Functional rafts in cell membranes

Abstract

A new aspect of cell membrane structure is presented, based on the dynamic clustering of sphingolipids and cholesterol to form rafts that move within the fluid bilayer. It is proposed that these rafts function as platforms for the attachment of proteins when membranes are moved around inside the cell and during signal transduction.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Model for the organization of rafts and caveolae in the plasma membrane.
Figure 2: Two postulated post-Golgi circuits in MDCK cells (a) and fibroblasts (b).

References

  1. 1

    Singer, S. J. & Nicolson, G. L. The fluid mosaic model of the structure of cell membranes. Science 175, 720–731 (1972).

    ADS  CAS  Article  Google Scholar 

  2. 2

    van Meer, G. Lipid traffic in animal cells. Annu. Rev. Cell Biol. 5, 247–275 (1989).

    CAS  Article  Google Scholar 

  3. 3

    Kusumi, A. & Sako, Y. Cell surface organization by the membrane skeleton. Curr. Opin. Cell Biol. 8, 566–574 (1996).

    CAS  Article  Google Scholar 

  4. 4

    Rodriguez-Boulan, E. & Nelson, W. J. Morphogenesis of the polarized epithelial cell phenotype. Science 245, 718–725 (1989).

    ADS  CAS  Article  Google Scholar 

  5. 5

    Simons, K. & van Meer, G. Lipid sorting in epithelial cells. Biochemistry 27, 6197–6202 (1988).

    CAS  Article  Google Scholar 

  6. 6

    van Helvoort, A. et al. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while M P-glycoprotein specifically translocates phosphatidylcholine. Cell 87, 507–518 (1996).

    CAS  Article  Google Scholar 

  7. 7

    Brown, D. & Rose, J. Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface. Cell 68, 533–544 (1992).

    CAS  Article  Google Scholar 

  8. 8

    Parton, R. G. Caveolae and caveolins. Curr. Opin. Cell Biol. 8, 542–548 (1996).

    CAS  Article  Google Scholar 

  9. 9

    Tran, D. J., Carpentier, J. L., Sawano, F., Gorden, P. & Orci, L. Ligands internalized through coated or non-coated invaginations follow a common intracellular pathway. Proc. Natl Acad. Sci. USA 84, 7957–7961 (1987).

    ADS  CAS  Article  Google Scholar 

  10. 10

    Rothberg, K. G., Ying, Y. S., Kamen, B. A. & Anderson, R. G. W. Cholesterol controls the clustering of the glycophospholipid-anchored membrane receptor for 5-methyltetrahydrofolate. J. Cell Biol. 111, 2931–2938 (1990).

    CAS  Article  Google Scholar 

  11. 11

    Ghitescu, L., Fixman, A., Simionescu, M. & Simionescu, N. Specific binding sites for albumin restricted to plasmalemmal vesicles of continuous capillary endothelium: receptor-mediated transcytosis. J. Cell Biol. 102, 1304–1311 (1986).

    CAS  Article  Google Scholar 

  12. 12

    Dupree, P., Parton, R. G., Raposo, G., Kurzchalia, T. V. & Simons, K. Caveolae and sorting in the trans-Golgi network of epithelial cells. EMBO J. 12, 1597–1605 (1993).

    CAS  Article  Google Scholar 

  13. 13

    Morrow, M. R., Singh, D., Lu, D. & Grant, C. W. M. Glycosphingolipid fatty acid arrangement in phospholipid bilayers: cholesterol effects. Biophysical J. 68, 179–186 (1995).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Boggs, J. M. & Koshy, K. M. Do the long fatty acid chains of sphingolipids interdigitate across the center of bilayer of shorter chain symmetric phospholipids? Biochim. Biophys. Acta 1189, 233–241 (1994).

    CAS  Article  Google Scholar 

  15. 15

    Parton, R. G. & Simons, K. Digging into caveolae. Science 269, 1398–1399 (1995).

    ADS  CAS  Article  Google Scholar 

  16. 16

    Schroeder, R., London, E. & Brown, D. Interactions between saturated acyl chains confer detergent resistance on lipids and glycosylphosphatidylinositol(GPI)-anchored proteins: GPI-anchored proteins in liposomes and cells show similar behavior. Proc. Natl Acad. Sci. USA 91, 12130–12134 (1994).

    ADS  CAS  Article  Google Scholar 

  17. 17

    Skibbens, J. E., Roth, M. G. & Matlin, K. S. Differential extractibility of influenza virus hemagglutinin during intracellular transport in polarized epithelial cells and nonpolar fibroblasts. J. Cell Biol. 108, 821–832 (1989).

