The caveolin gene family has three members in vertebrates: caveolin-1, caveolin-2, and caveolin-3. So far, most caveolin-related research has been conducted in mammals, but the proteins have also been found in other animals, including Xenopus laevis, Fugu rubripes, and Caenorhabditis elegans. Caveolins can serve as protein markers of caveolae ('little caves'), invaginations in the plasma membrane 50-100 nanometers in diameter. Caveolins are found predominantly at the plasma membrane but also in the Golgi, the endoplasmic reticulum, in vesicles, and at cytosolic locations. They are expressed ubiquitously in mammals, but their expression levels vary considerably between tissues. The highest levels of caveolin-1 (also called caveolin, Cav-1 and VIP2I) are found in terminally-differentiated cell types, such as adipocytes, endothelia, smooth muscle cells, and type I pneumocytes. Caveolin-2 (Cav-2) is colocalized and coexpressed with Cav-1 and requires Cav-1 for proper membrane targeting; the Cav-2 gene also maps to the same chromosomal region as Cav-1 (7q31.1 in humans). Caveolin-3 (Cav-3) has greater protein-sequence similarity to Cav-1 than to Cav-2, but it is expressed mainly in muscle cells, including smooth, skeletal, and cardiac myocytes. Caveolins participate in many important cellular processes, including vesicular transport, cholesterol homeostasis, signal transduction, and tumor suppression.
Gene organization and evolutionary history
Research into caveolae began with their morphological identification in 1953. By transmission electron microscopy, they appear as structures resembling 'little caves', which are vesicular invaginations of the plasma membrane of 50-100 nanometer (nm) in size . Caveolin-1 (also known as caveolin, Cav-1 or VIP21) was the first member of the caveolin family to be identified, and it was shown to be a structural component of caveolae and of transport vesicles derived from the trans-Golgi network [2,3]. It was isolated as one of several proteins that became phosphorylated on tyrosine residues in chicken embryo fibroblasts transformed with the v-Src oncogene . Monoclonal antibodies directed against Cav-1 decorated the cytoplasmic protein coat of caveolae, making Cav-1 the first true protein marker of caveolae . Subsequent cloning of the Cav-1 cDNA revealed that it was identical to another protein, VIP21, which had been cloned almost simultaneously [3,5]. Interestingly, VIP21 was isolated as an integral membrane protein component of transport vesicles derived from the trans-Golgi network in Madin-Darby canine kidney (MDCK) cells, suggesting that Cav-1/VTP21 may have a role in molecular trafficking as well as oncogenesis.
Caveolin-2 (Cav-2) and caveolin-3 (Cav-3) were identified in 1996 using different experimental methods. Cav-2 was discovered by the microsequencing of a 20 kDa protein that co-purified with adipocyte-derived caveolar membranes . Further characterization revealed that Cav-2 colocalizes with Cav-1 in caveolae, forms hetero-oligomers with Cav-1, is co-expressed in many of the same cells and tissues, and requires Cav-1 for proper membrane localization [7,8]. Cav-3 (also known as M-caveolin) was identified through database searches and traditional cDNA library screening in an attempt to find Cav-1 homologs [9,10].
Caveolin sequences have been obtained from a range of vertebrates, including human, cow, mouse, Xenopus, and Fugu rubripes. A caveolin gene family has also been found in Caenorhabditis elegans [11,12]. The three mammalian genes encoding members of the caveolin family are similar in sequence (Table 1). A phylogenetic tree of all known caveolins shows that the C. elegans Cav-1 sequence is only distantly related to all the others (Figure 1). Interestingly, Cav-1 and Cav-2 are in very close proximity (about 19 kilobases (kb) apart) on human chromosome 7q31.1, while Cav-3 is located on a different chromosome (3p25) [13,14]. Although the evolutionary history of the caveolin genes has not been clearly defined, there are clues within their sequences and genomic organization to suggest possible mechanisms for their origin. For instance, although C. elegans Cav-1 has two exons, the region that is homologous to mammalian cave-olins is encoded by only a single exon, suggesting that mammalian caveolins are derived from this particular exon . Also, two observations derived from the human genomic sequence suggest that some family members may have arisen through gene duplication events: firstly, the exon-intron boundaries in the last exons of Cav-1, Cav-2, and Cav-3 are in analogous positions; and secondly, exon 2 of Cav-2 is divided into two parts (2a and 2b) by an intron, whereas the two homologous portions in the Cav-1 and Cav-3 sequences are fused together to form the final exon [13,14]. This second point may suggest that Cav-2 served as the genomic precursor of Cav-1 and Cav-3.
