] believed to play an important role in organization of focal adhesions and with Actinin alpha 1 and MLP [40], [41] essential for subcellular zyxin localization and alpha-actinin recruitment. Zyxin interact also with CARP-1 (via LIM domain).

Pathology

Zyxin is a tumor suppresor protein and its reduced expression has been associated with bladder cancer progression[42]. Zyxin has also tumour suppresor activity in Ewing sarcoma, a family of pediatric malignancies of bone and soft tissues, which are mainly associated with a t(11;22) chromosomal translocation encoding the EWS-FLI1 oncoprotein. zyxin gene transfer into EWS-FLI1-transformed fibroblasts elicits reconstitution of zyxin-rich focal adhesions and intercellular junctions, dramatic reorganization of the actin cytoskeleton, decreased cell motility, inhibition of anchorage-independent growth and impairment of tumor formation in athymic mice. Similar phenotypic changes were observed after zyxin gene transfer in SK-N-MC cells, suggesting that zyxin has tumor suppressor activity in Ewing tumor cells[43]. Zyxin act also as a tumour suppresor in hepatocellular carcinoma tumors, where was shown common upregulations of zyxin compared to their corresponding nonmalignant liver tissue (17/52 cases; 33%)[44].

References

  1. ↑ Crawford AW, Beckerle MC. Purification and characterization of zyxin, an 82,000-dalton component of adherens junctions. J Biol Chem. 1991 Mar 25;266(9):5847-53. PMID:2005121
  2. ↑ Sadler I, Crawford AW, Michelsen JW, Beckerle MC. Zyxin and cCRP: two interactive LIM domain proteins associated with the cytoskeleton. J Cell Biol. 1992 Dec;119(6):1573-87. PMID:1469049
  3. ↑ PMID: PMC46519
  4. ↑ Sadler I, Crawford AW, Michelsen JW, Beckerle MC. Zyxin and cCRP: two interactive LIM domain proteins associated with the cytoskeleton. J Cell Biol. 1992 Dec;119(6):1573-87. PMID:1469049
  5. ↑ Crawford AW, Beckerle MC. Purification and characterization of zyxin, an 82,000-dalton component of adherens junctions. J Biol Chem. 1991 Mar 25;266(9):5847-53. PMID:2005121
  6. ↑ Sadler I, Crawford AW, Michelsen JW, Beckerle MC. Zyxin and cCRP: two interactive LIM domain proteins associated with the cytoskeleton. J Cell Biol. 1992 Dec;119(6):1573-87. PMID:1469049
  7. ↑ Beningo KA, Dembo M, Kaverina I, Small JV, Wang YL. Nascent focal adhesions are responsible for the generation of strong propulsive forces in migrating fibroblasts. J Cell Biol. 2001 May 14;153(4):881-8. PMID:11352946
  8. ↑ Macalma T, Otte J, Hensler ME, Bockholt SM, Louis HA, Kalff-Suske M, Grzeschik KH, von der Ahe D, Beckerle MC. Molecular characterization of human zyxin. J Biol Chem. 1996 Dec 6;271(49):31470-8. PMID:8940160
  9. ↑ Zaidel-Bar R, Ballestrem C, Kam Z, Geiger B. Early molecular events in the assembly of matrix adhesions at the leading edge of migrating cells. J Cell Sci. 2003 Nov 15;116(Pt 22):4605-13. PMID:14576354 doi:10.1242/jcs.00792
  10. ↑ PMCID:2136768
  11. ↑ Abdel-Hay Hafiez A, Abdel Aziz MT, Talaat M. Some reproductive aspects in albino rats treated with steroids. J Egypt Med Assoc. 1975;58(1-2):83-93. PMID:1236670
  12. ↑ Miller JA, Jacobs HS. Treatment of hirsutism and acne with cyproterone acetate. Clin Endocrinol Metab. 1986 May;15(2):373-89. PMID:2941191
  13. ↑ Macalma T, Otte J, Hensler ME, Bockholt SM, Louis HA, Kalff-Suske M, Grzeschik KH, von der Ahe D, Beckerle MC. Molecular characterization of human zyxin. J Biol Chem. 1996 Dec 6;271(49):31470-8. PMID:8940160
