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  • Review Article
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The multiple faces of caveolae

Nature Reviews Molecular Cell Biology volume 8, pages 185–194 (2007)Cite this article

Key Points

  • Caveolae are a characteristic feature of mammalian cells. But what are the key functions of caveolae and how does caveolae dysfunction lead to disease?

  • Caveolae form relatively stable domains at the plasma membrane that are enriched in lipid-raft markers and can function as carriers in the endocytic and exocytic pathways.

  • The functions of caveolae remain puzzling; increasing evidence argues against a general signalling role and only a few of the originally postulated signalling functions remain solidly documented.

  • Caveolae have been strongly linked to lipid regulation in adipocytes and other cell types.

  • Caveolae have a role in mechanosensation in specific cell types.

  • The underlying link between these functions might be a role in sensing membrane changes, a property that is reliant on the specific biophysical properties and lipid composition of the caveolar domain.

Abstract

Caveolae are a highly abundant but enigmatic feature of mammalian cells. They form remarkably stable membrane domains at the plasma membrane but can also function as carriers in the exocytic and endocytic pathways. The apparently diverse functions of caveolae, including mechanosensing and lipid regulation, might be linked to their ability to respond to plasma membrane changes, a property that is dependent on their specialized lipid composition and biophysical properties.

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Figure 1: Caveolae and caveolins.
Figure 2: Caveolin biosynthesis and trafficking to the plasma membrane.
Figure 3: Caveola endocytosis.

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References

  1. Palade, G.E. Fine structure of blood capillaries. J. Appl. Phys. 24, 1424 (1953).

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Stan, R.V. Structure of caveolae. Biochim. Biophys. Acta 1746, 334–348 (2005).

    CAS  PubMed  Google Scholar 

  4. Stan, R.V., Tkachenko, E. & Niesman, I.R. PV1 is a key structural component for the formation of the stomatal and fenestral diaphragms. Mol. Biol. Cell 15, 3615–3630 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Lisanti, M.P. et al. Caveolae, transmembrane signalling and cellular transformation. Mol. Membr. Biol. 12, 121–124 (1995).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. Williams, T.M. & Lisanti, M.P. Caveolin-1 in oncogenic transformation, cancer, and metastasis. Am. J. Physiol. Cell Physiol. 288, C494–C506 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  10. Fra, A.M., Williamson, E., Simons, K. & Parton, R.G. De novo formation of caveolae in lymphocytes by expression of VIP21-caveolin. Proc. Natl Acad. Sci. USA 92, 8655–8659 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Drab, M. et al. Loss of caveolae, vascular dysfunction, and pulmonary defects in Caveolin-1 gene-disrupted mice. Science 293, 2449–2452 (2001).

    CAS  PubMed  Google Scholar 

  12. Galbiati, F. et al. 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 (2001).

    CAS  PubMed  Google Scholar 

  13. Tang, Z. et al. Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle. J. Biol. Chem. 271, 2255–2261 (1996).

    CAS  PubMed  Google Scholar 

  14. Way, M. & Parton, R.G. M-caveolin, a muscle-specific caveolin-related protein. FEBS Lett. 376, 108–112 (1995).

    CAS  PubMed  Google Scholar 

  15. Razani, B. et al. Caveolin-2-deficient mice show evidence of severe pulmonary dysfunction without disruption of caveolae. Mol. Cell. Biol. 22, 2329–2344 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sowa, G., Pypaert, M., Fulton, D. & Sessa, W.C. The phosphorylation of caveolin-2 on serines 23 and 36 modulates caveolin-1-dependent caveolae formation. Proc. Natl Acad. Sci. USA 100, 6511–6516 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Lahtinen, U., Honsho, M., Parton, R.G., Simons, K. & Verkade, P. Involvement of caveolin-2 in caveolar biogenesis in MDCK cells. FEBS Lett. 538, 85–88 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  20. Rothberg, K.G. et al. Caveolin, a protein component of caveolae membrane coats. Cell 68, 673–682 (1992).

    CAS  PubMed  Google Scholar 

  21. Pelkmans, L. & Zerial, M. Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae. Nature 436, 128–133 (2005).

    CAS  PubMed  Google Scholar 

  22. Ortegren, U. et al. Lipids and glycosphingolipids in caveolae and surrounding plasma membrane of primary rat adipocytes. Eur. J. Biochem. 271, 2028–2036 (2004). Quantification of lipid levels within caveolae shows that glycosphingolipids and cholesterol are concentrated more within caveolae compared with the surrounding plasma membrane. Higher packing of total lipids is observed in caveolae compared with the surrounding plasma membrane.