Table 1. Genomic organization of the human caveolin genes and properties of their protein products
Figure 1. A phylogenetic tree depicting the evolutionary relationships of all known caveolin protein sequences. Note that C. elegans Cav-2 was not included in this analysis because of its low similarity to the mammalian caveolins. GenBank-derived protein sequences were entered into the ClustalW program to generate a phylogenetic tree using the neighbor-joining method. Numbers indicate horizontal branch lengths, which correspond to the estimated evolutionary distances between the protein sequences.
Characteristic structural features
Currently, the structural features of this family of proteins are poorly defined, but information gleaned from the protein sequence has enabled some predictions of structure and motifs within the proteins. For instance, all three caveolins have an invariant 'FEDVIAEP' stretch (in the single-letter amino-acid code) within their hydrophilic amino-terminal domains that has come to be termed the 'caveolin signature motif' [6,9]. The functional importance of this sequence or motif has yet to be determined, however.
Two Cav-1 isoforms (α and β) have been identified; the β isoform arises from an internal translational start site that gives a shorter amino terminus than that of the α form and is truncated by 31 residues . The predicted domains span almost the same number of residues in all three proteins: the amino-terminal domain comprises the first 101 residues in Cav-1α and the first 70-86 residues in Cav-1β, Cav-2, and Cav-3, with the putative transmembrane domain occupying 33 amino acids and the carboxy-terminal domain containing 43-44 amino acids (Figure 2).
Figure 2. Primary structure and topology of Cav-1. (a) The predicted membrane topology of Cav-1. Two caveolin-1 monomers are shown forming a dimer for simplicity, but about 14-16 monomers normally self-associate to form a single caveolin homo-oligomer (the caveolar assembly unit, akin to the clathrin triskelion). Note that both the amino- and carboxy-terminal domains are oriented towards the cytosolic face of the plasma membrane, with a hairpin loop structure inserted within the membrane bilayer. Modified from Razani et al. . (b) The domains present in Cav-1. Note that the amino-terminal membrane-attachment domain is also called the caveolin scaffolding domain (CSD).
Using a variety of experimental methods, it has been determined that the major sub-cellular location of Cav-1 is at the plasma membrane. From the primary sequence (hydrophilicity plots) and mutational analysis, Cav-1 is predicted to have a membrane-spanning hairpin-like structure, with both amino and carboxyl termini directed towards the cytoplasm (Figure 2). This atypical membrane-spanning model is supported by findings that antibodies directed against the Cav-1 amino or carboxyl terminus require cells to be permeabilized in order to bind Cav-1, that cell-surface biotinylation does not label Cav-1, and that there are known palmitoylation and tyrosine phosphorylation sites within both the amino- and the carboxy-terminal domains of the protein [16-19]; palmitoylation and tyrosine phosphorylation are both cytoplasmically generated post-translational modifications.
Generally speaking, caveolins are small proteins (18-24 kDa). Structurally, however, perhaps one of the most interesting and significant findings about Cav-1 is that it forms an oligomeric complex comprised of approximately 14-16 monomers, as discovered through velocity gradient ultracentrifugation. In this assay system, Cav-1 was found to migrate as 200-400 kDa complexes [16,20]. Experiments with Cav-1 deletion mutants mapped the oligomerization domain to residues 61-101  (Figure 2). Interestingly, Cav-3 also forms large oligomeric complexes of approximately 350-400 kDa in vivo, whereas Cav-2 requires Cav-1 to participate in the formation of these high-molecular-mass complexes [7-9].