    CAS  Article  Google Scholar 

  18. 18

    Sargiacomo, M., Sudol, M., Tang, Z. & Lisanti, M. P. Signal transducing molecules and GPI-linked proteins from a caveolin-rich insoluble complex in MDCK cells. J. Cell Biol. 122, 789–807 (1993).

    CAS  Article  Google Scholar 

  19. 19

    Fra, A. M., Williamson, E., Simons, K. & Parton, R. G. Detergent-insoluble glycolipid microdomains in lymphocytes in the absence of caveolae. J. Biol. Chem. 269, 30745–30748 (1994).

    CAS  PubMed  Google Scholar 

  20. 20

    Danielsen, E. M. Atransferrin-like GPI-linked iron-binding protein in detergent-insoluble noncaveolar microdomains at the apical surface of fetal intestinal epithelial cells. Biochemistry 34, 1596–1605 (1995).

    CAS  Article  Google Scholar 

  21. 21

    Casey, P. J. Protein lipidation in cell signalling. Science 268, 221–225 (1995).

    ADS  CAS  Article  Google Scholar 

  22. 22

    Cerneus, D. P., Ueffing, E., Posthuma, G., Strous, G. J. & van der Ende, A. Detergent insolubility of alkaline phosphatase during biosynthetic transport and endocytosis. Role of cholesterol. J. Biol. Chem. 268, 3150–3155 (1993).

    CAS  PubMed  Google Scholar 

  23. 23

    Hanada, K., Nishijima, M., Akamatsu, Y. & Pagano, R. E. Both sphingolipids and cholesterol participate in the detergent-insolubility of alkaline phosphatase, a glycosyl-phosphatidylinositol anchored protein in mammalian cells. J. Biol. Chem. 270, 6254–6260 (1995).

    CAS  Article  Google Scholar 

  24. 24

    Hannan, L. A. & Edidin, M. Glycosylphosphatidylinositol-anchored protein after LDL-deprivation of MDCK cells. J. Cell Biol. 133, 1265–1276 (1996).

    CAS  Article  Google Scholar 

  25. 25

    Kundu, A., Avalos, R. T., Sanderson, C. M. & Nayak, D. P. Transmembrane domain of influenza virus neuraminidase, a type II protein, possesses an apical sorting signal in polarized MDCK cells. J. Virol. 70, 6508–6515 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Murata, M. et al. VIP21-caveolin is a cholesterol-binding protein. Proc. Natl Acad. Sci. USA 92, 10339–10343 (1995).

    ADS  CAS  Article  Google Scholar 

  27. 27

    Lisanti, M. P., Sargiacomo, M., Graeve, L., Saltiel, A. & Rodriguez-Boulan, E. Polarized apical distribution of glycosyl-phosphatidylinositol-anchored proteins in a renal epithelial cell line. Proc. Natl Acad. Sci. USA 85, 9557–9561 (1989).

    ADS  Article  Google Scholar 

  28. 28

    Scheiffele, P., Peränen, J. & Simons, K. N-glycans as apical sorting signals in epithelial cells. Nature 378, 96–98 (1995).

    ADS  CAS  Article  Google Scholar 

  29. 29

    Fiedler, K., Parton, R. G., Kellner, R., Etzold, T. & Simons, K. VIP36, a novel component of glycolipid rafts and exocytic carrier vesicles in epithelial cells. EMBO J. 13, 1729–1740 (1994).

    CAS  Article  Google Scholar 

  30. 30

    Matter, K. & Mellman, I. Mechanisms of cell polarity: Sorting and transport in epithelial cells. Curr. Opin. Cell. Biol. 6, 545–554 (1994).

    CAS  Article  Google Scholar 

  31. 31

    Ikonen, E., Tagaya, M., Ullrich, O., Montecucco, C. & Simons, K. Different requirements for NSF, SNAP, and Rab proteins in apical and basolateral transport in MDCK cells. Cell 81, 1–20 (1995).

    Article  Google Scholar 

  32. 32

    Rothman, J. E. & Wieland, F. T. Protein sorting by transport vesicles. Science 272, 227–234 (1996).

    ADS  CAS  Article  Google Scholar 

  33. 33

    Müsch, A., Xu, H., Shield, D. & Rodriguez-Boulan, E. Transport of vesicular stomatitis virus G protein to the cell surface is signal mediated in polarized and nonpolarized cells. J. Cell Biol. 133, 543–558 (1996).

    Article  Google Scholar 

  34. 34

    Yoshimori, T., Keller, P., Roth, M. G. & Simons, K. Different biosynthetic transport routes to the plasma membrane in BHK and CHO cells. J. Cell Biol. 133, 247–256 (1996).