    PubMed  Google Scholar 

  23. Schuck, S. & Simons, K. Polarized sorting in epithelial cells: raft clustering and the biogenesis of the apical membrane. J. Cell Sci. 117, 5955–5964 (2004).

    CAS  PubMed  Google Scholar 

  24. Simons, K. & Vaz, W.L. Model systems, lipid rafts, and cell membranes. Annu. Rev. Biophys. Biomol. Struct. 33, 269–295 (2004). An extensive review of the data supporting lipid-based microdomain formation in model systems and in cell membranes.

    CAS  PubMed  Google Scholar 

  25. Hancock, J.F. Lipid rafts: contentious only from simplistic standpoints. Nature Rev. Mol. Cell Biol. 7, 456–462 (2006).

    CAS  Google Scholar 

  26. Lipardi, C. et al. Caveolin transfection results in caveolae formation but not apical sorting of glycosylphosphatidylinositol (GPI)-anchored proteins in epithelial cells. J. Cell Biol. 140, 617–626 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Parton, R.G., Hanzal-Bayer, M. & Hancock, J.F. Biogenesis of caveolae: a structural model for caveolin-induced domain formation. J. Cell Sci. 119, 787–796 (2006). Summary of current data on caveola biogenesis and a proposed model for the formation of caveolae through caveolin–lipid interactions.

    CAS  PubMed  Google Scholar 

  28. Monier, S. et al. VIP21–caveolin, a membrane protein constituent of the caveolar coat, oligomerizes in vivo and in vitro. Mol. Biol. Cell 6, 911–927 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Monier, S., Dietzen, D.J., Hastings, W.R., Lublin, D.M. & Kurzchalia, T.V. Oligomerization of VIP21–caveolin in vitro is stabilized by long chain fatty acylation or cholesterol. FEBS Lett. 388, 143–149 (1996).

    CAS  PubMed  Google Scholar 

  30. Pol, A. et al. Cholesterol and fatty acids regulate dynamic caveolin trafficking through the Golgi complex and between the cell surface and lipid bodies. Mol. Biol. Cell 16, 2091–2105 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Cheng, Z.J. et al. Distinct mechanisms of clathrin-independent cndocytosis have unique sphingolipid requirements. Mol. Biol. Cell 17, 3197–3210 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Tagawa, A. et al. Assembly and trafficking of caveolar domains in the cell: caveolae as stable, cargo-triggered, vesicular transporters. J. Cell Biol. 170, 769–779 (2005). Real-time microscopy and cell-fusion experiments show that caveolae are remarkably stable with evidence for formation of 'caveolae' in the Golgi complex that then fuse directly with the plasma membrane.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Lipowsky, R. Domain-induced budding of fluid membranes. Biophys. J. 64, 1133–1138 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Bauer, M. & Pelkmans, L. A new paradigm for membrane-organizing and -shaping scaffolds. FEBS Lett. 580, 5559–5564 (2006).

    CAS  PubMed  Google Scholar 

  35. Choudhury, A., Marks, D.L., Proctor, K.M., Gould, G.W. & Pagano, R.E. Regulation of caveolar endocytosis by syntaxin 6-dependent delivery of membrane components to the cell surface. Nature Cell Biol. 8, 317–328 (2006). Identifies syntaxin-6 as a regulator of CAV1, GPI-anchored proteins, and GM1 transport from Golgi to the plasma membrane and provides insights into the coupling of exocytosis and endocytosis of lipid-raft components.

    CAS  PubMed  Google Scholar 

  36. Manninen, A. et al. Caveolin-1 is not essential for biosynthetic apical membrane transport. Mol. Cell. Biol. 25, 10087–10096 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hernandez-Deviez, D.J. et al. Aberrant dysferlin trafficking in cells lacking caveolin or expressing dystrophy mutants of caveolin-3. Hum. Mol. Genet. 15, 129–142 (2006).

    CAS  PubMed  Google Scholar 

  38. Wyse, B.D. et al. Caveolin interacts with the angiotensin II type 1 receptor during exocytic transport but not at the plasma membrane. J. Biol. Chem. 278, 23738–23746 (2003).

    CAS  PubMed  Google Scholar 

  39. Cohen, A.W. et al. Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. Am. J. Physiol. Cell Physiol. 285, C222–C235 (2003).

