Key Points
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Caveolae, submicroscopic pits of the plasma membrane, consist of caveolin membrane proteins and cytoplasmic cavin proteins.
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Caveolae can bud from the plasma membrane, fuse with early endosomes and recycle back to the cell surface, or they can be turned over via a ubiquitylation-dependent mechanism and targeted to multivesicular bodies.
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Mutations in caveolins and cavins have been linked to diverse disease states, including cancer, lipodystrophy, cardiomyopathy and muscular dystrophies.
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The various diseases linked to caveolae dysfunction suggest a crucial cellular role in lipid regulation, membrane organization and in cell protection against physical stress.
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Flattening of caveolae in response to plasma membrane forces may provide a reservoir of membrane and activate signalling pathways through caveolins and cavins.
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Caveola dysfunction can influence a range of signalling pathways and lipid regulatory processes with widespread effects on cell function.
Abstract
Caveolae are submicroscopic, plasma membrane pits that are abundant in many mammalian cell types. The past few years have seen a quantum leap in our understanding of the formation, dynamics and functions of these enigmatic structures. Caveolae have now emerged as vital plasma membrane sensors that can respond to plasma membrane stresses and remodel the extracellular environment. Caveolae at the plasma membrane can be removed by endocytosis to regulate their surface density or can be disassembled and their structural components degraded. Coat proteins, called cavins, work together with caveolins to regulate the formation of caveolae but also have the potential to dynamically transmit signals that originate in caveolae to various cellular destinations. The importance of caveolae as protective elements in the plasma membrane, and as membrane organizers and sensors, is highlighted by links between caveolae dysfunction and human diseases, including muscular dystrophies and cancer.
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References
Palade, G. E. Fine structure of blood capillaries. J. Appl. Phys. 24, 1424 (1953).
Yamada, E. The fine structures of the gall bladder epithelium of the mouse. J. Biophys. Biochem. Cytol. 1, 445–458 (1955).
Hayashi, Y. K. et al. Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J. Clin. Invest. 119, 2623–2633 (2009).
Rajab, A. et al. Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF–CAVIN mutations. PLoS Genet. 6, e1000874 (2010). References 3 and 4 were the first papers showing that loss of cavins is associated with human disease.
Parton, R. G. & Simons, K. The multiple faces of caveolae. Nature Rev. Mol. Cell Biol. 8, 185–194 (2007).
Pelkmans, L. & Zerial, M. Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae. Nature 436, 128–133 (2005).
Richter, T. et al. High-resolution 3D quantitative analysis of caveolar ultrastructure and caveola–cytoskeleton interactions. Traffic 9, 893–909 (2008).
Schlormann, W. et al. The shape of caveolae is omega-like after glutaraldehyde fixation and cup-like after cryofixation. Histochem. Cell Biol. 133, 223–228 (2010).
Nixon, S. J. et al. Caveolin-1 is required for lateral line neuromast and notochord development. J. Cell Sci. 120, 2151–2161 (2007).
Peters, K. R., Carley, W. W. & Palade, G. E. Endothelial plasmalemmal vesicles have a characteristic striped bipolar surface structure. J. Cell Biol. 101, 2233–2238 (1985).
Rothberg, K. G. et al. Caveolin, a protein component of caveolae membrane coats. Cell 68, 673–682 (1992).
Zhuang, Z., Marshansky, V., Breton, S. & Brown, D. Is caveolin involved in normal proximal tubule function? Presence in model PT systems but absence in situ. Am. J. Physiol. Renal Physiol. 300, F199–F206 (2011).
Thorn, H. et al. Cell surface orifices of caveolae and localization of caveolin to the necks of caveolae in adipocytes. Mol. Biol. Cell 14, 3967–3976 (2003).
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).
Scheiffele, P. et al. Caveolin-1 and -2 in the exocytic pathway of MDCK cells. J. Cell Biol. 140, 795–806 (1998).
Parat, M. O., Anand-Apte, B. & Fox, P. L. Differential caveolin-1 polarization in endothelial cells during migration in two and three dimensions. Mol. Biol. Cell 14, 3156–3168 (2003).
Kurzchalia, T. V. et al. VIP21, a 21-kD membrane protein is an integral component of trans-Golgi-network-derived transport vesicles. J. Cell Biol. 118, 1003–1014 (1992).
Scherer, P. E. et al. Identification, sequence, and expression of caveolin-2 defines a caveolin gene family. Proc. Natl Acad. Sci. USA 93, 131–135 (1996).
Way, M. & Parton, R. G. M-caveolin, a muscle-specific caveolin-related protein. FEBS Lett. 376, 108–112 (1995).
Robenek, H., Weissen-Plenz, G. & Severs, N. J. Freeze-fracture replica immunolabelling reveals caveolin-1 in the human cardiomyocyte plasma membrane. J. Cell. Mol. Med. 12, 2519–2521 (2008).
