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Caveolae

Page updated 12/10/02

Caveolae are specialized lipid rafts that perform a number of signalling functions (Reviewed, Anderson, 1998). Caveolae were first identified by EM examination in the mid 50' by two workers (Palade, 1953; Yamada, 1955), as 50-100nm "flask shaped" invaginations of the plasma-membrane. They are found in a variety of cell types especially endothelial cells, but none exist as classical invaginated caveolae in neuronal tissues. Many proteins and lipids are known to be enriched in caveolae (see table 1), and labelling of cells with a PH domain protein marker for PIP2, indicates that this lipid is not concentrated in caveolae (Watt et al, 2002).  Caveolin (Rothberg et al, 1992), is a principle marker of the caveolae.
Figure 1. Caveolae.  Glycosphingolipids, and other lipids with long, straight acyl chains are depicted in orange, normal lipids in yellow. Caveolin are blue trans-membranous proteins. "Red rubies" represent GPI linked enzymes and receptors. Green spheres are palmitolated, Src-like kinases and the trans-membranous receptors grey and orange represent caveolae associated signalling receptors.

 

 

 

Constituent

Function

References

Arachidonic acid A signalling fatty acid Pike et al, 2002
Caveolin A principle protein of caveolae. Rothberg et al, 1992
Cholesterol    
Dystrophin associated glycoprotein  complex DAG is known to be associated with caveolin-3 in muscle cell membrane. Galbiati et al, 2001
EGF receptor A growth factor receptor that auto-phosphorylates itself upon binding EGF and dimerisation.  The presence of EGF in caveolae is contentious Ringerike et al, 2001
Flotillin    
Fyn   Wary et al, 1998
G-proteins monomeric    
GPI-linked enzymes    
Glycoshingolipid    
Integrins Adhesion and signalling proteins Wary et al, 1998
Insulin receptor    
PDGF receptors A growth factor receptor  
Striatin, SG2NA, zinedin A family of calmodulin-dependent scaffolding protein Gaillard et al, 2001; Bartoli et al, 1998
Plasmenylethanolamine   Pike et al, 2002
PrPc Infectious proteinaceous agent of prion diseases BSE and CJD. Massimino et al, 2002
NGF receptor A growth factor receptor Huang et al, 1999; 

Table 1

 

 


The role of Caveolin in Caveolae structure
Mouse knock out studies best illustrate the importance of caveolin in the formation and maintenance of caveolae. In the absence of caveolin no morphologically identifiable caveolae exist (
Razani & Lisanti, 2001).  Caveolin-1 is palmitolated on cysteine residues which will help stabilise membrane association but it is not necessary for the specific-association with caveolae (Dietzen et al, 1995).

A role for caveolae in Endocytosis?
Since their discovery, it has been anticipated that caveolae are sites of endocytosis perhaps because of their similarity in appearance to clatherin coated pits as they pinch off the plasma-membrane. Strong evidence has now been forwarded that caveolae are static fixed domains and are not involved in endocytosis (
Thomsen et al, 2002).  However, it has been convincingly shown that the SV40 virus is taken in by caveolae and that these structures can be switched from the stable state described by (Thomsen et al, 2002) by signals derived from the virus (Pelkmans et al, 2002).

Caveolae and Oncogenesis

Caveolin expression has been reported to correlate both to oncogenic transformation and its reversal. The down-regulation of caveolin resulted in transformation that could be reversed by removal of caveolin anti-sense (
Galbiati et al, 1998), whereas anchorage-independence of growth was abrogated by over-expression of caveolin-1 (Engelman et al, 1997).  The growth of human breast cancer cells is also reported to be inhibited by caveolin expression (Lee et al, 1998). 

Are Caveolae involved in the uptake of Pathogenic Bacteria?
Many bacteria that infect vertebrates have adopted a strategy of evading the immune systems of their hosts by invading cells (see Bacterial Cell Invasion).  The adhesion and uptake of bacteria is a complex business involving several bacterial proteins and a large number of host proteins (signalling and cytoskeletal proteins) hijacked by the bacteria.  Nucleolin has been identified as a receptor for EHEC E.coli, (
Sinclair & O'Brien, 2002) but it is not clear if nucleolin is associated with caveolae.  Bacteria may be taken up via caveolae by a similar mechanism as that described for the SV40 virus (Pelkmans et al, 2002).

Neuronal "Caveolae".
Whereas neuronal cells express caveolin-1 and caveolin-2, they do not produce morphologically recognisable caveolae. Instead, micro-domains enriched in caveolins in association with striatin and other associated proteins.  Striatins are enriched in dendritic spines (
Bartoli et al, 1998), in keeping with the widely held view that spines are regions enriched in signalling activity.