  14. ↑ Martynova NY, Eroshkin FM, Ermolina LV, Ermakova GV, Korotaeva AL, Smurova KM, Gyoeva FK, Zaraisky AG. The LIM-domain protein Zyxin binds the homeodomain factor Xanf1/Hesx1 and modulates its activity in the anterior neural plate of Xenopus laevis embryo. Dev Dyn. 2008 Mar;237(3):736-49. PMID:18297730 doi:10.1002/dvdy.21471
  15. ↑ Hansen MD, Beckerle MC. Opposing roles of zyxin/LPP ACTA repeats and the LIM domain region in cell-cell adhesion. J Biol Chem. 2006 Jun 9;281(23):16178-88. Epub 2006 Apr 13. PMID:16613855 doi:10.1074/jbc.M512771200
  16. ↑ 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 Jan 16;378(3):625-8. Epub 2008 Dec 4. PMID:19061869 doi:10.1016/j.bbrc.2008.11.100
  17. ↑ 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 Jan 16;378(3):625-8. Epub 2008 Dec 4. PMID:19061869 doi:10.1016/j.bbrc.2008.11.100
  18. ↑ Gene ID: 7791
  19. ↑ Beckerle MC. Zyxin: zinc fingers at sites of cell adhesion. Bioessays. 1997 Nov;19(11):949-57. PMID:9394617 doi:10.1002/bies.950191104
  20. ↑ Lele TP, Pendse J, Kumar S, Salanga M, Karavitis J, Ingber DE. Mechanical forces alter zyxin unbinding kinetics within focal adhesions of living cells. J Cell Physiol. 2006 Apr;207(1):187-94. PMID:16288479 doi:10.1002/jcp.20550
  21. ↑ Colombelli J, Besser A, Kress H, Reynaud EG, Girard P, Caussinus E, Haselmann U, Small JV, Schwarz US, Stelzer EH. Mechanosensing in actin stress fibers revealed by a close correlation between force and protein localization. J Cell Sci. 2009 May 15;122(Pt 10):1665-79. Epub 2009 Apr 28. PMID:19401336 doi:10.1242/jcs.042986
  22. ↑ Yoshigi M, Hoffman LM, Jensen CC, Yost HJ, Beckerle MC. Mechanical force mobilizes zyxin from focal adhesions to actin filaments and regulates cytoskeletal reinforcement. J Cell Biol. 2005 Oct 24;171(2):209-15. PMID:16247023 doi:10.1083/jcb.200505018
  23. ↑ Lele TP, Pendse J, Kumar S, Salanga M, Karavitis J, Ingber DE. Mechanical forces alter zyxin unbinding kinetics within focal adhesions of living cells. J Cell Physiol. 2006 Apr;207(1):187-94. PMID:16288479 doi:10.1002/jcp.20550
  24. ↑ Colombelli J, Besser A, Kress H, Reynaud EG, Girard P, Caussinus E, Haselmann U, Small JV, Schwarz US, Stelzer EH. Mechanosensing in actin stress fibers revealed by a close correlation between force and protein localization. J Cell Sci. 2009 May 15;122(Pt 10):1665-79. Epub 2009 Apr 28. PMID:19401336 doi:10.1242/jcs.042986
  25. ↑ Yoshigi M, Hoffman LM, Jensen CC, Yost HJ, Beckerle MC. Mechanical force mobilizes zyxin from focal adhesions to actin filaments and regulates cytoskeletal reinforcement. J Cell Biol. 2005 Oct 24;171(2):209-15. PMID:16247023 doi:10.1083/jcb.200505018
  26. ↑ Drees BE, Andrews KM, Beckerle MC. Molecular dissection of zyxin function reveals its involvement in cell motility. J Cell Biol. 1999 Dec 27;147(7):1549-60. PMID:10613911
  27. ↑ 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
  28. ↑ Hoffman LM, Jensen CC, Kloeker S, Wang CL, Yoshigi M, Beckerle MC. Genetic ablation of zyxin causes Mena/VASP mislocalization, increased motility, and deficits in actin remodeling. J Cell Biol. 2006 Feb 27;172(5):771-82. PMID:16505170 doi:10.1083/jcb.200512115
  29. ↑ Ngu H, Feng Y, Lu L, Oswald SJ, Longmore GD, Yin FC. Effect of focal adhesion proteins on endothelial cell adhesion, motility and orientation response to cyclic strain. Ann Biomed Eng. 2010 Jan;38(1):208-22. Epub 2009 Oct 27. PMID:19856213 doi:10.1007/s10439-009-9826-7