Head, B. P. et al. Microtubules and actin microfilaments regulate lipid raft/caveolae localization of adenylyl cyclase signaling components. J. Biol. Chem. 281, 26391–26399 (2006).
Patel, H. H. et al. Mechanisms of cardiac protection from ischemia/reperfusion injury: a role for caveolae and caveolin-1. FASEB J. 21, 1565–1574 (2007).
Tomassian, T. et al. Caveolin-1 orchestrates TCR synaptic polarity, signal specificity, and function in CD8 T cells. J. Immunol. 187, 2993–3002 (2011).
Fernandez-Rojo, M. A. et al. Caveolin-1 orchestrates the balance between glucose and lipid-dependent energy metabolism: implications for liver regeneration. Hepatology 55, 1574–1584 (2012).
Head, B. P. et al. Neuron-targeted caveolin-1 protein enhances signaling and promotes arborization of primary neurons. J. Biol. Chem. 286, 33310–33321 (2011).
Head, B. P. et al. Loss of caveolin-1 accelerates neurodegeneration and aging. PLoS ONE 5, e15697 (2010).
Drab, M. et al. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293, 2449–2452 (2001).
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).
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).
Walser, P. J. et al. Constitutive formation of caveolae in a bacterium. Cell 150, 752–763 (2012). Shows that caveolin expression in a prokaryotic system is sufficient to drive the formation of cytoplasmic vesicles analogous to mammalian caveolae. In this model system, caveolins can drive membrane curvature and fission from the membrane.
Hansen, C. G. & Nichols, B. J. Exploring the caves: cavins, caveolins and caveolae. Trends Cell Biol. 20, 177–186 (2010).
Bastiani, M. et al. MURC/cavin-4 and cavin family members form tissue-specific caveolar complexes. J. Cell Biol. 185, 1259–1273 (2009).
Jansa, P., Mason, S. W., Hoffmann-Rohrer, U. & Grummt, I. Cloning and functional characterization of PTRF, a novel protein which induces dissociation of paused ternary transcription complexes. EMBO J. 17, 2855–2864 (1998).
Gustincich, S. & Schneider, C. Serum deprivation response gene is induced by serum starvation but not by contact inhibition. Cell Growth Differ. 4, 753–760 (1993).
Izumi, Y. et al. A protein kinase Cδ-binding protein SRBC whose expression is induced by serum starvation. J. Biol. Chem. 272, 7381–7389 (1997).
Ogata, T. et al. MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance. Mol. Cell. Biol. 28, 3424–3436 (2008).
Tagawa, M. et al. MURC, a muscle-restricted coiled-coil protein, is involved in the regulation of skeletal myogenesis. Am. J. Physiol. Cell Physiol. 295, C490–C498 (2008).
Hill, M. M. et al. PTRF-cavin, a conserved cytoplasmic protein required for caveola formation and function. Cell 132, 113–124 (2008).
Liu, L. et al. Deletion of cavin/PTRF causes global loss of caveolae, dyslipidemia, and glucose intolerance. Cell Metab. 8, 310–317 (2008). Together with reference 33, the first demonstration of the crucial role of cavin 1 in regulating caveola formation in cells and whole animals.
Hansen, C. G., Bright, N. A., Howard, G. & Nichols, B. J. SDPR induces membrane curvature and functions in the formation of caveolae. Nature Cell Biol. 11, 807–814 (2009).
McMahon, K. A. et al. SRBC/cavin-3 is a caveolin adapter protein that regulates caveolae function. EMBO J. 28, 1001–1015 (2009).
Hayer, A., Stoeber, M., Bissig, C. & Helenius, A. Biogenesis of caveolae: stepwise assembly of large caveolin and cavin complexes. Traffic 11, 361–382 (2010). Identifies a Asp-X-Glu sequence in the N-terminal domain of CAV1 required for exit from the ER. Analyses the assembly of cavin 1 into caveolar domains.
Gustincich, S. et al. The human serum deprivation response gene (SDPR) maps to 2q32-q33 and codes for a phosphatidylserine-binding protein. Genomics 57, 120–129 (1999).
Fairn, G. D. et al. High-resolution mapping reveals topologically distinct cellular pools of phosphatidylserine. J. Cell Biol. 194, 257–275 (2011).
Wanaski, S. P., Ng, B. K. & Glaser, M. Caveolin scaffolding region and the membrane binding region of SRC form lateral membrane domains. Biochemistry 42, 42–56 (2003).
Sinha, B. et al. Cells respond to mechanical stress by rapid disassembly of caveolae. Cell 144, 402–413 (2011). Demonstrates reversible flattening of caveolae and caveolin–cavin dissociation in response to acute mechanical stimuli and shows the importance of the caveolar system in the protection of cells against mechanical stress.
Breen, M. R., Camps, M., Carvalho-Simoes, F., Zorzano, A. & Pilch, P. F. Cholesterol depletion in adipocytes causes caveolae collapse concomitant with proteosomal degradation of cavin-2 in a switch-like fashion. PLoS ONE 7, e34516 (2012).
