Skip to main content
SpringerLink
Log in

Tetraspanins and cell membrane tubular structures

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Tetraspanins regulate a variety of cellular functions. However, the general cellular mechanisms by which tetraspanins regulate these functions remain poorly understood. In this article we collected the observations that tetraspanins regulate the formation and/or development of various tubular structures of cell membrane. Because tetraspanins and their associated proteins (1) are localized at the tubular structures, such as the microvilli, adhesion zipper, foot processes, and penetration peg, and/or (2) regulate the morphogenesis of these membrane tubular structures, tetraspanins probably modulate various cellular functions through these membrane tubular structures. Some tetraspanins inhibit membrane tubule formation and/or extension, while others promote them. We predict that tetraspanins regulate the formation and/or development of various membrane tubular structures: (1) microvilli or nanovilli at the plasma membranes free of cell and matrix contacts, (2) membrane tubules at the plasma membrane of cell-matrix and cell-cell interfaces, and (3) membrane tubules at the intracellular membrane compartments. These different membrane tubular structures likely share a common morphogenetic mechanism that involves tetraspanins. Tetraspanins probably regulate the morphogenesis of membrane tubular structures by altering (1) the biophysical properties of the cell membrane such as curvature and/or (2) the membrane connections of cytoskeleton. Since membrane tubular structures are associated with cell functions such as adhesion, migration, and intercellular communication, in all of which tetraspanins are involved, the differential effects of tetraspanins on membrane tubular structures likely lead to the functional difference of tetraspanins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

EM:

Electron microscopy

ERM:

Ezrin/radixin/moesin

Memtubs:

Membrane tubular structures

MVB:

Multi-vesicular body

TEM:

Tetraspanin-enriched microdomain

References

  1. Horejsi V, Vlcek C (1991) Novel structurally distinct family of leucocyte surface glycoproteins including CD9, CD37, CD53 and CD63. FEBS Lett 288:1–4

    Article  PubMed  CAS  Google Scholar 

  2. Wright MD, Tomlinson MG (1994) The ins and outs of the transmembrane 4 superfamily. Immunol Today 15:588–594

    Article  PubMed  CAS  Google Scholar 

  3. Maecker HT, Todd SC, Levy S (1997) The tetraspanin superfamily: molecular facilitators. FASEB J 11:428–442

    PubMed  CAS  Google Scholar 

  4. Boucheix C, Rubinstein E (2001) Tetraspanins. Cell Mol Life Sci 58:1189–1205

    Article  PubMed  CAS  Google Scholar 

  5. Hemler ME (2005) Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 6:801–811

    Article  PubMed  CAS  Google Scholar 

  6. Richardson MM, Jennings LK, Zhang XA (2011) Tetraspanins and tumor progression. Clin Exp Metastasis 28:261–270

    Article  PubMed  CAS  Google Scholar 

  7. Zhang F, Kotha JP, Jennings LK, Zhang XA (2009) Tetraspanins and vascular function. Cardiovasc Res 83:7–15

    Article  PubMed  CAS  Google Scholar 

  8. Shum WW, Da Silva N, McKee M, Smith PJ, Brown D, Breton S (2008) Transepithelial projections from basal cells are luminal sensors in pseudostratified epithelia. Cell 135:1108–1117

    Article  PubMed  CAS  Google Scholar 

  9. Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, Vyas JM, Boes M, Ploegh HL, Fox JG, Littman DR, Reinecker HC (2005) CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307:254–258

    Article  PubMed  CAS  Google Scholar 

  10. Bari R, Guo Q, Xia B, Zhang YH, Giesert EE, Levy S, Zheng JJ, Zhang XA (2011) Tetraspanins regulate the protrusive activities of cell membrane. Biochem Biophys Res Commun 415:619–626

    Article  PubMed  CAS  Google Scholar 

  11. Gerdes H–H, Bukoreshtliev NV, Barroso JFV (2007) Tunneling nanotubes: a new route for the exchange of components between animal cells. FEBS Lett 581:2194–2201

    Article  PubMed  CAS  Google Scholar 

  12. Sherer NM, Mothes W (2008) Cytonemes and tunneling nanotubules in cell–cell communication and viral pathogenesis. Trends Cell Biol 18:414–420

    Article  PubMed  CAS  Google Scholar 

  13. Faix J, Rottner K (2006) The making of filopodia. Curr Opin Cell Biol 18:18–25

    Article  PubMed  CAS  Google Scholar 

  14. Mattila PK, Lappalainen P (2008) Filopodia: molecular architecture and cellular functions. Nat Rev Mol Cell Biol 9:446–454