    CAS  Article  Google Scholar 

  35. 35

    Danielsen, E. M. & van Deurs, B. Involvement of detergent-insoluble complexes in the intracellular transport of intestinal brush border enzymes. J. Cell Biol. 131, 939–950 (1995).

    CAS  Article  Google Scholar 

  36. 36

    Schnitzer, J. E., Oh, P., Pinney, E. & Allard, J. Filipin-sensitive caveolae-mediated transport in endothelium: reduced transcytosis, scavenger endocytosis, and capillary permeability of select macromolecules. J. Cell Biol. 127, 1217–1232 (1994).

    CAS  Article  Google Scholar 

  37. 37

    Anderson, R. G. W., Kamen, B. A., Rothberg, K. G. & Lacey, S. W. Potocytosis: sequestration and transport of small molecules by caveolae. Science 255, 410–411 (1992).

    ADS  CAS  Article  Google Scholar 

  38. 38

    Anderson, H. A., Chen, Y. & Norkin, L. C. Bound simian virus 40 translocates to caveolin-enriched membrane domains, and its entry is inhibited by drugs that selectively disrupt caveolae. Mol. Biol. Cell 7, 1825–1834 (1996).

    CAS  Article  Google Scholar 

  39. 39

    Deckert, M. et al. Endocytosis of GPI-anchored proteins in human lymphocytes: role of glycolipid-based domains, actin cytoskeleton, and protein kinases. J. Cell Biol. 133, 791–799 (1996).

    CAS  Article  Google Scholar 

  40. 40

    Mostov, K. E., Apodaca, G., Aroeti, B. & Okamoto, C. Plasma membrane protein sorting in polarized epithelial cells. J. Cell Biol. 116, 577–583 (1992).

    CAS  Article  Google Scholar 

  41. 41

    Simons, K. et al. The biogenesis of cell surface polarity in epithelial cells and neurons. Cold Spring Harbor Symp. Quant. Biol. LVII, 611–619 (1992).

    Article  Google Scholar 

  42. 42

    Pfeiffer, S. E., Warrington, A. E. & Bansal, R. The oligodendrocyte and its many cellular processes. Trends Cell Biol. 3, 191–197 (1993).

    CAS  Article  Google Scholar 

  43. 43

    Peränen, J., Auvinen, P., Virta, H., Wepf, R. & Simons, K. Rab8 promotes polarized membrane transport through reorganization of actin and microtubules in fibroblasts. J. Cell Biol. 135, 153–167 (1996).

    Article  Google Scholar 

  44. 44

    Anderson, R. G. W. Caveolae: where incoming and outgoing messengers meet. Proc. Natl Acad. Sci. USA 90, 10909–10913 (1993).

    ADS  CAS  Article  Google Scholar 

  45. 45

    Lisanti, M. P., Scherer, P. E., Tang, Z. L. & Sargiacomo, M. Caveolaer, caveolin and caveolin-rich membrane domains: a signalling hypothesis. Trends Cell Biol. 4, 231–235 (1994).

    CAS  Article  Google Scholar 

  46. 46

    Parpal, S., Gustavsson, J. & Strålfors, P. Isolation of phosphooligosaccharide/phosphoinositol glycan from caveolae and cytosol of insulin-stimulated cells. J. Cell Biol. 131, 125–135 (1995).

    CAS  Article  Google Scholar 

  47. 47

    Li, S. et al. Evidence for a regulated interaction between heterotrimeric G proteins and caveolin. J. Biol. Chem. 270, 15693–15701 (1995).

    CAS  Article  Google Scholar 

  48. 48

    Song, K. S. et al. Co-purification and direct interaciton of Ras with caveolin, an integral membrane protein of caveolae microdomains. J. Biol. Chem. 271, 9690–9697 (1996).

    CAS  Article  Google Scholar 

  49. 49

    Mineo, C., James, G. L., Smart, E. J. & Anderson, R. G. Localization of epidermal growth factor-stimulated Ras/Raf-1 interaction to caveolae membrane. J. Biol. Chem. 217, 11930–11935 (1996).

    Article  Google Scholar 

  50. 50

    Hope, H. R. & Pike, L. J. Phosphoinositides and phosphoinositide-utilizing enzymes in detergent-insoluble lipid domains. Mol. Biol. Cell 7, 843–851 (1996).

    CAS  Article  Google Scholar 

  51. 51

    Linardic, C. M. & Hannun, Y. A. Identification of a distinct pool of sphingomyelin involved in the sphingomyelin cycle. J. Biol. Chem. 269, 23530–23537 (1994).

    CAS  PubMed  Google Scholar 

  52. 52

    Liu, P. & Anderson, R. G. W. Compartmentalized production of ceramide at the cell surface. J. Biol. Chem. 270, 27179–27185 (1995).