Naslavsky, N. & Caplan, S. EHD proteins: key conductors of endocytic transport. Trends Cell Biol. 21, 122–131 (2011).
Daumke, O. et al. Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling. Nature 449, 923–927 (2007).
Moren, B. et al. EHD2 regulates caveolar dynamics via ATP-driven targeting and oligomerization. Mol. Biol. Cell 23, 1316–1329 (2012).
Stoeber, M. et al. Oligomers of the ATPase EHD2 confine caveolae to the plasma membrane through association with actin. EMBO J. 31, 2350–2364 (2012). Identifies, together with reference 50, the ATPase EHD2 as a new component of caveolae. Shows that EHD2 has a role in the regulation of caveolar dynamics.
Fujita, A., Cheng, J., Tauchi-Sato, K., Takenawa, T. & Fujimoto, T. A distinct pool of phosphatidylinositol 4,5-bisphosphate in caveolae revealed by a nanoscale labeling technique. Proc. Natl Acad. Sci. USA 106, 9256–9261 (2009).
Henley, J. R., Krueger, E. W., Oswald, B. J. & McNiven, M. A. Dynamin-mediated internalization of caveolae. J. Cell Biol. 141, 85–99 (1998).
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).
Hansen, C. G., Howard, G. & Nichols, B. J. Pacsin 2 is recruited to caveolae and functions in caveolar biogenesis. J. Cell Sci. 124, 2777–2785 (2011). Demonstrates a role for the F-BAR domain protein PACSIN2 in caveola formation.
Senju, Y., Itoh, Y., Takano, K., Hamada, S. & Suetsugu, S. Essential role of PACSIN2/syndapin-II in caveolae membrane sculpting. J. Cell Sci. 124, 2032–2040 (2011).
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).
del Pozo, M. A. et al. Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization. Nature Cell Biol. 7, 901–908 (2005).
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).
Echarri, A. et al. Caveolar domain organization and trafficking is regulated by Abl kinases and mDia1. J. Cell Sci. 125, 309–3113 (2012). Identifies the actin polymerization pathway that links caveolae to stress fibres and shows that adhesion strength and actin fibres modulate caveola plasticity from flattened structures to caveolar rosettes.
Echarri, A. & Del Pozo, M. A. Caveolae. Curr. Biol. 22, R114–R116 (2012).
Parton, R. G., Way, M., Zorzi, N. & Stang, E. Caveolin-3 associates with developing T-tubules during muscle differentiation. J. Cell Biol. 136, 137–154 (1997).
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).
Ewers, H. et al. GM1 structure determines SV40-induced membrane invagination and infection. Nature Cell Biol. 12, 11–18 (2010).
Damm, E. M. et al. Clathrin- and caveolin1-independent endocytosis: entry of simian virus 40 into cells devoid of caveolae. J. Cell Biol. 168, 477–488 (2005).
Oh, P. et al. Live dynamic imaging of caveolae pumping targeted antibody rapidly and specifically across endothelium in the lung. Nature Biotech. 25, 327–337 (2007).
Rippe, B., Rosengren, B. I., Carlsson, O. & Venturoli, D. Transendothelial transport: the vesicle controversy. J. Vasc. Res. 39, 375–390 (2002).
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).
Hayer, A. et al. Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation. J. Cell Biol. 191, 615–629 (2010).
Boucrot, E., Howes, M. T., Kirchhausen, T. & Parton, R. G. Redistribution of caveolae during mitosis. J. Cell Sci. 124, 1965–1972 (2011).
Parton, R. G., Joggerst, B. & Simons, K. Regulated internalization of caveolae. J. Cell Biol. 127, 1199–1215 (1994).
Le Lay, S. et al. Cholesterol-induced caveolin targeting to lipid droplets in adipocytes: a role for caveolar endocytosis. Traffic 7, 549–561 (2006).
Sharma, D. K. et al. Selective stimulation of caveolar endocytosis by glycosphingolipids and cholesterol. Mol. Biol. Cell 15, 3114–3122 (2004).
Muriel, O. et al. Phosphorylated filamin A regulates actin-linked caveolae dynamics. J. Cell Sci. 124, 2763–2776 (2011). Shows, using high-spatio-temporal resolution particle tracking, that filamin A mediates stable arrest of CAV1 vesicles in confined areas and subsequent internalization.
Balasubramanian, N., Scott, D. W., Castle, J. D., Casanova, J. E. & Schwartz, M. A. Arf6 and microtubules in adhesion-dependent trafficking of lipid rafts. Nature Cell Biol. 9, 1381–1391 (2007).
Ritz, D. et al. Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations. Nature Cell Biol. 13, 1116–1123 (2011). Identifies monoubiquitylated oligomeric caveolin as a binding partner of the VCP–UBXD1 complex and links caveolin turnover to human degenerative diseases associated with VCP mutations.