    CAS  PubMed  Google Scholar 

  40. Brazer, S.C., Singh, B.B., Liu, X., Swaim, W. & Ambudkar, I.S. Caveolin-1 contributes to assembly of store-operated Ca2+ influx channels by regulating plasma membrane localization of TRPC1. J. Biol. Chem. 278, 27208–27215 (2003).

    CAS  PubMed  Google Scholar 

  41. Maroto, R. et al. TRPC1 forms the stretch-activated cation channel in vertebrate cells. Nature Cell Biol. 7, 179–185 (2005).

    CAS  PubMed  Google Scholar 

  42. Scheiffele, P. et al. Caveolin-1 and -2 in the exocytic pathway of MDCK cells. J. Cell Biol. 140, 795–806 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Verkade, P., Harder, T., Lafont, F. & Simons, K. Induction of caveolae in the apical plasma membrane of Madin–Darby canine kidney cells. J. Cell Biol. 148, 727–739 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Pelkmans, L., Burli, T., Zerial, M. & Helenius, A. Caveolin-stabilized membrane domains as multifunctional transport and sorting devices in endocytic membrane traffic. Cell 118, 767–780 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kirkham, M. et al. Ultrastructural identification of uncoated caveolin-independent early endocytic vehicles. J. Cell Biol. 168, 465–476 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  48. Sharma, D.K. et al. Selective stimulation of caveolar endocytosis by glycosphingolipids and cholesterol. Mol. Biol. Cell 15, 3114–3122 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Oh, P., McIntosh, D.P. & Schnitzer, J.E. Dynamin at the neck of caveolae mediates their budding to form transport vesicles by GTP-driven fission from the plasma membrane of endothelium. J. Cell Biol. 141, 101–114 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Henley, J.R., Krueger, E.W., Oswald, B.J. & McNiven, M.A. Dynamin-mediated internalization of caveolae. J. Cell Biol. 141, 85–99 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Yao, Q. et al. Caveolin-1 interacts directly with dynamin-2. J. Mol. Biol. 348, 491–501 (2005).

    CAS  PubMed  Google Scholar 

  52. Damm, E.M. et al. Clathrin- and caveolin-1-independent endocytosis: entry of simian virus 40 into cells devoid of caveolae. J. Cell Biol. 168, 477–488 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Kirkham, M. & Parton, R.G. Clathrin-independent endocytosis: new insights into caveolae and non-caveolar lipid raft carriers. Biochim. Biophys. Acta 1745, 273–286 (2005).

    CAS  PubMed  Google Scholar 

  54. Nabi, I.R. & Le, P.U. Caveolae/raft-dependent endocytosis. J. Cell Biol. 161, 673–677 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Pelkmans, L. et al. Genome-wide analysis of human kinases in clathrin- and caveolae/raft-mediated endocytosis. Nature 436, 78–86 (2005). A high-throughput screen of kinases involved in endocytosis provides fascinating insights into the complex interplay between endocytosis and other cellular processes, such as cell adhesion and cell division.

    CAS  PubMed  Google Scholar 

  56. Sharma, D.K. et al. The glycosphingolipid, lactosylceramide, regulates β1-integrin clustering and endocytosis. Cancer Res. 65, 8233–8241 (2005). Evidence for glycosphingolipid-stimulated β1-integrin internalization through a caveolae-mediated pathway.

    CAS  PubMed  Google Scholar 

  57. Sottile, J. & Chandler, J. Fibronectin matrix turnover occurs through a caveolin-1-dependent process. Mol. Biol. Cell 16, 757–768 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. del Pozo, M.A. et al. Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization. Nature Cell Biol. 7, 901–908 (2005). Demonstrates striking internalization of lipid-raft components upon cell detachment from the substratum through a phospho-CAV1-dependent pathway.

    CAS  PubMed  Google Scholar 

  59. Parton, R.G. Ultrastructural localization of gangliosides; GM1 is concentrated in caveolae. J. Histochem. Cytochem. 42, 155–166 (1994).

    CAS  PubMed  Google Scholar 

  60. Nichols, B.J. GM1-containing lipid rafts are depleted within clathrin-coated pits. Curr. Biol. 13, 686–690 (2003).

    CAS  PubMed  Google Scholar 

  61. Watarai, M., Makino, S., Fujii, Y., Okamoto, K. & Shirahata, T. Modulation of Brucella-induced macropinocytosis by lipid rafts mediates intracellular replication. Cell Microbiol. 4, 341–355 (2002).