Localization and function
Caveolae are considered by many to be a subset of lipid rafts, which are highly-ordered microdomains residing within the plasma membrane that are enriched in certain lipids [21-23]; this may not be completely accurate, however, as some proteins are known to localize selectively to either lipid rafts or caveolae but not both . Caveolae-enriched membrane fractions can be purified efficiently on the basis of their buoyancy and resistance to solubilization by mild non-ionic detergents at 4°C [25-30], but other types of membrane microdomains may also be enriched by this kind of purification.
Cav-1 localizes to plasma-membrane caveolae and also to the Golgi apparatus and trans-Golgi-derived transport vesicles [3,5,31]. Cav-1 may have a soluble cytoplasmic form, as well as a secreted form, depending on the cell type , and the first 31 amino acids may be important in selectively targeting isoforms of Cav-1 to different cellular compartments . Cav-1 is expressed ubiquitously, although at different levels in different tissues, with the highest levels in adipocytes, endothelial cells, fibroblasts, smooth-muscle cells, and a variety of epithelial cells. Cav-2 is tightly co-expressed with Cav-1, whereas Cav-3 is expressed predominantly in striated muscle cells . Interestingly, Cav-1 is required for the proper membrane localization of Cav-2.
Mice deficient in Cav-1, Cav-2, or Cav-3 are viable and fertile, but each has abnormal cellular and tissue-specific phenotypes peculiar to the specific ablated gene [35-43]. A mutant form found in up to 16% of human breast cancers, Cav-1 (P132L), does not localize properly to the plasma membrane and behaves in a dominant-negative manner, causing the mislocalization and intracellular retention of wild-type Cav-1 [44,45]. An analogous P-to-L mutation in Cav-3 (P104L) has been detected in patients with autosomal dominant limb-girdle muscular dystrophy type-1C, and this mutation also behaves in a dominant-negative fashion [46-49]. Wild-type Cav-3 localizes to caveolae and the plasma membrane and also associates with the T tubules that form from invaginations of the muscle membrane [50,51].
Caveolin-related research has shown that caveolae function in vesicle trafficking , cholesterol homeostasis, signal transduction and tumor suppression. Endothelial caveolae may be involved in transcytosis; they have the molecular components used by other transport vesicles during vesicle formation, docking, and fusion , and the motor protein dynamin, which is important for vesicle fission, also localizes to caveolae [54,55]. Regarding endocytosis, it appears that certain ligands and extracellular molecules, such as cholera and tetanus toxins, are transported across the plasma membrane through caveolae, rather than via clathrin-dependent mechanisms [56,57]. Pathogens appear to have evolved mechanisms to gain entry into eukaryotic cells through caveolae, including simian virus 40 and certain strains of Escherichia coli .
Caveolae are enriched with cholesterol and Cav-1 is one of the few proteins that binds cholesterol tightly and specifically [59,60]; free cholesterol is required for the proper formation of caveolae [61-63] and regulates the Cav-1 promoter . Intracellular cholesterol balance may be affected by caveolins , as a dominant-negative Cav-1 mutant causes intracellular retention of free cholesterol as well as a decrease in cholesterol synthesis and its efflux from the cell . Also, caveolae have been linked to the process of reverse cholesterol transport, during which excess free cholesterol is released into the blood plasma via uptake by high-density lipoprotein (HDL) particles [67-71], and caveolae appear to be involved in the uptake of cholesterol esters from the plasma.