Yamanaka, K., Sasagawa, Y. & Ogura, T. Recent advances in p97/VCP/Cdc48 cellular functions. Biochim. Biophys. Acta 1823, 130–137 (2011).
Stahlhut, M. & van Deurs, B. Identification of filamin as a novel ligand for caveolin-1: evidence for the organization of caveolin-1-associated membrane domains by the actin cytoskeleton. Mol. Biol. Cell 11, 325–337 (2000).
Wickstrom, S. A. et al. Integrin-linked kinase controls microtubule dynamics required for plasma membrane targeting of caveolae. Dev. Cell 19, 574–588 (2010). Demonstrates a loss of caveolae in mice lacking β1 integrins or ILK and identifies the underlying cause as the defective microtubule-dependent trafficking of caveolae to the plasma membrane.
Singh, R. D. et al. Gangliosides and β1-integrin are required for caveolae and membrane domains. Traffic 11, 348–360 (2010).
Sverdlov, M., Shinin, V., Place, A. T., Castellon, M. & Minshall, R. D. Filamin A regulates caveolae internalization and trafficking in endothelial cells. Mol. Biol. Cell 20, 4531–4540 (2009).
Sharma, P. et al. β-dystroglycan binds caveolin-1 in smooth muscle: a functional role in caveolae distribution and Ca2+ release. J. Cell Sci. 123, 3061–3070 (2010).
Lee, J. & Schmid-Schonbein, G. W. Biomechanics of skeletal muscle capillaries: hemodynamic resistance, endothelial distensibility, and pseudopod formation. Ann. Biomed. Eng. 23, 226–246 (1995).
Dulhunty, A. F. & Franzini-Armstrong, C. The relative contributions of the folds and caveolae to the surface membrane of frog skeletal muscle fibres at different sarcomere lengths. J. Physiol. 250, 513–539 (1975). References 83 and 84 use elegant quantitative electron microscopy and different experimental systems to demonstrate flattening of caveolae in response to plasma membrane deformation.
Kozera, L., White, E. & Calaghan, S. Caveolae act as membrane reserves which limit mechanosensitive ICl, swell channel activation during swelling in the rat ventricular myocyte. PLoS ONE 4, e8312 (2009).
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).
Rizzo, V., Sung, A., Oh, P. & Schnitzer, J. E. Rapid mechanotransduction in situ at the luminal cell surface of vascular endothelium and its caveolae. J. Biol. Chem. 273, 26323–26329 (1998).
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).
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).
Zhang, B. et al. Caveolin-1 phosphorylation is required for stretch-induced EGFR and Akt activation in mesangial cells. Cell. Signal. 19, 1690–1700 (2007).
Joshi, B. et al. Phosphocaveolin-1 is a mechanotransducer that induces caveola biogenesis via Egr1 transcriptional regulation. J. Cell Biol. 199, 425–435 (2012).
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).
Grande-Garcia, A. et al. Caveolin-1 regulates cell polarization and directional migration through Src kinase and Rho GTPases. J. Cell Biol. 177, 683–694 (2007).
Goetz, J. G. et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146, 148–163 (2011). First direct demonstration of the role of CAV1 in mechanical regulation of the extracellular environment and its role in tumour invasion.
Yang, B., Radel, C., Hughes, D., Kelemen, S. & Rizzo, V. p190 RhoGTPase-activating protein links the β1 integrin/caveolin-1 mechanosignaling complex to RhoA and actin remodeling. Arterioscler. Thromb. Vasc. Biol. 31, 376–383 (2011).
Boettcher, J. P. et al. Tyrosine-phosphorylated caveolin-1 blocks bacterial uptake by inducing Vav2–RhoA-mediated cytoskeletal rearrangements. PLoS Biol. 8, e1000457 (2010). Shows that CAV1 is Tyr phosphorylated in response to bacterial uptake, which induces actin cytoskeletal reorganization via VAV2 and RHOA.
Bai, L. et al. Regulation of cellular senescence by the essential caveolar component PTRF/cavin-1. Cell Res. 21, 1088–1101 (2011).
Hasegawa, T. et al. PTRF (polymerase I and transcript-release factor) is tissue-specific and interacts with the BFCOL1 (binding factor of a type-I collagen promoter) zinc-finger transcription factor which binds to the two mouse type-I collagen gene promoters. Biochem. J. 347 (Pt. 1), 55–59 (2000).
Albinsson, S., Nordstrom, I., Sward, K. & Hellstrand, P. Differential dependence of stretch and shear stress signaling on caveolin-1 in the vascular wall. Am. J. Physiol. Cell Physiol. 294, C271–C279 (2008).
Bernatchez, P. N., Sharma, A., Kodaman, P. & Sessa, W. C. Myoferlin is critical for endocytosis in endothelial cells. Am. J. Physiol. Cell Physiol. 297, C484–C492 (2009).