    CAS  PubMed  Google Scholar 

  62. Minshall, R.D. et al. Endothelial cell-surface gp60 activates vesicle formation and trafficking via G(i)-coupled Src kinase signaling pathway. J. Cell Biol. 150, 1057–1070 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Schubert, W. et al. Caveolae-deficient endothelial cells show defects in the uptake and transport of albumin in vivo. J. Biol. Chem. 276, 48619–48622 (2001).

    CAS  PubMed  Google Scholar 

  64. Miyawaki-Shimizu, K. et al. siRNA-induced caveolin-1 knockdown in mice increases lung vascular permeability via the junctional pathway. Am. J. Physiol. Lung Cell. Mol. Physiol. 290, L405–L413 (2006). siRNA-mediated downregulation of CAV1 in vivo causes a loss of endothelial caveolae and an increase in vascular hyperpermeability to albumin. Ultrastructural studies showed dilation of interendothelial junctions.

    CAS  PubMed  Google Scholar 

  65. Rosengren, B.I. et al. Transvascular protein transport in mice lacking endothelial caveolae. Am. J. Physiol. Heart Circ. Physiol. 291, H1371–H1377 (2006). Evidence for a passive porous pathway for transport of albumin across the endothelium in vivo in both Cav1 -knockout and wild-type mice, arguing against caveolae as a quantitatively important transport route.

    CAS  PubMed  Google Scholar 

  66. Schubert, W. et al. Microvascular hyperpermeability in caveolin-1 (−/−) knock-out mice. Treatment with a specific nitric-oxide synthase inhibitor, L-NAME, restores normal microvascular permeability in Cav-1 null mice. J. Biol. Chem. 277, 40091–40098 (2002).

    CAS  PubMed  Google Scholar 

  67. Sigismund, S. et al. Clathrin-independent endocytosis of ubiquitinated cargos. Proc. Natl Acad. Sci. USA 102, 2760–2765 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Di Guglielmo, G.M., Le Roy, C., Goodfellow, A.F. & Wrana, J.L. Distinct endocytic pathways regulate TGF-β receptor signalling and turnover. Nature Cell Biol. 5, 410–421 (2003).

    CAS  PubMed  Google Scholar 

  69. 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  PubMed  PubMed Central  Google Scholar 

  70. Stang, E., Kartenbeck, J. & Parton, R.G. Major histocompatibility complex class I molecules mediate association of SV40 with caveolae. Mol. Biol. Cell 8, 47–57 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Sukumaran, S.K., Quon, M.J. & Prasadarao, N.V. Escherichia coli K1 internalization via caveolae requires caveolin-1 and protein kinase Cα interaction in human brain microvascular endothelial cells. J. Biol. Chem. 277, 50716–50724 (2002).

    CAS  PubMed  Google Scholar 

  72. Zaas, D.W., Duncan, M.J., Li, G., Wright, J.R. & Abraham, S.N. Pseudomonas invasion of type I pneumocytes is dependent on the expression and phosphorylation of caveolin-2. J. Biol. Chem. 280, 4864–4872 (2005).

    CAS  PubMed  Google Scholar 

  73. Tamai, R., Asai, Y. & Ogawa, T. Requirement for intercellular adhesion molecule 1 and caveolae in invasion of human oral epithelial cells by Porphyromonas gingivalis. Infect. Immun. 73, 6290–6298 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Rohde, M., Muller, E., Chhatwal, G.S. & Talay, S.R. Host cell caveolae act as an entry-port for group A streptococci. Cell. Microbiol. 5, 323–342 (2003).

    CAS  PubMed  Google Scholar 

  75. Millan, J. et al. Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains. Nature Cell Biol. 8, 113–123 (2006).

    CAS  PubMed  Google Scholar 

  76. Muro, S. et al. A novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1. J. Cell Sci. 116, 1599–1609 (2003).

    CAS  PubMed  Google Scholar 

  77. Li, J. et al. Impaired phagocytosis in caveolin-1 deficient macrophages. Cell Cycle 4, 1599–1607 (2005).

    CAS  PubMed  Google Scholar 

  78. Beardsley, A. et al. Loss of caveolin-1 polarity impedes endothelial cell polarization and directional movement. J. Biol. Chem. 280, 3541–3547 (2005). Provides evidence for a functional role for CAV1 in endothelial-cell motility. In actively migrating cells, caveolae are localized at the rear of the cell and excluded from the leading edge.