Caveolae appear to serve as signaling platforms by compartmentalizing and concentrating signaling molecules (this is referred to as the 'caveolae signaling hypothesis') . Various classes of signaling molecules, including G-protein subunits, receptor and non-receptor tyrosine kinases, endothelial nitric oxide synthase (eNOS), and small GTPases [27,42], bind Cav-1 through its 'caveolin-scaffolding domain' (CSD) (Figure 2). Cav-1 also appears to inhibit the downstream activation and signaling of many proteins, including c-Src, H-Ras, mitogen-activated protein (MAP) kinases, and eNOS [72-78]. The evidence that Cav-2 is a signaling modulator is less clear, partly perhaps because its CSD sequence is divergent from that of Cav-1. The Cav-3 CSD is very similar to the Cav-1 CSD, however, and Cav-3-generated caveolae have been shown to compartmentalize and modulate a number of signaling proteins, including eNOS, β-adrenergic receptors, protein kinase C isoforms, G proteins, Src-family kinases, and multiple components of the dystrophin-glycoprotein complex [34,76-79].
Several lines of evidence have implicated Cav-1 in tumor suppression [18,19,80-84], and there is also accumulating evidence that Cav-1 has an anti-proliferative function. Furthermore, the Cav-1 and Cav-2 genes are close to the microsatellite marker D7S522 on human chromosome 7q31.1 [13,14], a region that is commonly deleted and implicated in the pathogenesis of many human epithelial-based cancers, including breast, colorectal, prostate, ovarian, and renal-cell carcinomas. Recent results [85-90] strongly argue that Cav-1 functions either as a negative regulator of cell proliferation or as a tumor suppressor, in both cultured cells and whole animals.
The ubiquitous nature and diverse tissue expression of caveolin family members in mammals suggest that caveolins are indeed important for normal cellular and tissue physiology in highly evolved organisms. The discovery of a caveolin gene family in the invertebrate C. elegans  raises the questions of when caveolins joined the cellular repertoire and whether they are present in more primitive animals, plants or fungi. Another equally important area of research is deciphering the structure of caveolins, as such knowledge would greatly contribute to our understanding of how caveolins function. Recently, gene knockout and transgenic technology has facilitated the study of caveolins in mice, from a whole-organism point of view, allowing the generation of caveolin-deficient or caveolin-overexpressing transgenic mice. The molecular-genetic analysis of these caveolin-deficient mouse models, and cell lines derived from these animals, will greatly facilitate the progress of caveolae-related research into the next decade.
This work was supported by grants from the National Institutes of Health (NIH), the Muscular Dystrophy Association, the Susan G. Komen Breast Cancer Foundation, and the American Heart Association, as well as a Hirschl/Weil-Caulier Career Scientist Award (all to M.P.L.). T.M.W. was supported by a NIH Medical Scientist Training Grant (T32-GM07288).
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J Biol Chem 1996, 271:29182-29190.
Binding and negative regulation of signaling molecules by Cav-1.PubMed Abstract | Publisher Full Text
Couet J, Li S, Okamoto T, Ikezu T, Lisanti MP: Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins.
J Biol Chem 1997, 272:6525-6533.
Characterization of protein ligands for the caveolin scaffolding domain.PubMed Abstract | Publisher Full Text
J Biol Chem 1997, 272:30429-30438.
Interaction of Cav-1 with growth-factor receptors.PubMed Abstract | Publisher Full Text
Mol Biol Cell 1997, 8:2365-2378.
Partial colocalization of G-protein subunits with caveolae.PubMed Abstract | Publisher Full Text
Feron O, Belhassen L, Kobzik L, Smith TW, Kelly RA, Michel T: Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells.
J Biol Chem 1996, 271:22810-22814.
This paper describes the localization of eNOS to caveolae in cardiomy-ocytes.PubMed Abstract | Publisher Full Text
Rybin VO, Xu X, Lisanti MP, Steinberg SF: Differential targeting of beta-adrenergic receptor subtypes and adenylyl cyclase to cardiomyocyte caveolae. A mechanism to functionally regulate the cAMP signaling pathway.