Cai, C. et al. Membrane repair defects in muscular dystrophy are linked to altered interaction between MG53, caveolin-3, and dysferlin. J. Biol. Chem. 284, 15894–15902 (2009).
Zhu, H. et al. Polymerase transcriptase release factor (PTRF) anchors MG53 protein to cell injury site for initiation of membrane repair. J. Biol. Chem. 286, 12820–12824 (2011).
Ohsawa, Y. et al. Muscular atrophy of caveolin 3-deficient mice is rescued by myostatin inhibition. J. Clin. Invest. 116, 2924–2934 (2006).
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).
Cerezo, A. et al. The absence of caveolin-1 increases proliferation and anchorage- independent growth by a Rac-dependent, Erk-independent mechanism. Mol. Cell. Biol. 29, 5046–5059 (2009).
Borza, C. M. et al. Integrin α1β1 promotes caveolin-1 dephosphorylation by activating T cell protein-tyrosine phosphatase. J. Biol. Chem. 285, 40114–40124 (2010).
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 growth. Cell 94, 625–634 (1998).
Du, J. et al. Integrin activation and internalization on soft ECM as a mechanism of induction of stem cell differentiation by ECM elasticity. Proc. Natl Acad. Sci. USA 108, 9466–9471 (2011).
Goetz, J. G. et al. Concerted regulation of focal adhesion dynamics by galectin-3 and tyrosine-phosphorylated caveolin-1. J. Cell Biol. 180, 1261–1275 (2008).
Paszek, M. J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).
Sanz-Moreno, V. et al. ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell 20, 229–245 (2011).
Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).
Gaggioli, C. et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nature Cell Biol. 9, 1392–1400 (2007).
Couet, J., Li, S., Okamoto, T., Ikezu, T. & Lisanti, M. P. Identification of peptide and protein ligands for the caveolin- scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins. J. Biol. Chem. 272, 6525–6533 (1997).
Okamoto, T., Schlegel, A., Scherer, P. E. & Lisanti, M. P. Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J. Biol. Chem. 273, 5419–5422 (1998).
Collins, B. M., Davis, M. J., Hancock, J. F. & Parton, R. G. Structure-based reassessment of the caveolin signaling model: do caveolae regulate signaling through caveolin–protein interactions? Dev. Cell 23, 11–20 (2012).
Byrne, D. P., Dart, C. & Rigden, D. J. Evaluating caveolin interactions: do proteins interact with the caveolin scaffolding domain through a widespread aromatic residue-rich motif? PLoS ONE 7, e44879 (2012).
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).
Sowa, G., Pypaert, M. & Sessa, W. C. Distinction between signaling mechanisms in lipid rafts versus caveolae. Proc. Natl Acad. Sci. USA 98, 14072–14077 (2001).
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).
Place, A. T. et al. Cooperative role of caveolin-1 and C-terminal Src kinase binding protein in C-terminal Src kinase-mediated negative regulation of c-Src. Mol. Pharmacol. 80, 665–672 (2011).
Kronstein, R. et al. Caveolin-1 opens endothelial cell junctions by targeting catenins. Cardiovasc. Res. 93, 130–140 (2012).
Blouin, C. M. et al. Plasma membrane subdomain compartmentalization contributes to distinct mechanisms of ceramide action on insulin signaling. Diabetes 59, 600–610 (2010).
Mattsson, C. L., Csikasz, R. I., Shabalina, I. G., Nedergaard, J. & Cannon, B. Caveolin-1-ablated mice survive in cold by nonshivering thermogenesis despite desensitized adrenergic responsiveness. Am. J. Physiol. Endocrinol. Metab. 299, e374–e383 (2010).
Gonzalez-Munoz, E. et al. Caveolin-1 loss of function accelerates glucose transporter 4 and insulin receptor degradation in 3T3-L1 adipocytes. Endocrinology 150, 3493–3502 (2009).
Hernandez-Deviez, D. J. et al. Caveolin regulates endocytosis of the muscle repair protein, dysferlin. J. Biol. Chem. 283, 6476–6488 (2008).
Marchiando, A. M. et al. Caveolin-1-dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo. J. Cell Biol. 189, 111–126 (2010).
Orlichenko, L. et al. Caveolae mediate growth factor-induced disassembly of adherens junctions to support tumor cell dissociation. Mol. Biol. Cell 20, 4140–4152 (2009).
Upla, P. et al. Clustering induces a lateral redistribution of α2 β1 integrin from membrane rafts to caveolae and subsequent protein kinase C-dependent internalization. Mol. Biol. Cell 15, 625–636 (2004).
Shi, F. & Sottile, J. Caveolin-1-dependent β1 integrin endocytosis is a critical regulator of fibronectin turnover. J. Cell Sci. 121, 2360–2371 (2008).
Arjonen, A., Alanko, J., Veltel, S. & Ivaska, J. Distinct recycling of active and inactive β1 integrins. Traffic 13, 610–625 (2012).