    CAS  PubMed  Google Scholar 

  79. Souto, R.P. et al. Immunopurification and characterization of rat adipocyte caveolae suggest their dissociation from insulin signaling. J. Biol. Chem. 278, 18321–18329 (2003).

    CAS  PubMed  Google Scholar 

  80. Li, S., Couet, J. & Lisanti, M.P. Src tyrosine kinases, Gα subunits, and H-Ras share a common membrane-anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases. J. Biol. Chem. 271, 29182–29190 (1996).

    CAS  PubMed  Google Scholar 

  81. Schlegel, A., Schwab, R.B., Scherer, P.E. & Lisanti, M.P. A role for the caveolin scaffolding domain in mediating the membrane attachment of caveolin-1. The caveolin scaffolding domain is both necessary and sufficient for membrane binding in vitro. J. Biol. Chem. 274, 22660–22667 (1999).

    CAS  PubMed  Google Scholar 

  82. Epand, R.M., Sayer, B.G. & Epand, R.F. Caveolin scaffolding region and cholesterol-rich domains in membranes. J. Mol. Biol. 345, 339–350 (2005).

    CAS  PubMed  Google Scholar 

  83. Arbuzova, A. et al. Membrane binding of peptides containing both basic and aromatic residues. Experimental studies with peptides corresponding to the scaffolding region of caveolin and the effector region of MARCKS. Biochemistry 39, 10330–10339 (2000).

    CAS  PubMed  Google Scholar 

  84. Gonzalez, E., Nagiel, A., Lin, A.J., Golan, D.E. & Michel, T. Small interfering RNA-mediated down-regulation of caveolin-1 differentially modulates signaling pathways in endothelial cells. J. Biol. Chem. 279, 40659–40669 (2004).

    CAS  PubMed  Google Scholar 

  85. Bernatchez, P.N. et al. Dissecting the molecular control of endothelial NO synthase by caveolin-1 using cell-permeable peptides. Proc. Natl Acad. Sci. USA 102, 761–766 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  87. Bauer, P.M. et al. Endothelial-specific expression of caveolin-1 impairs microvascular permeability and angiogenesis. Proc. Natl Acad. Sci. USA 102, 204–209 (2005). Transgenic overexpression of CAV1 impairs eNOS activation and decreases VEGF-stimulated vascular permeability. CAV1 overexpression reduced VEGF-mediated angiogenesis after experimentally induced tissue ischaemia.

    CAS  PubMed  Google Scholar 

  88. Bucci, M. et al. In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation. Nature Med. 6, 1362–1367 (2000).

    CAS  PubMed  Google Scholar 

  89. Garcia-Cardena, G. et al. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the NOS caveolin binding domain in vivo. J. Biol. Chem. 272, 25437–25440 (1997).

    CAS  PubMed  Google Scholar 

  90. Reddy, M.A. et al. Key role of Src kinase in S100B-induced activation of the receptor for advanced glycation end products in vascular smooth muscle cells. J. Biol. Chem. 281, 13685–13693 (2006).

    CAS  PubMed  Google Scholar 

  91. Swaney, J.S. et al. Focal adhesions in (myo)fibroblasts scaffold adenylyl cyclase with phosphorylated caveolin. J. Biol. Chem. 281, 17173–17179 (2006).

    CAS  PubMed  Google Scholar 

  92. Cheng, X. & Jaggar, J.H. Genetic ablation of caveolin-1 modifies Ca2+ spark coupling in murine arterial smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 290, H2309–H2319 (2006).

    CAS  PubMed  Google Scholar 

  93. Wang, X.L. et al. Caveolae targeting and regulation of large conductance Ca2+-activated K+ channels in vascular endothelial cells. J. Biol. Chem. 280, 11656–11664 (2005).

    CAS  PubMed  Google Scholar 

  94. Trigatti, B.L., Anderson, R.G. & Gerber, G.E. Identification of caveolin-1 as a fatty acid binding protein. Biochem. Biophys. Res. Commun. 255, 34–39 (1999).

    CAS  PubMed  Google Scholar 

  95. Martin, S. & Parton, R.G. Lipid droplets: a unified view of a dynamic organelle. Nature Rev. Mol. Cell Biol. 7, 373–378 (2006).