  30. ↑ 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
  31. ↑ Hoffman LM, Jensen CC, Kloeker S, Wang CL, Yoshigi M, Beckerle MC. Genetic ablation of zyxin causes Mena/VASP mislocalization, increased motility, and deficits in actin remodeling. J Cell Biol. 2006 Feb 27;172(5):771-82. PMID:16505170 doi:10.1083/jcb.200512115
  32. ↑ Nix DA, Fradelizi J, Bockholt S, Menichi B, Louvard D, Friederich E, Beckerle MC. Targeting of zyxin to sites of actin membrane interaction and to the nucleus. J Biol Chem. 2001 Sep 14;276(37):34759-67. Epub 2001 Jun 6. PMID:11395501 doi:10.1074/jbc.M102820200
  33. ↑ Zaidel-Bar R, Ballestrem C, Kam Z, Geiger B. Early molecular events in the assembly of matrix adhesions at the leading edge of migrating cells. J Cell Sci. 2003 Nov 15;116(Pt 22):4605-13. PMID:14576354 doi:10.1242/jcs.00792
  34. ↑ Yu YP, Tseng GC, Luo JH. Inactivation of myopodin expression associated with prostate cancer relapse. Urology. 2006 Sep;68(3):578-82. Epub 2006 Sep 18. PMID:16979744 doi:10.1016/j.urology.2006.03.027
  35. ↑ Degenhardt YY, Silverstein S. Interaction of zyxin, a focal adhesion protein, with the e6 protein from human papillomavirus type 6 results in its nuclear translocation. J Virol. 2001 Dec;75(23):11791-802. PMID:11689660 doi:10.1128/JVI.75.23.11791-11802.2001
  36. ↑ Hirota T, Morisaki T, Nishiyama Y, Marumoto T, Tada K, Hara T, Masuko N, Inagaki M, Hatakeyama K, Saya H. Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor. J Cell Biol. 2000 May 29;149(5):1073-86. PMID:10831611
  37. ↑ 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
  38. ↑ Harbeck B, Huttelmaier S, Schluter K, Jockusch BM, Illenberger S. Phosphorylation of the vasodilator-stimulated phosphoprotein regulates its interaction with actin. J Biol Chem. 2000 Oct 6;275(40):30817-25. PMID:10882740 doi:10.1074/jbc.M005066200
  39. ↑ Li B, Zhuang L, Trueb B. Zyxin interacts with the SH3 domains of the cytoskeletal proteins LIM-nebulette and Lasp-1. J Biol Chem. 2004 May 7;279(19):20401-10. Epub 2004 Mar 5. PMID:15004028 doi:10.1074/jbc.M310304200
  40. ↑ Reinhard M, Zumbrunn J, Jaquemar D, Kuhn M, Walter U, Trueb B. An alpha-actinin binding site of zyxin is essential for subcellular zyxin localization and alpha-actinin recruitment. J Biol Chem. 1999 May 7;274(19):13410-8. PMID:10224105
  41. ↑ Li B, Trueb B. Analysis of the alpha-actinin/zyxin interaction. J Biol Chem. 2001 Sep 7;276(36):33328-35. Epub 2001 Jun 22. PMID:11423549 doi:10.1074/jbc.M100789200
  42. ↑ Sanchez-Carbayo M, Socci ND, Charytonowicz E, Lu M, Prystowsky M, Childs G, Cordon-Cardo C. Molecular profiling of bladder cancer using cDNA microarrays: defining histogenesis and biological phenotypes. Cancer Res. 2002 Dec 1;62(23):6973-80. PMID:12460915
  43. ↑ Amsellem V, Kryszke MH, Hervy M, Subra F, Athman R, Leh H, Brachet-Ducos C, Auclair C. The actin cytoskeleton-associated protein zyxin acts as a tumor suppressor in Ewing tumor cells. Exp Cell Res. 2005 Apr 1;304(2):443-56. Epub 2004 Dec 13. PMID:15748890 doi:10.1016/j.yexcr.2004.10.035
  44. ↑ Sy SM, Lai PB, Pang E, Wong NL, To KF, Johnson PJ, Wong N. Novel identification of zyxin upregulations in the motile phenotype of hepatocellular carcinoma. Mod Pathol. 2006 Aug;19(8):1108-16. Epub 2006 May 5. PMID:16680155 doi:10.1038/modpathol.3800626

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