Pellinen, T. et al. Integrin trafficking regulated by Rab21 is necessary for cytokinesis. Dev. Cell 15, 371–385 (2008).
Guo, J. et al. Cell surface expression of human ether-a-go-go-related gene (hERG) channels is regulated by caveolin-3 protein via the ubiquitin ligase Nedd4-2. J. Biol. Chem. 287, 33132–33141 (2012).
Lee, I. H. et al. The activity of the epithelial sodium channels is regulated by caveolin-1 via a Nedd4-2-dependent mechanism. J. Biol. Chem. 284, 12663–12669 (2009).
Otsu, K. et al. Caveolin gene transfer improves glucose metabolism in diabetic mice. Am. J. Physiol. Cell Physiol. 298, C450–C456 (2010).
Gervasio, O. L., Whitehead, N. P., Yeung, E. W., Phillips, W. D. & Allen, D. G. TRPC1 binds to caveolin-3 and is regulated by Src kinase — role in Duchenne muscular dystrophy. J. Cell Sci. 121, 2246–2255 (2008).
Langlois, S., Cowan, K. N., Shao, Q., Cowan, B. J. & Laird, D. W. Caveolin-1 and -2 interact with connexin43 and regulate gap junctional intercellular communication in keratinocytes. Mol. Biol. Cell 19, 912–928 (2008).
Pani, B. et al. Activation of TRPC1 by STIM1 in ER–PM microdomains involves release of the channel from its scaffold caveolin-1. Proc. Natl Acad. Sci. USA 106, 20087–20092 (2009).
Sundivakkam, P. C. et al. Caveolin-1 scaffold domain interacts with TRPC1 and IP3R3 to regulate Ca2+ store release-induced Ca2+ entry in endothelial cells. Am. J. Physiol. Cell Physiol. 296, C403–C413 (2009).
Fuhs, S. R. & Insel, P. A. Caveolin-3 undergoes SUMOylation by the SUMO E3 ligase PIASy: sumoylation affects G-protein-coupled receptor desensitization. J. Biol. Chem. 286, 14830–14841 (2011).
Nethe, M. et al. Focal-adhesion targeting links caveolin-1 to a Rac1-degradation pathway. J. Cell Sci. 123, 1948–1958 (2010).
Hezel, M., de Groat, W. C. & Galbiati, F. Caveolin-3 promotes nicotinic acetylcholine receptor clustering and regulates neuromuscular junction activity. Mol. Biol. Cell 21, 302–310 (2010).
Isshiki, M. et al. Endothelial Ca2+ waves preferentially originate at specific loci in caveolin-rich cell edges. Proc. Natl Acad. Sci. USA 95, 5009–5014 (1998).
Yamamoto, K. et al. Visualization of flow-induced ATP release and triggering of Ca2+ waves at caveolae in vascular endothelial cells. J. Cell Sci. 124, 3477–3483 (2011). Demonstrates that localized release of calcium in response to shear stress occurs in caveolin-rich areas of the plasma membrane and is lost in CAV1-deficient cells.
Vassilopoulos, S. et al. Caveolin 3 is associated with the calcium release complex and is modified via in vivo triadin modification. Biochemistry 49, 6130–6135 (2010).
Adebiyi, A., Narayanan, D. & Jaggar, J. H. Caveolin-1 assembles type 1 inositol 1,4,5-trisphosphate receptors and canonical transient receptor potential 3 channels into a functional signaling complex in arterial smooth muscle cells. J. Biol. Chem. 286, 4341–4348 (2011).
Hoffmann, C. et al. Caveolin limits membrane microdomain mobility and integrin-mediated uptake of fibronectin-binding pathogens. J. Cell Sci. 123, 4280–4291 (2010). Provides evidence for a general effect of CAV1 on membrane properties as indicated by the effects on membrane microdomain mobility and the consequences for pathogen entry.
Gaus, K., Le Lay, S., Balasubramanian, N. & Schwartz, M. A. Integrin-mediated adhesion regulates membrane order. J. Cell Biol. 174, 725–734 (2006).
Roy, S. et al. Dominant-negative caveolin inhibits H-Ras function by disrupting cholesterol-rich plasma membrane domains. Nature Cell Biol. 1, 98–105 (1999).
Lingwood, D. & Simons, K. Lipid rafts as a membrane-organizing principle. Science 327, 46–50 (2010).
Carozzi, A. J. et al. Inhibition of lipid raft-dependent signaling by a dystrophy-associated mutant of caveolin-3. J. Biol. Chem. 277, 17944–17949 (2002).
Kirkham, M. et al. Evolutionary analysis and molecular dissection of caveola biogenesis. J. Cell Sci. 121, 2075–2086 (2008).
Ortegren, U. et al. Lipids and glycosphingolipids in caveolae and surrounding plasma membrane of primary rat adipocytes. Eur. J. Biochem. 271, 2028–2036 (2004).