    CAS  Google Scholar 

  96. Murphy, D.J. The biogenesis and functions of lipid bodies in animals, plants and microorganisms. Prog. Lipid Res. 40, 325–438 (2001).

    CAS  PubMed  Google Scholar 

  97. Martin, S. & Parton, R.G. Caveolin, cholesterol, and lipid bodies. Semin. Cell Dev. Biol. 16, 163–174 (2005).

    CAS  PubMed  Google Scholar 

  98. Brasaemle, D.L., Dolios, G., Shapiro, L. & Wang, R. Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3-L1 adipocytes. J. Biol. Chem. 279, 46835–46842 (2004).

    CAS  PubMed  Google Scholar 

  99. Pol, A. et al. Dynamic and regulated association of caveolin with lipid bodies: modulation of lipid body motility and function by a dominant negative mutant. Mol. Biol. Cell 15, 99–110 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Meshulam, T., Simard, J.R., Wharton, J., Hamilton, J.A. & Pilch, P.F. Role of caveolin-1 and cholesterol in transmembrane fatty acid movement. Biochemistry 45, 2882–2893 (2006).

    CAS  PubMed  Google Scholar 

  101. Fu, Y. et al. Expression of caveolin-1 enhances cholesterol efflux in hepatic cells. J. Biol. Chem. 279, 14140–14146 (2004).

    CAS  PubMed  Google Scholar 

  102. Fielding, C.J. & Fielding, P.E. Caveolae and intracellular trafficking of cholesterol. Adv. Drug Deliv. Rev. 49, 251–264 (2001).

    CAS  PubMed  Google Scholar 

  103. Frank, P.G. et al. Caveolin-1 and the regulation of cellular cholesterol homeostasis. Am. J. Physiol. Heart Circ. Physiol. 291, H677–H686 (2006).

    CAS  PubMed  Google Scholar 

  104. Pol, A. et al. A caveolin dominant negative mutant associates with lipid bodies and induces intracellular cholesterol imbalance. J. Cell Biol. 152, 1057–1070 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Fernandez, M.A. et al. Caveolin-1 is essential for liver regeneration. Science 313, 1628–1632 (2006).

    CAS  PubMed  Google Scholar 

  106. Razani, B. et al. Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. J. Biol. Chem. 277, 8635–8647 (2002).

    CAS  PubMed  Google Scholar 

  107. Le Lay, S. et al. Cholesterol-induced caveolin targeting to lipid droplets in adipocytes: a role for caveolar endocytosis. Traffic 7, 549–561 (2006).

    CAS  PubMed  Google Scholar 

  108. Landh, T. From entangled membranes to eclectic morphologies: cubic membranes as subcellular space organizers. FEBS Lett. 369, 13–17 (1995).

    CAS  PubMed  Google Scholar 

  109. Vogel, V. & Sheetz, M. Local force and geometry sensing regulate cell functions. Nature Rev. Mol. Cell Biol. 7, 265–275 (2006).

    CAS  Google Scholar 

  110. Rizzo, V., Morton, C., DePaola, N., Schnitzer, J.E. & Davies, P.F. Recruitment of endothelial caveolae into mechanotransduction pathways by flow conditioning in vitro. Am. J. Physiol. Heart Circ. Physiol. 285, H1720–H1729 (2003). In cultured endothelial cells, chronic exposure to shear stress causes increased surface localization of CAV1 and caveolae; this effect is linked to increased mechanosensitivity and activation of specific signalling pathways.

    CAS  PubMed  Google Scholar 

  111. Boyd, N.L. et al. Chronic shear induces caveolae formation and alters ERK and Akt responses in endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 285, H1113–H1122 (2003).

    CAS  PubMed  Google Scholar 

  112. Radel, C. & Rizzo, V. Integrin mechanotransduction stimulates caveolin-1 phosphorylation and recruitment of Csk to mediate actin reorganization. Am. J. Physiol. Heart Circ. Physiol. 288, H936–H945 (2005). Cultured bovine aortic endothelial cells subjected to shear stress show rapid Tyr14 phosphorylation of CAV1, which is dependent on β1-integrin activation, supporting a role for caveolae in mechanosensing.