    Article  PubMed  CAS  Google Scholar 

  15. Monsky WL, Chen WT (1993) Proteases of cell adhesion proteins in cancer. Semin Cancer Biol 4:251–258

    PubMed  CAS  Google Scholar 

  16. Gimona M, Buccione R, Courtneidge SA, Linder S (2008) Assembly and biological role of podosomes and invadopodia. Curr Opin Cell Biol 20:235–241

    Article  PubMed  CAS  Google Scholar 

  17. McConnell RE, Higginbotham JN, Shifrin DA Jr, Tabb DL, Coffey RJ, Tyska MJ (2009) The enterocyte microvillus is a vesicle-generating organelle. J Cell Biol 185:1285–1298

    Article  PubMed  CAS  Google Scholar 

  18. Kaji K, Oda S, Shikano T, Ohnuki T, Uematsu Y, Sakagami J, Tada N, Miyazaki S, Kudo A (2000) The gamete fusion process is defective in eggs of CD9-deficient mice. Nat Genet 24:279–282

    Article  PubMed  CAS  Google Scholar 

  19. Runge KE, Evans JE, He Z-Y, Gupta S, McDonald KL, Stahlberg H, Primakoff P, Myles DG (2007) Oocyte CD9 is enriched on the microvillar membrane and required for normal microvillar shape and distribution. Dev Biol 304:317–325

    Article  PubMed  CAS  Google Scholar 

  20. Miyado K, Yoshida K, Yamagata K, Sakakibara K, Okabe M, Wang X, Miyamoto K, Akutsu H, Kondo T, Takahashi Y, Ban T, Ito C, Toshimori K, Nakamura A, Ito M, Miyado M, Mekada E, Umezawa A (2008) The fusing ability of sperm is bestowed by CD9-containing vesicles released from eggs in mice. Proc Natl Acad Sci USA 105:12921–12926

    Article  PubMed  CAS  Google Scholar 

  21. Israels SJ, McMillan-Ward EM (2007) Platelet tetraspanin complexes and their association with lipid rafts. Thromb Haemost 98:1081–1087

    PubMed  CAS  Google Scholar 

  22. Brisson C, Azorsa DO, Jennings LK, Moog S, Cazenave JP, Lanza F (1997) Co-localization of CD9 and GPIIb-IIIa (alpha IIb beta 3 integrin) on activated platelet pseudopods and alpha-granule membranes. Histochem J 29:153–165

    Article  PubMed  CAS  Google Scholar 

  23. Pan Y, Brown C, Wang X, Geisert EE (2007) The developmental regulation of CD81 in the rat retina. Mol Vis 13:181–189

    PubMed  CAS  Google Scholar 

  24. Zukauskas A, Merley A, Li D, Ang LH, Sciuto TE, Salman S, Dvorak AM, Dvorak HF, Jaminet SC (2011) TM4SF1: a tetraspanin-like protein necessary for nanopodia formation and endothelial cell migration. Angiogenesis 14:345–354

    Article  PubMed  CAS  Google Scholar 

  25. Vasioukhin V, Bauer C, Yin M, Fuchs E (2000) Directed actin polymerization is the driving force for epithelial cell–cell adhesion. Cell 100:209–219

    Article  PubMed  CAS  Google Scholar 

  26. Jacinto A, Wood W, Balayo T, Turmaine M, Martinez-Arias A, Martin P (2000) Dynamic actin-based epithelial adhesion and cell matching during Drosophila dorsal closure. Curr Biol 10:1420–1426

    Article  PubMed  CAS  Google Scholar 

  27. Raich WB, Agbunag C, Hardin J (1999) Rapid epithelial-sheet sealing in the Caenorhabditis elegans embryo requires cadherin-dependent filopodial priming. Curr Biol 9:1139–1146

    Article  PubMed  CAS  Google Scholar 

  28. Zhang F, Michaelson JE, Moshiach S, Sachs N, Zhao W, Sun Y, Sonnenberg A, Lahti JM, Huang H, Zhang XA (2011) Tetraspanin CD151 maintains vascular stability by balancing the forces of cell adhesion and cytoskeletal tension. Blood 118:4274–4284

    Article  PubMed  CAS  Google Scholar 

  29. Singethan K, Müller N, Schubert S, Lüttge D, Krementsov DN, Khurana SR, Krohne G, Schneider-Schaulies S, Thali M, Schneider-Schaulies J (2008) CD9 clustering and formation of microvilli zippers between contacting cells regulates virus-induced cell fusion. Traffic 9:924–935