Sharma, D. K. et al. The glycosphingolipid, lactosylceramide, regulates β1-integrin clustering and endocytosis. Cancer Res. 65, 8233–8241 (2005).
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).
Prinetti, A. et al. GM3 synthase overexpression results in reduced cell motility and in caveolin-1 upregulation in human ovarian carcinoma cells. Glycobiology 20, 62–77 (2010).
Murata, M. et al. VIP21/caveolin is a cholesterol-binding protein. Proc. Natl Acad. Sci. USA 92, 10339–10343 (1995).
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).
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).
Martin, S. & Parton, R. G. Caveolin, cholesterol, and lipid bodies. Semin. Cell Dev. Biol. 16, 163–174 (2005).
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).
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).
Bosch, M. et al. Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility. Curr. Biol. 21, 681–686 (2011). Identifies mitochondrial dysfunction due to aberrant cholesterol accumulation as a common feature in CAV1-deficient cells.
Asterholm, I. W., Mundy, D. I., Weng, J., Anderson, R. G. & Scherer, P. E. Altered mitochondrial function and metabolic inflexibility associated with loss of caveolin-1. Cell. Metab. 15, 171–185 (2012).
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).
Simard, J. R. et al. Caveolins sequester fatty acids on the cytoplasmic leaflet of the plasma membrane, augment triglyceride formation and protect cells from lipotoxicity. J. Lipid Res. 51, 914–922 (2009).
Pohl, J. et al. Long-chain fatty acid uptake into adipocytes depends on lipid raft function. Biochemistry 43, 4179–4187 (2004).
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).
Frank, P. G. et al. Caveolin-1 and regulation of cellular cholesterol homeostasis. Am. J. Physiol. Heart Circ. Physiol. 291, H677–H686 (2006).
Cohen, A. W. et al. Role of caveolin-1 in the modulation of lipolysis and lipid droplet formation. Diabetes 53, 1261–1270 (2004).
Fernandez, M. A. et al. Caveolin-1 is essential for liver regeneration. Science 313, 1628–1632 (2006).
Siasos, G. et al. Adiponectin and cardiovascular disease: mechanisms and new therapeutic approaches. Curr. Med. Chem. 19, 1193–1209 (2012).
Pilch, P. F. & Liu, L. Fat caves: caveolae, lipid trafficking and lipid metabolism in adipocytes. Trends Endocrinol. Metab. 22, 318–324 (2011).
Martin, S. et al. Caveolin-1 deficiency leads to increased susceptibility to cell death and fibrosis in white adipose tissue: characterization of a lipodystrophic model. PLoS ONE 7, e46242 (2012).
Khan, T. et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29, 1575–1591 (2009).
Berchtold, D. et al. Plasma membrane stress induces relocalization of Slm proteins and activation of TORC2 to promote sphingolipid synthesis. Nature Cell Biol. 14, 542–547 (2012). In yeast cells, mechanical stretching of the plasma membrane causes redistribution of Slm proteins and activation of TORC2, leading to changes in the lipid composition of the plasma membrane possibly analogous to those occurring in mammalian cells upon disassembly of caveolae.
Styers, M. L., O'Connor, A. K., Grabski, R., Cormet-Boyaka, E. & Sztul, E. Depletion of β-COP reveals a role for COP-I in compartmentalization of secretory compartments and in biosynthetic transport of caveolin-1. Am. J. Physiol. Cell Physiol. 294, C1485–C1498 (2008).
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).
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).
Manninen, A. et al. Caveolin-1 is not essential for biosynthetic apical membrane transport. Mol. Cell. Biol. 25, 10087–10096 (2005).
Aung, C. S., Hill, M. M., Bastiani, M., Parton, R. G. & Parat, M. O. PTRF-cavin-1 expression decreases the migration of PC3 prostate cancer cells: role of matrix metalloprotease 9. Eur. J. Cell Biol. 90, 136–142 (2011).
Gould, M. L., Williams, G. & Nicholson, H. D. Changes in caveolae, caveolin, and polymerase 1 and transcript release factor (PTRF) expression in prostate cancer progression. Prostate 70, 1609–1621 (2010).
Doyon, J. B. et al. Rapid and efficient clathrin-mediated endocytosis revealed in genome-edited mammalian cells. Nature Cell Biol. 13, 331–337 (2011).
Nassoy, P. & Lamaze, C. Stressing caveolae new role in cell mechanics. Trends Cell Biol. 22, 381–389 (2012).
Vorgerd, M. et al. A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation. Neurology 57, 2273–2277 (2001).
McNally, E. M. et al. Caveolin-3 in muscular dystrophy. Hum. Mol. Genet. 7, 871–877 (1998).
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).
Minetti, C. et al. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nature Genet. 18, 365–368 (1998).
Matsuda, C. et al. The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle. Hum. Mol. Genet. 10, 1761–1766 (2001).
Bansal, D. & Campbell, K. P. Dysferlin and the plasma membrane repair in muscular dystrophy. Trends Cell Biol. 14, 206–213 (2004).