    CAS  PubMed  Google Scholar 

  113. Yu, J. et al. Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels. J. Clin. Invest. 116, 1284–1291 (2006). Endothelial expression of CAV1 in Cav1 -null mice shows that CAV1 is required for eNOS activation in response to endothelial flow; these data provide further support for a mechanosensing role of caveolae.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Rudic, R.D. et al. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J. Clin. Invest. 101, 731–736 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Sedding, D.G. et al. Caveolin-1 facilitates mechanosensitive protein kinase B (Akt) signaling in vitro and in vivo. Circ. Res. 96, 635–642 (2005). Smooth-muscle cells subjected to cyclic stretch show rapid redistribution of CAV1 to focal contacts. CAV1 is required for stretch-triggered cell-cycle progression.

    CAS  PubMed  Google Scholar 

  116. Oh, P. & Schnitzer, J.E. Segregation of heterotrimeric G proteins in cell surface microdomains. Gq binds caveolin to concentrate in caveolae, whereas Gi and Gs target lipid rafts by default. Mol. Biol. Cell 12, 685–698 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Czarny, M. & Schnitzer, J.E. Neutral sphingomyelinase inhibitor scyphostatin prevents and ceramide mimics mechanotransduction in vascular endothelium. Am. J. Physiol. Heart. Circ Physiol. 287, H1344–H1352 (2004).

    CAS  PubMed  Google Scholar 

  118. Alenghat, F.J. & Ingber, D.E. Mechanotransduction: all signals point to cytoskeleton, matrix, and integrins. Sci. STKE 2002, PE6 (2002).

    PubMed  Google Scholar 

  119. Lundbaek, J.A. et al. Regulation of sodium channel function by bilayer elasticity: the importance of hydrophobic coupling. Effects of micelle-forming amphiphiles and cholesterol. J. Gen. Physiol. 123, 599–621 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Lundbaek, J.A., Andersen, O.S., Werge, T. & Nielsen, C. Cholesterol-induced protein sorting: an analysis of energetic feasibility. Biophys. J. 84, 2080–2089 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Sens, P. & Turner, M.S. Budded membrane microdomains as tension regulators. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 73, 031918 (2006).

    PubMed  Google Scholar 

  122. Koleske, A.J., Baltimore, D. & Lisanti, M.P. Reduction of caveolin and caveolae in oncogenically transformed cells. Proc. Natl Acad. Sci. USA 92, 1381–1385 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  124. Hayashi, K. et al. Invasion activating caveolin-1 mutation in human scirrhous breast cancers. Cancer Res. 61, 2361–2364 (2001).

    CAS  PubMed  Google Scholar 

  125. Williams, T.M. et al. Loss of caveolin-1 gene expression accelerates the development of dysplastic mammary lesions in tumor-prone transgenic mice. Mol. Biol. Cell 14, 1027–1042 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Capozza, F. et al. Absence of caveolin-1 sensitizes mouse skin to carcinogen-induced epidermal hyperplasia and tumor formation. Am. J. Pathol. 162, 2029–2039 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Li, T. et al. Caveolin-1 mutations in human breast cancer: functional association with estrogen receptor α-positive status. Am. J. Pathol. 168, 1998–2013 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Sunaga, N. et al. Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer. Cancer Res. 64, 4277–4285 (2004).

    CAS  PubMed  Google Scholar 

  129. Thompson, T.C., Timme, T.L., Li, L. & Goltsov, A. Caveolin-1, a metastasis-related gene that promotes cell survival in prostate cancer. Apoptosis 4, 233–237 (1999).

    CAS  PubMed  Google Scholar 

  130. Yang, G., Timme, T.L., Frolov, A., Wheeler, T.M. & Thompson, T.C. Combined c-Myc and caveolin-1 expression in human prostate carcinoma predicts prostate carcinoma progression. Cancer 103, 1186–1194 (2005).

    CAS  PubMed  Google Scholar 

  131. Vorgerd, M. et al. A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation. Neurology 57, 2273–2277 (2001).

    CAS  PubMed  Google Scholar 

  132. McNally, E.M. et al. Caveolin-3 in muscular dystrophy. Hum. Mol. Genet. 7, 871–877 (1998).

    CAS  PubMed  Google Scholar 

  133. Woodman, S.E., Sotgia, F., Galbiati, F., Minetti, C. & Lisanti, M.P. Caveolinopathies: mutations in caveolin-3 cause four distinct autosomal dominant muscle diseases. Neurology 62, 538–543 (2004).