    Article  PubMed  CAS  Google Scholar 

  30. Garcia-España A, Chung PJ, Sarkar IN, Stiner E, Sun TT, Desalle R (2008) Appearance of new tetraspanin genes during vertebrate evolution. Genomics 91:326–334

    Article  PubMed  Google Scholar 

  31. Huang S, Yuan S, Dong M, Su J, Yu C, Shen Y, Xie X, Yu Y, Yu X, Chen S, Zhang S, Pontarotti P, Xu A (2005) The phylogenetic analysis of tetraspanins projects the evolution of cell–cell interactions from unicellular to multicellular organisms. Genomics 86:674–684

    Article  PubMed  CAS  Google Scholar 

  32. Kreidberg JA, Donovan MJ, Goldstein SL, Rennke H, Shepherd K, Jones RC, Jaenisch R (1996) Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development 122:3537–3547

    PubMed  CAS  Google Scholar 

  33. Sachs N, Kreft M, van den Bergh Weerman MA, Beynon AJ, Peters TA, Weening J, Sonnenberg A (2006) Kidney failure in mice lacking the tetraspanin CD151. J Cell Biol 175:33–39

    Article  PubMed  CAS  Google Scholar 

  34. Baleato RM, Guthrie PL, Gubler MC, Ashman LK, Roselli S (2008) Deletion of CD151 results in a strain-dependent glomerular disease due to severe alterations of the glomerular basement membrane. Am J Pathol 173:927–937

    Article  PubMed  CAS  Google Scholar 

  35. Clergeot PH, Gourgues M, Cots J, Laurans F, Latorse MP, Pepin R, Tharreau D, Notteghem JL, Lebrun MH (2001) PLS1, a gene encoding a tetraspanin-like protein, is required for penetration of rice leaf by the fungal pathogen Magnaporthe grisea. Proc Natl Acad Sci USA 98:6963–6968

    Article  PubMed  CAS  Google Scholar 

  36. Escola JM, Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, Geuze HJ (1998) Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem 273:20121–201277

    Article  PubMed  CAS  Google Scholar 

  37. Xu C, Zhang YH, Thangavel M, Richardson MM, Liu L, Zhou B, Zheng Y, Ostrom RS, Zhang XA (2009) CD82 endocytosis and cholesterol-dependent reorganization of tetraspanin webs and lipid rafts. FASEB J. 23:3273–3288

    Article  PubMed  CAS  Google Scholar 

  38. Quast T, Eppler F, Semmling V, Schild C, Homsi Y, Levy S, Lang T, Kurts C, Kolanus W (2011) CD81 is essential for the formation of membrane protrusions and regulates Rac1-activation in adhesion-dependent immune cell migration. Blood 118:1818–1827

    Article  PubMed  CAS  Google Scholar 

  39. Wang HX, Kolesnikova TV, Denison C, Gygi SP, Hemler ME (2011) The C-terminal tail of tetraspanin protein CD9 contributes to its function and molecular organization. J Cell Sci 124:2702–2710

    Article  PubMed  CAS  Google Scholar 

  40. Shigeta M, Sanzen N, Ozawa M, Gu J, Hasegawa H, Sekiguchi K (2003) CD151 regulates epithelial cell–cell adhesion through PKC- and Cdc42-dependent actin cytoskeletal reorganization. J Cell Biol 163:165–176

    Article  PubMed  CAS  Google Scholar 

  41. Bari R, Zhang YH, Zhang F, Wang NX, Stipp CS, Zheng JJ, Zhang XA (2009) The transmembrane domain interactions are needed for kai1/cd82-mediated suppression of cancer invasion and metastasis. Am J Pathol 174:647–660

    Article  PubMed  CAS  Google Scholar 

  42. Zyłkiewicz E, Nowakowska J, Maleszewski M (2010) Decrease in CD9 content and reorganization of microvilli may contribute to the oolemma block to sperm penetration during fertilization of mouse oocyte. Zygote 18:195–201

    Article  PubMed  Google Scholar 

  43. Jégou A, Ziyyat A, Barraud-Lange V, Perez E, Wolf JP, Pincet F, Gourier C (2011) CD9 tetraspanin generates fusion competent sites on the egg membrane for mammalian fertilization. Proc Natl Acad Sci USA 108:10946–10951

    Article  PubMed  Google Scholar 

  44. Kopczynski CC, Davis GW, Goodman CS (1996) A neural tetraspanin, encoded by late bloomer, that facilitates synapse formation. Science 271:1867–1870