Vatta, M. et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 114, 2104–2112 (2006).
Cao, H., Alston, L., Ruschman, J. & Hegele, R. A. Heterozygous CAV1 frameshift mutations (MIM 601047) in patients with atypical partial lipodystrophy and hypertriglyceridemia. Lipids Health Dis. 7, 3 (2008).
Dwianingsih, E. K. et al. A Japanese child with asymptomatic elevation of serum creatine kinase shows PTRF-CAVIN mutation matching with congenital generalized lipodystrophy type 4. Mol. Genet. Metab. 101, 233–237 (2010).
Shastry, S. et al. Congenital generalized lipodystrophy, type 4 (CGL4) associated with myopathy due to novel PTRF mutations. Am. J. Med. Genet. A 152A, 2245–2253 (2010).
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).
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).
Witkiewicz, A. K. et al. An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am. J. Pathol. 174, 2023–2034 (2009).
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).
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).
Patani, N. et al. Non-existence of caveolin-1 gene mutations in human breast cancer. Breast Cancer Res. Treat. 131, 307–310 (2012).
Hayashi, K. et al. Invasion activating caveolin-1 mutation in human scirrhous breast cancers. Cancer Res. 61, 2361–2364 (2001).
Felicetti, F. et al. Caveolin-1 tumor-promoting role in human melanoma. Int. J. Cancer 125, 1514–1522 (2009).
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).
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).
Capozza, F. et al. Genetic ablation of Cav1 differentially affects melanoma tumor growth and metastasis in mice. Role of Cav1 in Shh heterotypic signaling and transendothelial migration. Cancer Res. 72, 2262–2274 (2012).
Trimmer, C. et al. CAV1 inhibits metastatic potential in melanomas through suppression of the integrin/Src/FAK signaling pathway. Cancer Res. 70, 7489–7499 (2010).
Xu, X. L. et al. Inactivation of human SRBC, located within the 11p15.5-p15.4 tumor suppressor region, in breast and lung cancers. Cancer Res. 61, 7943–7949 (2001).
Zochbauer-Muller, S. et al. Expression of the candidate tumor suppressor gene hSRBC is frequently lost in primary lung cancers with and without DNA methylation. Oncogene 24, 6249–6255 (2005).
Bai, L. et al. Down-regulation of the cavin family proteins in breast cancer. J. Cell Biochem. 113, 322–328 (2012).
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).
Acknowledgements
The authors thank R. Moreno-Vicente for help in drawing the schematics and A. Echarri, M. Montoya and M. Fernández-Rojo and other members of the Parton laboratory for critical reading of the manuscript. R.G.P. is supported by an National Health and Medical Research Council (NHMRC) Australia Fellowship. M.A.d.P. is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) through grants SAF2011-25047 and CSD 2009–00016. The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by MINECO and the Pro-CNIC Foundation.
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Glossary
- Lipodystrophy
-
Abnormal fat metabolism associated with loss of adipose tissue.
- Clathrin-coated pits
-
Plasma membrane invaginations that are coated on their cytoplasmic face by a complex of coat proteins, including clathrin. Best-characterized internalization mechanism for surface receptors, ligands and solutes.
- Multivesicular bodies
-
(MVBs). Endosomal compartment that contains internal vesicles in which membrane proteins destined for lysosomal degradation are concentrated.
- Metaphase
-
Phase of mitosis in which chromosomes are aligned along the equatorial plane of the spindle.
- Ubiquitylation
-
Modification of a protein by addition of a polypeptide, ubiquitin. This post- translational modification acts as a signal to mark a protein for internalization or degradation.
- Stress fibres
-
Contractile actomyosin bundles that are formed by actin filaments, crosslinking proteins (that bind two or more filaments together) and myosin motors.
- Mechanosensing
-
Mechanisms that cells use to detect and respond to forces.
- Focal adhesion
-
Large and dynamic protein complex (composed of integrins and cytoskeletal and signalling molecules) through which the cytoskeleton connects to the extracellular matrix to transmit both mechanical force and regulatory signals.
- Store-operated calcium entry
-
(SOCE). A calcium entry mechanism that is activated by depletion of internal calcium stores in the endoplasmic reticulum.
- Membrane rafts
-
Small, heterogeneous, highly dynamic, sterol- and sphingolipid-enriched domains that are formed by lipid–lipid interactions and that compartmentalize cellular processes. Small rafts can be stabilized to form larger platforms through protein–protein and protein–lipid interactions.
- Eisosome
-
Stable Pil1- and Lsp1-positive domain of the yeast plasma membrane implicated in mechanosensation and lipid regulation.
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Parton, R., del Pozo, M. Caveolae as plasma membrane sensors, protectors and organizers. Nat Rev Mol Cell Biol 14, 98–112 (2013). https://doi.org/10.1038/nrm3512
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DOI: https://doi.org/10.1038/nrm3512
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