J Biol Chem 2000, 275:41447-41457.
The localization of 3-adrenergic receptors and adenylyl cyclase to cardiomyocyte caveolae.PubMed Abstract | Publisher Full Text
Circ Res 1999, 84:980-988.
The localization of protein kinase C isoforms to cardiomyocyte caveolae.PubMed Abstract | Publisher Full Text
Sotgia F, Lee JK, Das K, Bedford M, Petrucci TC, Macioce P, Sargia-como M, Bricarelli FD, Minetti C, Sudol M, Lisanti MP: Caveolin-3 directly interacts with the carboxy-terminal tail of beta-dystroglycan. Identification of a central WW-like domain within caveolin family members.
J Biol Chem 2000, 275:38048-38058.
Interaction of Cav-3 with β-dystroglycan.PubMed Abstract | Publisher Full Text
J Biol Chem 1989, 264:20163-20166.
Tyrosine phosphorylation of Cav-1.PubMed Abstract | Publisher Full Text
Proc Natl Acad Sci USA 1995, 92:1381-1385.
This paper describes the downregulation of caveolin and caveolae in oncogenically transformed cells.PubMed Abstract | Publisher Full Text
J Biol Chem 1997, 272:16374-16381.
Caveolin-1 overexpression in oncogene-transformed cells inhibits anchorage-independent growth.PubMed Abstract | Publisher Full Text
Cold Spring Harb Sym Quant Biol 1994, 59:537-546.
This paper describes the identification of Cav-1 as one of the genes downregulated in human breast-cancer cells.
Oncogene 1998, 16:1391-1397.
Cav-1 re-expression inhibits cell growth in human breast-cancer cells.PubMed Abstract | Publisher Full Text
Engelman JA, Chu C, Lin A, Jo H, Ikezu T, Okamoto T, Kohtz DS, Lisanti MP: Caveolin-mediated regulation of signaling along the p42/44 MAP kinase cascade in vivo. A role for the caveolin-scaffolding domain.
FEBS Lett 1998, 428:205-211.
Cav-1 inhibits activation of the p42/44 MAP kinase pathway.PubMed Abstract | Publisher Full Text
Galbiati F, Volonte D, Engelman JA, Watanabe G, Burk R, Pestell RG, Lisanti MP: Targeted downregulation of caveolin-1 is sufficient to drive cell transformation and hyperactivate the p42/44 MAP kinase cascade.
EMBO J 1998, 17:6633-6648.
Cav-1 downregulation results in cellular transformation.PubMed Abstract | Publisher Full Text
J Biol Chem 2000, 275:21203-21209.
Cav-1 transcriptionally represses the cyclin D1 gene.PubMed Abstract | Publisher Full Text
Williams TM, Cheung MW, Park DS, Razani B, Cohen AW, Muller WJ, Di Vizio D, Chopra NG, Pestell RG, Lisanti MP: Loss of caveolin-1 gene expression accelerates the development of dysplastic mammary lesions in tumor-prone transgenic mice.
Mol Biol Cell 2003, 14:1027-1042.
Cav-1-deficient mice have accelerated development of mammary dysplastic lesions.PubMed Abstract | Publisher Full Text
Am J Pathol 2003, 162:2029-2039.
Cav-1-deficient mice are more susceptible to skin carcinogenic treatment.PubMed Abstract | Publisher Full Text
Park DS, Lee H, Frank PG, Razani B, Nguyen AV, Parlow AF, Russell RG, Hulit J, Pestell RG, Lisanti MP: Caveolin-1-deficient mice show accelerated mammary gland development during pregnancy, premature lactation, and hyperactivation of the Jak-2/STAT5 a signaling cascade.
Mol Biol Cell 2002, 13:3416-3430.
Caveolin-1-deficient mice have premature lactation and hyperactivation of the p42/44 MAP kinase and STAT5a signaling pathways.PubMed Abstract | Publisher Full Text