    CAS  PubMed  Google Scholar 

  134. Minetti, C. et al. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nature Genet. 18, 365–368 (1998).

    CAS  PubMed  Google Scholar 

  135. Galbiati, F., Volonte, D., Minetti, C., Chu, J.B. & Lisanti, M.P. Phenotypic behavior of caveolin-3 mutations that cause autosomal dominant limb girdle muscular dystrophy (LGMD-1C). Retention of LGMD-1C caveolin-3 mutants within the golgi complex. J. Biol. Chem. 274, 25632–25641 (1999).

    CAS  PubMed  Google Scholar 

  136. Matsuda, C. et al. The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle. Hum. Mol. Genet. 10, 1761–1766 (2001).

    CAS  PubMed  Google Scholar 

  137. Parton, R.G., Molero, J.C., Floetenmeyer, M., Green, K.M. & James, D.E. Characterization of a distinct plasma membrane macrodomain in differentiated adipocytes. J. Biol. Chem. 277, 46769–46778 (2002).

    CAS  PubMed  Google Scholar 

  138. Foster, L.J., De Hoog, C.L. & Mann, M. Unbiased quantitative proteomics of lipid rafts reveals high specificity for signaling factors. Proc. Natl Acad. Sci. USA 100, 5813–5818 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Nixon, S.J. et al. Zebrafish as a model for caveolin-associated muscle disease; caveolin-3 is required for myofibril organization and muscle cell patterning. Hum. Mol. Genet. 14, 1727–1743 (2005).

    CAS  PubMed  Google Scholar 

  140. Ohsawa, Y. et al. Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity. Hum. Mol. Genet. 13, 151–157 (2004).

    CAS  PubMed  Google Scholar 

  141. Sharma, D.K. et al. Glycosphingolipids internalized via caveolar-related endocytosis rapidly merge with the clathrin pathway in early endosomes and form microdomains for recycling. J. Biol. Chem. 278, 7564–7572 (2003).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are extremely grateful to R. Stan, B. Sessa, J. Hancock, and members of the Parton and Simons laboratories for comments on the manuscript. The authors acknowledge the continuing support of the National Health and Medical Research Council of Australia (R.G.P.), the National Institutes of Health, USA (R.G.P.), the Max Planck Society (K.S.), Deutsche Forschungsgemeinschaft (K.S.) and the European Commission (K.S.). The Institute for Molecular Bioscience is a Special Research Centre of the Australian Research Council. We would also like to apologize to those researchers whose primary research could not be cited owing to space constraints.

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Authors and Affiliations

  1. Institute for Molecular Bioscience and Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, 4072, Queensland, Australia

    Robert G. Parton

  2. Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse 110, Dresden, D-01307, Germany

    Kai Simons

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Glossary

Stomatal diaphragm

A specialized structure at the neck of caveolae in certain endothelial cells that consists of a central density and radial spikes, and is generated by the transmembrane protein PV1.

Lipid rafts

Small, heterogeneous, highly dynamic, sterol- and sphingolipid-enriched domains that are formed by lipid–lipid interactions that compartmentalize cellular processes. Small lipid rafts can be stabilized to form larger platforms through protein–protein and protein–lipid interactions.

Signal recognition particle

(SRP). A complex of polypeptides and RNA involved in synthesis of proteins on membrane-bound ribosomes of the ER. SRP interaction with a specific signal on the nascent polypeptide dictates co-translational insertion of the protein into the ER.

Detergent-resistant membrane

(DRM). DRM fractions remain insoluble after cold Triton X-100 extraction. This is a crude biochemical measure for lipid-raft association.

Exocytic caveolar carrier

A carrier produced in the Golgi that resembles a fully formed caveola in caveolin density. We suggest the terms endocytic caveolar carrier and recycling caveolar carrier for budded caveolae or caveolae recycling back to the cell surface.

SNAREs

(Soluble N-ethylmaleimide-sensitive factor attachment-protein receptors). A protein family that consists of a cognate group of integral and peripheral membrane proteins that are required for bilayer recognition and fusion during membrane trafficking.

Caveosome

A neutral pH endosomal compartment that lacks classic endosomal markers but contains markers that are internalized through caveolae.

Lipid droplet

A lipid-storage organelle that comprises a core of triacylglycerol and/or cholesterol esters surrounded by a phospholipid monolayer.

Mechanosensation

The sensing of mechanical stimuli, for example stretch or flow, by cells.

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Parton, R., Simons, K. The multiple faces of caveolae. Nat Rev Mol Cell Biol 8, 185–194 (2007). https://doi.org/10.1038/nrm2122

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