Caveolar membrane traffic, the cavicles and the caveolosome.
Experiments with GFP-labelled caveolin 1 (
Pelkmans et al, 2001; Mundy et al, 2002), have demonstrated a multi-step trafficking pathway, whereby caveolin containing bodies "cavicles" (Mundy et al, 2002) are transported from the "caveosome" (Pelkmans et al, 2001) to the cell surface caveolae via microtubules (Mundy et al, 2002).  It appears that the actin cortex holds caveolae at the PM as disruption of the actin cortex with latrunculin A causes caveolin staining to move rapidly to the centrosomal region of the cell presumably to the caveosome (Mundy et al, 2002).  The caveosome seems distinct from the Golgi apparatus as they do not form beside the centrosome in all cell types and they appear to have distinct markers which presently include; dextran, cholera toxin, caveolin-1, and SV-40 virus (Nichols, 2002; Mundy et al, 2002).

Figure 2. Trafficking of the caveolin-1 containing structures to and from the plasma-membrane to the caveosome. Kinesin and dyneins presumably are responsible for motility of cavicles on microtubules at speeds between 0.3um and 2um/sec (Mundy et al, 2002).
 

References:-

Anderson, R. G. W. (1998) The caveolae membrane system. Ann.Rev.Biochem. 67, 199-225.

Bartoli, M., Monneron, A. & Ladant, D. (1998) Interaction of calmodulin with striatin, a WD-repeat protein present in neuronal dendritic spines., J.Biol.Chem. 273, 22248-22253.

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.

Dietzen, D. J., Hastings, W. R. & Lublin, D. M. (1995) Caveolin is palmitoylated on multiple cysteine residues. Palmitoylation is not necessary for localization of caveolin to caveolae. J.Biol.Chem. 270, 6838-6842.

Engelman, J.A., Wykoff, C.C., Yasuhara, S., Song, K.S., Okamoto, T., and Lisanti, M.P. (1997). Recombinant expression of caveolin-1 in oncogenically transformed cells abrogates anchorage-independent growth. J. Biol. Chem. 272, 16364-16381.

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.

Gaillard, S., Bartoli, M., Castets, F. & Monneron, A. (2001) Striatin, a calmodulin-dependent scaffolding protein, directly binds caveolin-1. FEBS letters. 508, 49-52.

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.

Galbiati, F., Volonte, D., Engelman, J.A., Watanabe, G., Burk, R., Pestell, R., and Lisanti, M.P. (1998). Targeted down-regulation of caveolin-1 is sufficient to drive cell transformation and hyperactivate the p42/44 MAP kinase cascade. EMBO J. 17: 6633-6648.

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.

Lee, S.W., Reimer, C.L., Oh, P., Campbell, D.B., and Schnitzer, J.E. (1998). Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells. Oncogene 16: 1391-1397.

Massimino, M. L., Griffoni, C., Spisni, E., Toni, M. & Tomasi, V. (2002) Involvement of caveolae and caveolae-like domains in signalling cell survival and angiogenesis. Celluar Signalling. 14, 93-98.

Mundy, D. I., Machleidt, T., Ying, Y.-s., Anderson, R. G. W. & Bloom, G. S. (2002) Dual control of caveolar membrane traffic by microtubules and the actin cytoskeleton. J Cell Sci. 115, 4327-4339.

Nichols, B. J. (2002) A distinct class of endosome mediates clathrin-independent endocytosis to the Golgi complex. Nature Cell Biol. 4, 374-378.

Pelkmans, L., Kartenbeck, J. & Helenius, A. (2001) Caveolar endocytosis of simian virus 40 reveals a new two-step vesicular-transport pathway to the ER. Nature Cell Biol. 3, 473-483.

Pelkmans, L., Puntener, D. & Helenius, A. (2002) Local actin polymerization and dynamin recruitment in SV40-induced internalization of caveolae. Science. 296, 535-539.

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.

Razani, B. & Lisanti, M. P. (2001) Caveolin-deficient mice: insights into caveolar function and human disease. J. Clin. Invest. 108, 1553-1561.

Ringerike, T., Blystad, F. D., Levy, F. O., Madshus, I. H. & Stang, E. (2002) Cholesterol is important in control of EGF receptor kinase activity but EGF receptors are not concentrated in caveolae. J.Cell Sci. 115, 1331-1340.

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.

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.

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

Sinclair, J. F. & O'Brien, A. D. (2002) Cell surface-localized nucleolin is a eukaryotic receptor for the adhesin intimin-g of enterohemorrhagic Escherichia coli 0157:H7., J.Biol.Chem. 277, 2876-2885.

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.

Uittenbogaard, A., Everson, W. V., Matveev, S. V. & Smart, E. J. (2002) Cholesteryl ester is transported from caveolae to internal membranes as part of a caveolin-annexin II lipid-protein complex.  J.Biol.Chem. 277, 4925-4931.

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

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.

Watt, S. A., Kular, G., Fleming, I. N., Downes, C. P. & Lucocq, J. M. (2002) Subcellular localization of phosphatidylinositol 4,5-bisphosphate using the plackstrin homology domain of phospholipase Cd1. Biochem. J. 363, 657-666.

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.

 
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