    Article  PubMed  CAS  Google Scholar 

  45. Berditchevski F, Odintsova E (2007) Tetraspanins as regulators of protein trafficking. Traffic 8:89–96

    Article  PubMed  CAS  Google Scholar 

  46. Liu L, He B, Liu WM, Zhou D, Cox JV, Zhang XA (2007) Tetraspanin CD151 promotes cell migration through regulating integrin trafficking. J Biol Chem 282:31631–31642

    Article  PubMed  CAS  Google Scholar 

  47. Volkman LE (2007) Baculovirus infectivity and the actin cytoskeleton. Curr Drug Targets 8:1075–1083

    Article  PubMed  CAS  Google Scholar 

  48. Gamliel H, Polliack A (1979) Virus–cell interactions as seen by scanning electron microscopy. Isr J Med Sci 15:647–652

    PubMed  CAS  Google Scholar 

  49. Nydegger S, Khurana S, Krementsov DN, Foti M, Thali M (2006) Mapping of tetraspanin-enriched microdomains that can function as gateways for HIV-1. J Cell Biol 173:795–807

    Article  PubMed  CAS  Google Scholar 

  50. Espenel C, Margeat E, Dosset P, Arduise C, Le Grimellec C, Royer CA, Boucheix C, Rubinstein E, Milhiet P-E (2008) Single-molecule analysis of CD9 dynamics and partitioning reveals multiple modes of interaction in the tetraspanin web. J Cell Biol 182:765–776

    Article  PubMed  CAS  Google Scholar 

  51. Arikawa K, Molday LL, Molday RS, Williams DS (1992) Localization of peripherin/rds in the disk membranes of cone and rod photoreceptors: relationship to disk membrane morphogenesis and retinal degeneration. J Cell Biol 116:659–667

    Article  PubMed  CAS  Google Scholar 

  52. Kedzierski W, Moghrabi WN, Allen AC, Jablonski-Stiemke MM, Azarian SM, Bok D, Travis GH (1996) Three homologs of rds/peripherin in Xenopus laevis photoreceptors that exhibit covalent and non-covalent interactions. J Cell Sci 109:2551–2560

    PubMed  CAS  Google Scholar 

  53. Conley SM, Stuck MW, Naash MI (2011) Structural and functional relationships between photoreceptor tetraspanins and other superfamily members. Cell Mol Life Sci Epub ahead of print

  54. Wrigley JD, Ahmed T, Nevett CL, Findlay JB (2000) Peripherin/rds influences membrane vesicle morphology. Implications for retinopathies. J Biol Chem 275:13191–13194

    Article  PubMed  CAS  Google Scholar 

  55. McMahon HT, Gallop JL (2005) Membrane curvature and mechanisms of dynamic cell membrane remodelling. Nature 438:590–596

    Article  PubMed  CAS  Google Scholar 

  56. Zimmerberg J, Kozlov MM (2006) How proteins produce cellular membrane curvature. Nat Rev Mol Cell Biol 7:9–19

    Article  PubMed  CAS  Google Scholar 

  57. Niggli V, Rossy J (2008) Ezrin/radixin/moesin: versatile controllers of signaling molecules and of the cortical cytoskeleton. Int J Biochem Cell Biol 40:344–349

    Article  PubMed  CAS  Google Scholar 

  58. Bretscher A, Edwards K, Fehon RG (2002) ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 3:586–599

    Article  PubMed  CAS  Google Scholar 

  59. Sala-Valdes M, Ursa A, Charrin S, Rubinstein E, Hemler ME, Sanchez-Madrid F, Yanez-Mo M (2006) EWI-2 and EWI-F link the tetraspanin web to the actin cytoskeleton through their direct association with ERM proteins. J Biol Chem 281:19665–19675

    Article  PubMed  CAS  Google Scholar 

  60. Coffey GP, Rajapaksa R, Liu R, Sharpe O, Kuo CC, Krauss SW, Sagi Y, Davis RE, Staudt LM, Sharman JP, Robinson WH, Levy S (2009) Engagement of CD81 induces ezrin tyrosine phosphorylation and its cellular redistribution with filamentous actin. J Cell Sci 122:3137–3144

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by National Institutes of Health Research Grant CA096991 (to X.A.Z.).

Author information

Authors and Affiliations

  1. Department of Medicine, Vascular Biology and Cancer Centers, University of Tennessee Health Science Center, Cancer Research Building Room 220, 19 South Manassas Street, Memphis, TN, 38163, USA

    Xin A. Zhang & Chao Huang

Authors
  1. Xin A. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xin A. Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, X.A., Huang, C. Tetraspanins and cell membrane tubular structures. Cell. Mol. Life Sci. 69, 2843–2852 (2012). https://doi.org/10.1007/s00018-012-0954-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-012-0954-0

Keywords

Search

Navigation