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Lipid Rafts, Signalling and the Cytoskeleton

Lipid rafts are specialised membrane domains enriched in certain lipids cholesterol and proteins. The existence of lipid rafts was first hypothesised in 1988 (Simons & van Meer, 1988; Simon & Ikonen, 1997), but what we know as "caveolae" were first observed  much earlier (Palade, 1953; Yamada, 1955).  Caveolae are flask shaped invaginations on the cell surface that are a type of membrane raft, these were named "caveolae intracellulare" (Yamada, 1955).  After a long argument (Jacobson & Dietrich, 1999), most now consider that these rafts actually exist, however, there is some confusion surrounding the classification of these rafts. It presently seems that there could be three types; caveolae, glycosphingolipid enriched membranes (GEM), and polyphospho inositol rich rafts. It may also be that there are inside rafts (PIP2 rich and caveolae) and outside rafts (GEM). 

The fatty-acid chains of lipids within the rafts tend to be extended and so more tightly packed, creating domains with higher order. It is therefore thought that  rafts exist in a separate ordered phase that floats in a sea of poorly ordered lipids.  Glycosphingolipids, and other lipids with long, straight acyl chains are preferentially incorporated into the rafts.

Raft type






Cholesterol, glycoshingolipid, Arachidonic acid, Plasmenylethanolamine,  Caveolin1 and 2, hetero- trimeric G-proteins and monomeric G-proteins, EGF & PDGF receptors, Fyn, GPI-linked enzymes, integrins. Flotillin

Invaginations of membranes rich in signalling molecules

Presumed to be signalling centres and perhaps regions of cholesterol import

Pike et al, 2002; Wary et al, 1998; Huang et al, 1999; Rothberg et al, 1992

Glycosphingolipid enriched

Cholesterol, glycoshingolipid, low in PI and other anionic phospholipids

Detergent resistant membranes.



PIP2 enriched



Signalling, Structural.

Laux et al, 2000; Rozelle et al, 2000.

Table 1





Caveolae are similar in composition to GEMs that lack caveolae and in fact cells that lack caveolin-1 do not have morphologically identifiable caveolae but instead have extra GEM.  These cells can then be transfected with caveolin-1 cDNA and the caveolae then appear.  This suggests that GEM are merely caveolae without caveolin-1.  Caveolin-1 is a 21kDa integral membrane protein that binds cholesterol (
Maruta et al, 1995). In cells lacking caveolin-1, caveolin-2 is synthesised but remains in the Golgi.  Caveolin 1 and 2 colocalise when expressed in the same cells and they may form hetero-dimers (Scherer et al, 1997). Caveolin-3 is expressed in muscle where it forms muscle-type caveolae.  Caveolin-3 is involved in certain types of muscular dystrophy (Galbiati et al, ). A slightly confusing finding is that caveolae are the reported site of integrin signalling ().  It is difficult to imagine integrins being available in the depths of membrane invaginations for binding extra-cellular ligands.

The function of rafts

Many functions have been attributed to rafts, from cholesterol transport, endocytosis and signal transduction.  The later is almost certainly the case. It has been suggested that the primary function of caveolae was in constitutive endocytic trafficking but recent data show that this is not the case, instead caveolae are very stable regions of membranes that are not involved in  endocytosis (
Thompsen et al, 2002).

Rafts and the Cytoskeleton
Many actin binding proteins are known to bind to polyphosphoinositides and to be regulated by them (see PI and ABPs), by a series of protein domains such as PH, PX and ENTH (see Domains).  It is consequently scarcely surprising that some ABPs are suggested to link the actin cytoskeleton and PIP2-enriched rafts. One of these is gelsolin, a Ca2+, pH and polyphosphoinositide regulated actin capping and severing protein (see Gelsolin Family), that partitions into rafts isolated biochemically from brain (
Fanatsu et al, 2000).
GEMs too are suggested to link to the actin cytoskeleton through ABPs particularly ERM proteins through EBP50, a protein that binds members of the ERM proteins through the ERM C-terminus (
Brdickova et al, 2001).
Deborah Brown's Lab   Kai Simon's Lab   


Brdickova, N., Brdicka, T., Andrea, L., Spicka, J., Angelisova, P., Milgram, S. L. & Horejsi, V. (2001) Interaction between two adaptor proteins, PAG and EBP50: a possible link between membrane rafts and actin cytoskeleton.  FEBS letters. 507, 133-136.

Cary, L. A. & Cooper, J. A. (2000) Molecular switches in lipid rafts.  Nature. 404, 945-947.

Czarny, M., Fiucci, G., Lavie, Y., Banno, Y., Nozawa, Y. & Liscovitch, M. (2000) Phospholipase D2: functional interaction with caveolin in low-density membrane microdomains.,  FEBS letters.

Foger, N., Marhaba, R. & Zoller, M. (2001) Involvement of CD44 in cytoskeleton rearrangement and raft reorganization in T cells.  J.Cell Sci. 114, 1169-1178.

Funatsu, N., Kumanogoh, H., Sokawa, Y. & Maekawa, S. (2000) Identification of gelsolin as an actin regulatory component in a Triton insoluble low density fraction (raft) of newborn bovine brain.  Neuroscience Research. 36, 311-317.

Galbiati, F., Engelman, J. A., Volonte, D., Zhang, X. L., Minetti, C., Li, M., Hou jr, H., Kneitz, B., Edelman, W. & Lisanti, M. P. (2001) Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex, and T-tubule abnormalities.  J. Biol.Chem. 276, 21425-21433.

Gomez-Mouton, C., Abad, J. L., Mira, E., Lacalle, R. A., Gallardo, E., Jimenez-Baranda, S., Illa, I., Bernad, A., Manes, S. & Martinez-A, C. (2001) Segregation of leading-edge and uropod components into specific lipid rafts during T cell polarization. PNAS. 98, 9642-9647.

Harder, T., &  Simons, K. (1999). Clusters of glycolipid and glycosylphosphatidylinositol-anchored proteins in lymphoid cells: accumulation of actin regulated by local tyrosine phosphorylation. Eur. J. Immunol. 29, 556-562.

Huang, C.-s., Zhou, J., Feng, A. K., Lynch, C. C., Klumperman, J., DeArmond, S. J. & Mobley, W. C. (1999) Nerve growth factor signalling in caveolae-like domains at the plasma membrane. J.Biol.Chem. 274, 36707-36714.

Jacobson, K. & Dietrich, C. (1999) Looking at lipid rafts? Trends Cell Biol. 9, 87-91.

Ko, Y.-G., Liu, P., Pathak, R. K., Craig, L. C. & Anderson, R. G. W. (1998) Early effects of PP60v-src kinase activation on caveolae. J.Cellular Biochem. 71, 524-535.

Kurzchalia, T. V. & Parton, R. G. (1999) Membrane microdomains and caveolae. Curr.Op.Cell Biol. 11, 424-431.

Laux, T., Fukami, K., Thelen, M., Golub, T., Frey, D. & Caroni, P. (2000) GAP43, MARKS, and CAP23 modulate PI(4,5)P2 at plasmalemmal rafts, and regulate cell cortex actin dynamics through a common mechanism. J.Cell Biol. 149, 1455-1471.

Manes, S., Mira, E., Gomez-Mouton, C., Lacalle, R. A., Keller, P., Labrador, J. P. & Martinez-A, C. (1999) Membrane raft microdomains mediate front-rear polarity in migrating cells. EMBO J. 18, 6211-6220.

Maruta, M., Peranen, J., Schreiner, R., Wieland, F., Kurzchalia, T.V. & Simons, K. (1995). PNAS  92, 10339-10343.

Moffett, S., Brown, D. A. & Linder, M. E. (2000) Lipid-dependent targeting of G proteins into rafts. J. Biol.Chem. 275, 2191-2198.

Palade, C.E. (1953) J.Applied Phys. 24, 1424.

Pike, L. J., Han, X., Chung, K.-N. & Gross, R. W. (2002) Lipid rafts are enriched in arachidonic acid and plasmenylethanolamine and their composition is independent of caveolin-1 expression: A quantitative electrospray ionization/mass spectroscopic analysis. Biochemistry. 41, 2075-2088.

Pralle, A., Keller, P., Florin, E.L., Simons, K., and Hörber, J.K. (2000). Sphingolipid-cholesterol rafts diffuse as small entities in the plasma membrane of mammalian cells.  J. Cell Biol. 148, 997-1008.

Rothberg, K. G., Heuser, J. E., Donzell, W. C., Ying, Y.-S., Glenney, J. R. & Anderson, R. G. L. (1992) Caveolin, a protein component of caveolae membrane coats., Cell. 68, 673-682.

Rozelle, A. L., Machesky, L. M., Yamamoto, M., Driessens, M. H. E., Insall, R. H., Roth, M. G., Luby-Phelps, K., Marriott, G., Hall, A. & Yin, H. L. (2000) Phosphatidylinositol 4,5-bisphosphate induces actin-based movement of raft-enriched vesicles through WASP-Arp2/3. Current Biology. 10, 311-320.

Sargiacomo, M., Sudol, M., Tang, Z. L. & Lisanti, M. P. (1993) Signal transducing molecules and glycosyl-phosphatidylinositol-linked protein form a caveolin-rich insoluble complex in MDCK cells. J.Cell Biol. 122, 789-8807.

Scherer, P. E., Lewis, R. Y., Volonte, D., Engelman, J. A., Galbiati, F., Couet, J., Kohtz, D. S., van Donselaar, E., Peters, P. & Lisanti, M. P. (1997) Cell-type and tisue-specific expression of caveolin-2, Caveolins 1 and 2 colacalize and form a stable hetero-oligomeric complex in vivo., J.Biol.Chem. 2772, 29337-29346.

Seveau, S., Eddy, R. J., Maxfield, F. R. & Pierini, L. M. (2001) Cytoskeleton-dependent membrane domain segregation during neutrophil polarization. Mol. Biol. of the Cell. 12, 3550-3562.

Shin, J.-S., Gao, Z. & Abraham, S. N. (2000) Involvement of cellular caveolae in bacterial entry into mast cells. Science. 289, 785-788.

Simons, K. & van Meer, G. (1988). Biochemistry 27, 6197-6202.

Simons, K. & Ikonen, E  (1997). Functional rafts in cell membranes. Nature 387, 569-572.

Sowa, G., Pypaert, M. & Sessa, W. C. (2001) Distinction between signaling mechanisms in lipid rafts vs. caveolae. PNAS. 98, 14072-14077.

Sternberg, P. W. & Schmid, S. L. (1999) Caveolin, cholesterol and Ras signalling. Nature Cell Biol. 1, E35-E37.

Thompsen, P., Roepstorff, K., Stahlhut, M. & van Deurs, B. (2002) Caveolae are highly immobile plasma membrane microdomains, which are not involved in constitutive endocytis trafficking. Mol.Biol. Cell. 13, 238-250.

van Meer, G. (2001) Caveolin, cholesterol, and lipid drops. J.Cell Biol. 152, F29-F34.

Villalba, M., Bi, K., Rodriguez, F., Tanaka, Y., Schoenberger, S. & Altman, A. (2001) Vav1/Rac-dependent actin cytoskeleton reorganization is required for lipid raft clustering in T cells. J.Cell Biol. 155, 331-338.

Wary, K. K., Mariotti, A., Zurzolo, C. & Giancotti, F. G. (1998) A requirement for calveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth. Cell. 94, 625-634.

Waugh, M. G., Lawson, D. & Hsuan, J. J. (1999) Epidermal growth factor receptor activiation is localized within low-buoyant density, non-caveolar membrane domains. Biochem.J. 337, 591-597.

Xiao, Z. & Devreotes, P. N. (1997) Identification of detergent resistant plasma membrane microdomains in Dictyostelium: enrichment of signal transduction proteins.  Mol.Biol.Cell. 8, 855-869.

Yamada, E. (1955) The fine structure of the gall bladder epithelium of the mouse. J.Biophys.Biochem.Cytol. 1, 445-458.

Zajchowski, L. D. & Robbins, S. M. (2002) Lipid rafts. Eur. J. Biochem. 269, 737-752.

Zobiack, N., Rescher, U., Laarmann, S., Michgehl, S., Schmidt, M. A. & Gerke, V. (115) Cell-surface attachment of pedestal-forming enteropathogenic E.coli induces a clustering of raft components and a recruitment of annexin 2. J. Cell Sci. 115, 91-98.

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