    CAS  Article  Google Scholar 

  53. 53

    Mayor, S., Rothberg, K. G. & Maxfield, F. R. Sequestration of GPI-anchored proteins in caveolae triggered by cross-linking. Science 264, 1948–1951 (1994).

    ADS  CAS  Article  Google Scholar 

  54. 54

    Nykjaer, A. et al. Regions involved in binding of urokinase-type-1 inhibitor complex and pro-urokinase to the endocytic α2-macroglobulin receptor/low density lipoprotein receptor-related protein. J. Biol. Chem. 269, 25668–25676 (1994).

    CAS  PubMed  Google Scholar 

  55. 55

    Field, K. A., Holowka, D. & Baird, B. FcεRI-mediated recruitment of p53/56lyn to detergent-resistant membrane domains accompanies cellular signaling. Proc. Natl Acad. Sci. USA 92, 9201–9205 (1995).

    ADS  CAS  Article  Google Scholar 

  56. 56

    Klein, U., Gimpl, G. & Fahrenholz, F. Alteration of myometrial plasma membrane cholesterol content with β-cyclodextrin modulates the binding affinity of the oxytocin receptor. Biochemistry 34, 13784–13793 (1995).

    CAS  Article  Google Scholar 

  57. 57

    Mutoh, T., Tokuda, A., Miyadai, T., Hamaguchi, M. & Fujiki, N. Ganglioside GM1 binds to the Trk protein and regulates receptor function. Proc. Natl Acad. Sci. USA 92, 5087–5091 (1995).

    ADS  CAS  Article  Google Scholar 

  58. 58

    Bretscher, M. S. & Munro, S. Cholesterol and the Golgi apparatus. Science 261, 1280–1281 (1993).

    ADS  CAS  Article  Google Scholar 

  59. 59

    Rock, P., Allietta, M., Young, W. W. J, Thompson, T. E. & Tillack, T. W. Organization of glycosphingolipids in phosphatidylcholine bilayers: use of antibody molecules and Fab fragments as morphologic markers. Biochemistry 29, 8484–8490 (1990).

    CAS  Article  Google Scholar 

  60. 60

    Spiegel, S., Kassis, S., Wilchek, M. & Fishman, P. H. Direct visualization of redistribution and cappiang of fluorescent gangliosides on lymphocytes. J. Cell Biol. 99, 1575–1581 (1984).

    CAS  Article  Google Scholar 

  61. 61

    Boggs, J. M. Lipid intermolecular hydrogen bonding: influence on structural organization and membrane function. Biochim. Biophys. Acta 906, 353–404 (1987).

    CAS  Article  Google Scholar 

  62. 62

    Smaby, J. M., Momsen, M., Kulkarni, V. S. & Brown, R. E. Cholesterol-induced interfacial area condensations of galactosylceramides and sphingomyelins with identical acyl chains. Biochemistry 35, 5696–5704 (1996).

    CAS  Article  Google Scholar 

  63. 63

    Silvius, J. R. Cholesterol modulation of lipid intermixing in phospholipid and glycosphingolipid mixtures. Evaluation using fluorescent lipid probes and brominated lipid quenchers. Biochemistry 31, 3398–3408 (1992).

    CAS  Article  Google Scholar 

  64. 64

    Sankaram, M. B. & Thompson, T. E. Interaction of cholesterol with various glycerophospholipids and sphingomyelin. Biochemistry 29, 10670–10675 (1990).

    CAS  Article  Google Scholar 

  65. 65

    Neuringer, L. J., Sears, B. & Jungalwala, F. B. Deuterium NMR studies of cerebroside-phospholipid bilayers. Biochim. Biophys. Acta 558, 325–329 (1979).

    CAS  Article  Google Scholar 

  66. 66

    Chong, P.-L. Evidence for regular distribution of sterols in liquid crystalline phosphatidylcholine bilayers. Proc. Natl Acad. Sci. USA 91, 10069–10073 (1994).

    ADS  CAS  Article  Google Scholar 

  67. 67

    Fiedler, K., Lafont, F., Parton, R. G. & Simons, K. Annexin XIIIb: A novel epithelial specific annexin is implicated in vesicular traffic to the apical plasma membrane. J. Cell Biol. 128, 1043–1053 (1995).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank E. Radeck for preparing the manuscript, and D. Brown, R. Brown, A. Kusumi, A. Helenius, G. van Meer, A. Watts, and members of K.S.'s laboratory for helpful criticism.

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Simons, K., Ikonen, E. Functional rafts in cell membranes. Nature 387, 569–572 (1997). https://doi.org/10.1038/42408

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing