INVITED REVIEW
Role of plasmalemmal caveolae in signal transduction

Departments of ¹ Pediatrics and ² Cell Biology and Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9063

	ABSTRACT

Top Abstract Introduction References

Caveolae are specialized plasmalemmal microdomains originally studied in numerous cell types for their involvement in the transcytosis of macromolecules. They are enriched in glycosphingolipids, cholesterol, sphingomyelin, and lipid-anchored membrane proteins, and they are characterized by a light buoyant density and resistance to solubilization by Triton X-100 at 4°C. Once the identification of the marker protein caveolin made it possible to purify this specialized membrane domain, it was discovered that caveolae also contain a variety of signal transduction molecules. This includes G protein-coupled receptors, G proteins and adenylyl cyclase, molecules involved in the regulation of intracellular calcium homeostasis, and their effectors including the endothelial isoform of nitric oxide synthase, multiple components of the tyrosine kinase-mitogen-activated protein kinase pathway, and numerous lipid signaling molecules. More recent work has indicated that caveolae further serve to compartmentalize, modulate, and integrate signaling events at the cell surface. This specialized plasmalemmal domain warrants direct consideration in future investigations of both normal and pathological signal transduction in pulmonary cell types.

adenylyl cyclase; caveolin; cholesterol; endothelial nitric oxide synthase; mitogen-activated protein kinase

	INTRODUCTION

Top Abstract Introduction References

THE TERM CAVEOLAE (little caves) was coined by Yamada in 1955 (108) to describe "a small pocket, vesicle, cave or recess communicating with the outside of the cell" in gallbladder epithelium. Two years earlier, Palade (66) had described morphologically similar invaginations on the plasma membrane of endothelial cells that Bruns and Palade (5) later named plasmalemmal vesicles because they appeared to shuttle molecules into and out of the cell. The term caveolae then became synonymous with the terms "flask-shaped" or "omega-shaped" membrane because of their appearance in endothelial and smooth muscle cells.

Investigations that followed supported the hypothesis raised by Palade that caveolae are endocytic structures involved in the transcellular movement of molecules (85). This included the landmark observation of receptor-mediated uptake of folate by caveolae (1). After the first marker protein for caveolae, caveolin, was discovered (75), it was then possible to purify this specialized membrane domain, and it was found that caveolae contain a variety of signal transduction molecules. Recent research in the field (49, 83) has further indicated that caveolae serve to compartmentalize and integrate numerous signaling events at the cell surface. As such, caveolae are likely to be critically involved in both physiological and pathological events in numerous cell types in complex organs such as the lung.

In an effort to reveal the potential functions of caveolae in pulmonary health and disease, this review focuses on the role of caveolae in signal transduction as elucidated in a variety of cell types. After a discussion of the definition, structural composition, and purification of caveolae, the processes regulating caveolae function are examined. The important signaling molecules known to be enriched in this domain and the mechanisms underlying their targeting to caveolae are then addressed. Finally, examples of signal compartmentalization, modulation, and integration in caveolae are presented. It is anticipated that this specialized plasmalemmal domain will warrant direct consideration in future investigations of both normal and pathological signal transduction in pulmonary cell types.

	DEFINITION AND STRUCTURAL COMPOSITION OF CAVEOLAE

Definition. As mentioned in the introduction, the working definition of caveolae includes both morphological and biochemical parameters. Although the term caveolae was intended to refer to membrane invaginations at the cell surface (Fig. 1A), membranes with such classic morphological features are not found in all cells. With the use of the caveolae marker protein caveolin, purification techniques established new biochemical criteria for identifying this specialized membrane. These include a light buoyant density (92), resistance to solubilization by Triton X-100 at 4°C (77), and enrichment in glycosphingolipids (GSLs), cholesterol, sphingomyelin (SPH), and lipid-anchored membrane proteins including glycosylphosphatidylinositol (GPI)-anchored proteins. Membrane fractions with these properties can be isolated from the plasma membranes of essentially all cells. Thus it is likely that all cells have plasma membrane domains with the biochemical characteristics of caveolae, but only a portion of these membranes display flask-shaped morphology. Caveolae can assume a variety of shapes, including flat, vesicular, and tubular, and they can be either open or closed at the cell surface to yield endocytic or exocytic compartments. As such, the term caveolae is not limited to plasma membrane domains with a specific shape but should alternatively be considered to represent a dynamic cell surface-membrane system.

View larger version (107K): [in this window] [in a new window]   Fig. 1.   Thin-section electron micrograph (A) and rapid-freeze deep-etch (B) images of fibroblast caveolae.

Composition. Caveolae in endothelial cells and fibroblasts have a striated coat on their cytoplasmic surface (69, 75). Rapid-freeze, deep-etch electron micrographs reveal that the coat decorates plasma membrane domains with variable amounts of curvature (Fig. 1B), suggesting that the coat may be involved in determining the shape of the membrane. The striated coat is composed of integral membrane proteins including the protein caveolin (75). There are at least four caveolin isoforms in mammals, and the known isoforms are referred to as caveolin-1 and -1, caveolin-2, and caveolin-3 (29, 39, 40, 78, 100, 106). The amino and carboxy domains of each isoform reside free in the cytoplasm, being separated by a 33-amino acid hydrophobic domain that is believed to anchor caveolin in the membrane (39). Caveolin-1 and -3 have cysteine residues at positions 134, 144, and 157, and these cysteines are acylated in caveolin-1 (13). Caveolin-1 and caveolin-2 are ubiquitously expressed, whereas caveolin-3 is primarily found in muscle cells (78, 100, 106). Most studies to date have evaluated the presence and function of caveolin-1, and the potential role of caveolin-2 has often not been checked. The expression of caveolin-1 in cells is correlated with the appearance of invaginated caveolae and the presence of the striated coat (21, 91). Although caveolin-1 forms homotypic oligomers (46, 58), it most likely does not serve a mechanical function in shaping the membrane because invaginated caveolae can lack the molecule (10, 90). The depletion of intracellular cholesterol and the sequestration of membrane cholesterol with agents such as filipin cause the striated coat to disassemble and the invaginated caveolae to disappear (6, 75). Because caveolin appears to be a cholesterol-binding protein and cholesterol stabilizes caveolin oligomers (44, 58, 62), it is likely that cholesterol and caveolin work in concert to form the striated coat.

	PURIFICATION OF CAVEOLAE

The isolation of caveolae by cell subfractionation most frequently relies on the use of caveolin-1 as the marker protein. To date, six methods have been reported for the purification of caveolae from tissues or cultured cells. These methods can be generally divided into four categories: 1) flotation of a detergent-insoluble membrane on sucrose gradients (77), 2) flotation of sonicated plasma membranes on OptiPrep gradients (92), 3) differential centrifugation of tissue homogenates (7), and 4) recovery by either immunoadsorption or centrifugation from endothelial cell plasma membranes purified by adsorption to cationized silica (80, 95). The caveolae obtained by these procedures are most often not directly comparable, primarily because there is no morphological standard with which to judge the purity of the caveolae fraction. Coatlike material is visible in some preparations but is generally difficult to recognize. Caveolin-1 content is also not an optimal means to assess purity because the concentration in caveolae can be variable. As importantly, the physical interventions employed in purification, such as sonication, Triton X-100, immunoadsorption, and cationized silica, can alter the molecular composition of caveolae. Furthermore, detergents solubilize resident proteins (7), yielding extracted preparations of caveolae. As such, it may be difficult to make direct comparisons between results reported by different laboratories. As a result of these variables, investigators are obliged whenever possible to confirm any findings obtained by cell subfractionation with independent methods such as immunofluorescence or immunoelectron microscopy.

	MECHANISMS REGULATING CAVEOLAE FUNCTION

Biogenesis of caveolae. The initial assembly of caveolae first involves the formation of the detergent-insoluble, GSL-SPH-cholesterol lipid core of the caveolae membrane in the transitional region of the Golgi apparatus (4, 46). GPI proteins and caveolin arriving from the endoplasmic reticulum (ER) after synthesis (46) are then incorporated to complete the initial assembly step. Anticaveolin immunoprecipitation and chemical cross-linking experiments indicate that other proteins associate with the caveolin-enriched membrane at this point (46). Caveolae are then transported to the cell surface embedded in the membranes of exocytic vesicles (15). This overall process contrasts with that of other membrane domains coated with peripheral proteins such as clathrin. Whereas caveolae are assembled in the Golgi apparatus and are then transported to other locations, clathrin-coated membranes are assembled de novo at sites of vesicle formation (79). Caveolae-like domains may exist in all membranes that traffic to and from the cell surface.

Maintenance of caveolae. SPH and cholesterol are the major components of the lipid core of caveolae. Cholesterol, however, is constantly fluxing out of the cell (65). As stated in Composition, if caveolae cholesterol levels were to get excessively low, GPI proteins would no longer cluster properly in caveolae (6), the striated coat would disassemble (75) and the number of invaginated caveolae would decline (6). Pharmacological agents that block cholesterol transport to the cell surface have exactly these effects (91), suggesting that the maintenance of caveolae is dependent on the continuous transport of cholesterol to caveolae. A novel transport system has been identified that appears to be necessary for maintaining the proper level of cholesterol in caveolae. There is bidirectional movement of cholesterol between the ER and the plasma membrane, and caveolin appears to play a critical role in this process. Caveolin binds cholesterol (62), preferentially incorporates into cholesterol-containing membranes in vitro (44, 62), and moves between caveolae and internal membranes. There is evidence that a heat shock protein-caveolin chaperone complex may transport cholesterol through the cytoplasm (101). Furthermore, increasing the cellular cholesterol level also causes an increase in caveolin mRNA expression (20, 32). Thus caveolin appears to be an integral part of an intracellular lipid transport system that is required for the maintenance of caveolae.

	SIGNAL TRANSDUCTION MOLECULES ENRICHED IN CAVEOLAE

Biochemical and morphological techniques have identified a number of signal transduction molecules that appear to be concentrated in caveolae relative to the surrounding membrane (Table 1). Approximately 40% have been localized by both morphological and biochemical methods (see Table 1). Four major groups of signal transduction molecules can be considered.

View this table: [in this window] [in a new window]   Table 1.   Signaling molecules enriched in caveolae

G protein-mediated signaling molecules. There has previously been considerable debate whether G protein-coupled receptors, G proteins, and their effectors are organized or randomly distributed at the cell surface (63). However, studies employing both cell subfractionation and immunocytochemistry have revealed that all three components are concentrated in caveolae. Receptors for endothelin, cholecystokinin, acetylcholine, and bradykinin are associated with caveolae (8, 12, 18, 74), and G proteins are found in most caveolae preparations (Table 1). In addition, there is evidence that the receptors are functionally interactive with their effectors in caveolae. Isolated caveolae fractions contain a significant proportion of total cellular adenylyl cyclase activity (34), and isoproterenol-stimulated adenylyl cyclase activity has been histochemically localized to membrane organelles resembling caveolae (71, 86, 105). Moreover, the agonist bradykinin activates the movement of G_q and G_i to caveolae (12). There is evidence that caveolin plays a role in the recruitment of G proteins to caveolae and in the modulation of their activity (42, 43, 78).

Calcium-mediated signaling molecules. Several studies have indicated that caveolae are sites of calcium storage and entry. In smooth muscle cells, pyroantimonate precipitates of calcium are present in caveolae under quiescent conditions, and the stimulation of contraction yields a diffuse distribution of the precipitate in the mycoplasm (98), suggesting that there is a movement of calcium into the cell. A morphological study (68) indicated that smooth muscle cell caveolae interact with smooth ER, similar to the interaction between sarcoplasmic reticulum and T tubules in skeletal muscle. In addition, there is evidence that critical molecules involved in calcium transport, including inositol 1,4,5-trisphosphate [Ins(1,4,5)P₃] receptors, calcium ATPase, and calmodulin, are concentrated in caveolae (22, 23, 80, 83). It has been demonstrated that ATP-induced calcium waves in endothelial cells, which are at least partially mediated by Ins(1,4,5)P₃ receptors, originate at specific discrete loci in caveolin-rich cell edges (36). Furthermore, endothelial nitric oxide (NO) synthase (eNOS), one of the key signaling molecules in endothelial cells that is acutely regulated by changes in calcium influx, is concentrated in caveolae. In a study (83) of cell fractions of quiescent cultured endothelial cells, 51-86% of total NOS enzymatic activity in the postnuclear supernatant was recovered in the plasma membrane, and 57-100% of the activity in the plasma membrane was recovered in caveolae. Thus caveolae appear to be critically involved in the regulation of calcium-mediated signaling at the cell surface.

Tyrosine kinase-mitogen-activated protein kinase pathway components. Both receptor and nonreceptor tyrosine kinases have been found to be enriched in caveolae in studies employing immunoblotting, determinations of enzymatic activity, and immunocytochemistry. The immunoprecipitation of multiple GPI-anchored proteins coprecipitates tyrosine kinases (96). A major substrate for tyrosine kinases is caveolin (27, 28, 30), and tyrosine phosphorylation of caveolin occurs in response to a variety of stimuli including insulin (52), oxidants (104), sulfonylurea (61), and cell transformation (28). In addition, a peptide sequence in caveolin known as the scaffolding domain (amino acids 82-101) interacts with c-Src and may modulate the activity of tyrosine kinase (42). Furthermore, more distal components of the tyrosine kinase-mitogen-activated protein (MAP) kinase signaling pathway including Ras, Raf-1, and MAP kinases have been localized to caveolae (Table 1).

Lipid signaling molecules. Besides being critically important to the establishment and maintenance of the molecular environment that is unique to caveolae, certain lipid moieties and lipid-anchored proteins in the lipid core are substrates for enzymes that release lipid signals. SPH, phosphatidylinositol 4,5-bisphosphate, and GPI-anchored proteins yield ceramide, Ins(1,4,5)P₃, and inositolphosphoglycans (IPGs), respectively (2, 9, 33, 48, 70). Each is produced in caveolae in response to specific stimuli. Ceramide increases in response to neurotrophin or interleukin-1 (2, 48), Ins(1,4,5)P₃ is produced on stimulation with either bradykinin or epidermal growth factor (EGF) (33), and IPGs are produced in response to insulin (67, 97), and the respective lipid signals elicit specific cellular processes. There is evidence that these responses are unique to caveolae because neither ceramide nor Ins(1,4,5)P₃ is generated in noncaveolae subcellular fractions, and the IPG released extracellularly is internalized, presumably by caveolae. Thus both the receptors and the transducers of lipid signaling are concentrated in the same, unique plasmalemmal domain.

	MECHANISMS UNDERLYING TARGETING TO CAVEOLAE

The association of certain signaling proteins with the plasma membrane is quite predictable based on the presence of moieties such as transmembrane spanning domains. However, another important mechanism underlying targeting of signaling proteins to caveolae is lipid modification. Proteins modified with either GPI or fatty acids are found to be enriched in caveolae fractions obtained by most methods of purification (77, 92). Mutations that abolish either the GPI anchor addition (38, 72) or the fatty acylation (73, 83, 84) shift the protein to other fractions, suggesting that the lipid moiety is necessary for targeting to caveolae. For example, in studies of caveolae-containing COS-7 cells transfected with wild-type eNOS cDNA, NOS activity is enriched 27-fold in caveolae compared with noncaveolae plasma membrane (Fig. 2). In contrast, transfection with a myristoylation-deficient mutant eNOS that is incapable of either myristoylation or palmitoylation results in a complete lack of targeting of eNOS to the caveolae fraction. However, transfection with a palmitoylation-deficient mutant eNOS that can be myristoylated yields modest enrichment of eNOS in the caveolae fraction, which exhibits threefold more NOS activity than noncaveolae membranes. Such studies have revealed that both myristoylation and palmitoylation are required to target eNOS to caveolae and that each acylation process enhances targeting 10-fold (83). These two different covalent modifications, GPI anchoring and fatty acylation, are responsible for targeting proteins with a broad range of biochemical activities to opposing surfaces of the same membrane domain. Because the acyl chains on these proteins intercalate in the lipid bilayer, they probably collect in caveolae as a result of a slowed lateral mobility on encountering the GSL-SPH-cholesterol lipid core. Altering the lipid core with cholesterol-sequestering agents such as filipin disperses GPI proteins in the plane of the membrane (76, 88). In addition, protein-protein and protein-lipid interactions within caveolae influence how long the molecules remain at that site (19, 109). Thus the properties of the lipid core play a key role in the maintenance of the complex molecular environment found in caveolae that enables many signaling proteins to be targeted there.

View larger version (12K): [in this window] [in a new window]   Fig. 2.   Nitric oxide synthase (NOS) enzymatic activity in subcellular fractions of  COS-7 cells transfected with wild-type (A), myristoylation-deficient mutant (B) or palmitoylation-deficient mutant (C) endothelial NOS. Activity [in pmol citrulline formed · mg protein (prot)1 · min1] was measured 72 h after transfection in postnuclear supernatant (PNS), cytosol (CYTO), plasma membrane (PM), noncaveolae portion of plasma membrane (NCM), and caveolae membrane (CM). Values are means ± SE; n = 4 samples. Similar findings were obtained in 3 independent experiments. * P < 0.05 vs PM. [Adapted from data presented in Shaul et al. (83).]

	SIGNAL COMPARTMENTALIZATION, MODULATION, AND INTEGRATION IN CAVEOLAE

Inspection of the long list of signal transduction molecules that have been demonstrated to be enriched in caveolae (Table 1) suggests that there may be close association of multiple interacting molecules involved in the cellular responses to a specific external stimulus. This is perhaps best illustrated by a recent study (49) of MAP kinase activation by platelet-derived growth factor (PDGF) in human fibroblasts. The various cellular responses to PDGF-receptor activation, which include effects on mitogenesis, cell differentiation, apoptosis, and calcium mobilization, appear to occur through multiple phosphorylation cascades that are all initiated by phosphorylation of the receptor itself. This suggests the existence of a signaling module associated with PDGF receptors at the cell surface, consisting of components of the tyrosine kinase-MAP kinase pathway. Immunoblotting reveals that caveolae fractions from unstimulated fibroblasts contain PDGF receptor, Ras, Raf-1, MAP kinase kinase-1, and extracellular signal-related kinase (ERK) 2, and immunoelectron microscopy confirms colocalization of PDGF receptors and ERK2 in caveolae. In addition, a 2-min exposure of intact fibroblasts to PDGF activates MAP kinase in the caveolae fraction, indicating that these components are functional in vivo. Activated MAP kinase was not detected in noncaveolae plasma membrane fractions, which also do not contain ERK2, suggesting that caveolae are a cell-surface domain where MAP kinase is functionally linked to the PDGF receptor. Furthermore, PDGF can stimulate tyrosine kinase activity and also MAP kinase activity in isolated caveolae, and these effects are blocked by both suramine, which prevents PDGF binding to its receptor, and genistein, which inhibits tyrosine kinase (Fig. 3). Thus the entire pathway required for this receptor tyrosine kinase to stimulate the activation of MAP kinase, which may involve as many as 11 different molecules (35, 51), is functional in isolated caveolae. These data complement previous demonstrations of signaling events originating specifically in caveolae, which include isoproterenol-stimulated adenylyl cyclase activation (71, 86, 105), EGF-stimulated Raf-1 recruitment (57), interleukin-1-stimulated ceramide production (48), and histamine regulation of caveolae internalization (89). In addition, it has recently been demonstrated that the cationic amino acid transporter-1 protein, which is responsible for the majority of endothelial cell uptake of the eNOS substrate arginine, is colocalized with eNOS in caveolae (53). This is the first example of a functional complex between a plasma membrane transport protein and an enzyme. When considered collectively, these observations indicate that caveolae play an important role in the compartmentalization of specific signaling events at the cell surface.

View larger version (43K): [in this window] [in a new window]   Fig. 3.   Platelet-derived growth factor (PDGF) stimulates tyrosine phosphorylation and mitogen-activated protein (MAP) kinase activation in vitro. Caveolae were isolated from normal human fibroblasts grown overnight in absence of serum. A: aliquots of caveolae membranes were incubated in presence of indicated concentrations of PDGF for 30 min on ice followed by 5 min at 37°C. B: aliquots of caveolae membranes were pretreated with either genistein (Gen; 100 µg/ml) or suramine (100 µg/ml) for 30 min on ice. Samples were then incubated in presence (+) and absence () of PDGF (100 ng/ml) for an additional 30 min followed by 5 min at 37°C. Reactions were stopped with addition of 7% trichloroacetic acid and then immunoblotted with either anti-phosphotyrosine IgG (PY) or anti-activated MAP kinase IgG (AK). Nos. on left, molecular-mass markers. Distortion in gel (blank space) is due to high concentration of BSA present in phosphorylation buffer. [From Liu et al. (49). Copyright 1997, National Academy of Sciences, USA.]

There is also evidence that the structural protein caveolin may modulate the function of resident signaling molecules in caveolae. This has been evaluated particularly in investigations of eNOS interaction with caveolin. First, it was demonstrated in studies of endothelial and cardiac myocyte cell lysates that eNOS coimmunoprecipitates with caveolin-1 and caveolin-3, respectively (16, 24). Then, in vitro studies and experiments with eNOS and caveolin-1 overexpression in COS-7 cells revealed that both NH₂- and COOH-terminal domains of caveolin interact directly with the eNOS oxygenase domain and inhibit eNOS catalytic activity (25, 37, 54, 55). Interestingly, the neuronal isoform of NOS and caveolin-3 have also been coimmunoprecipitated from rat skeletal muscle (103). In vitro manipulations further indicated that calcium-calmodulin may disrupt the interaction between eNOS and caveolin, leading to enhanced enzymatic activity (54). Experiments using particulate and soluble cellular fractions suggest that this may be a cyclic phenomenon, with dissociation of eNOS and caveolin and mobilization of eNOS from the particulate fraction on agonist stimulation, followed later by reassociation of eNOS and caveolin in the particulate fraction (17). Further work (11, 55, 64) indicates that it is the 20-amino acid scaffolding domain of caveolin mentioned earlier that binds and modifies the activity of eNOS as well as that of other resident signaling molecules including protein kinase C and G protein -subunits. However, a degree of caution is warranted in the interpretation of these findings because it has not yet been determined whether these processes lead to modifications in eNOS enzymatic activity in vivo under physiological conditions. In addition, because both caveolin and eNOS may be found in large abundance in the Golgi apparatus and other internal membranes (44, 62, 81), experiments have yet to be performed to demonstrate whether these interactions take place and have functional relevance within caveolae per se.

Along with involvement in the compartmentalization of specific signaling cascades and the potential modulation of the function of resident signaling molecules, it is likely that caveolae also serve as a site for feedback interplay between different signaling processes or signal integration. For example, GPI-anchored proteins can activate tyrosine kinases and lead to calcium influx (59, 102). Tyrosine kinases also phosphorylate eNOS, causing enzyme inhibition and enhancing its interaction with caveolin (24). However, the calcium entering the cell will bind calmodulin and thereby activate eNOS. The NO generated can stimulate the MAP kinase pathway via Ras (41). In this manner, the physical proximity of the different signaling pathways can lead to cross talk between them, resulting in higher levels of control of the cellular responses to external stimuli.

	FUTURE DIRECTIONS

Recent studies (49, 83) have demonstrated that caveolae are critically involved in multiple signal transduction events at the surface of a variety of cell types. Investigations indicating that numerous individual signal transduction molecules are housed in caveolae have been complemented by demonstrations of signal pathway compartmentalization, modulation, and integration in caveolae. In the process, our understanding of normal signaling events has been considerably advanced. The challenge is to determine the role of caveolae in pathological disorders, including those involving pulmonary epithelial, endothelial, and smooth muscle cells. Future progress in this field may lead to novel therapies for a variety of lung diseases.

	ACKNOWLEDGEMENTS

We thank Marilyn Dixon for secretarial assistance.

	FOOTNOTES

This work was supported by National Heart, Lung, and Blood Institute (NHLBI) Grant HL-58888 and National Institute of Child Health and Human Development Grant HD-30276 (to P. W. Shaul); NHLBI Grant HL-20948 and National Institute of General Medical Sciences Grant GM-43169 (to R. G. W. Anderson); the American Heart Association (P. W. Shaul); and the Perot Family Foundation (R. G. W. Anderson).

Address for reprint requests: P. W. Shaul, Dept. of Pediatrics, Univ. of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9063.

	REFERENCES

Top Abstract Introduction References

1.   Anderson, R. G., B. A. Kamen, K. G. Rothberg, and S. W. Lacey. Potocytosis: sequestration and transport of small molecules by caveolae. Science 255: 410-411, 1992[Free Full Text].

2.   Bilderback, T. R., R. J. Grigsby, and R. T. Dobrowsky. Association of p75 (NTR) with caveolin and localization of neurotrophin-induced sphingomyelin hydrolysis to caveolae. J. Biol. Chem. 272: 10922-10927, 1997[Abstract/Free Full Text].

3.   Bohuslav, J., T. Cinek, and V. Horejsí. Large, detergent-resistant complexes containing murine antigens Thy-1 and Ly-6 and protein tyrosine kinase p56lck. Eur. J. Immunol. 23: 825-831, 1993[Medline].

4.   Brown, D. A., and J. K. Rose. Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface. Cell 68: 533-544, 1992[Medline].

5.   Bruns, R. R., and G. E. Palade. Studies on blood capillaries. I. general organization of blood capillaries in muscle. J. Cell Biol. 37: 244-276, 1968[Abstract/Free Full Text].

6.   Chang, W. J., K. G. Rothberg, B. A. Kamen, and R. G. Anderson. Lowering the cholesterol content of MA104 cells inhibits receptor-mediated transport of folate. J. Cell Biol. 118: 63-69, 1992[Abstract/Free Full Text].

7.   Chang, W. J., Y. S. Ying, K. G. Rothberg, N. M. Hooper, A. J. Turner, H. A. Gambliel, J. De Gunzburg, S. M. Mumby, A. G. Gilman, and R. G. Anderson. Purification and characterization of smooth muscle cell caveolae. J. Cell Biol. 126: 127-138, 1994[Abstract/Free Full Text].

8.   Chun, M., U. K. Liyanage, M. P. Lisanti, and H. F. Lodish. Signal transduction of a G protein-coupled receptor in caveolae: colocalization of endothelin and its receptor with caveolin. Proc. Natl. Acad. Sci. USA 91: 11728-11732, 1994[Abstract/Free Full Text].

9.   Clemente, R., D. R. Jones, P. Ochoa, G. Romero, J. M. Mato, and I. Varela-Nieto. Role of glycosyl-phosphatidylinositol hydrolysis as a mitogenic signal for epidermal growth factor. Cell. Signal. 7: 411-421, 1995[Medline].

10.   Conrad, P. A., E. J. Smart, Y. S. Ying, R. G. Anderson, and G. S. Bloom. Caveolin cycles between plasma membrane caveolae and the Golgi complex by microtubule-dependent and microtubule-independent steps. J. Cell Biol. 131: 1421-1433, 1995[Abstract/Free Full Text].

11.   Couet, J., S. Li, T. Okamoto, T. Ikezu, and M. P. Lisanti. 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[Abstract/Free Full Text].

12.   De Weerd, W. F., and L. M. Leeb-Lundberg. Bradykinin sequesters B2 bradykinin receptors and the receptor-coupled G subunits G_q and G_i in caveolae in DDT¹ MF-2 smooth muscle cells. J. Biol. Chem. 272: 17858-17866, 1997[Abstract/Free Full Text].

13.   Dietzen, D. J., W. R. Hastings, and D. M. Lublin. Caveolin is palmitoylated on multiple cysteine residues. Palmitoylation is not necessary for localization of caveolin to caveolae. J. Biol. Chem. 270: 6838-6842, 1995[Abstract/Free Full Text].

14.   Dráberová, L., and P. Dráber. Thy-1 glycoprotein and src-like protein-tyrosine kinase p53/p56lyn are associated in large detergent-resistant complexes in rat basophilic leukemia cells. Proc. Natl. Acad. Sci. USA 90: 3611-3615, 1993[Abstract/Free Full Text].

15.   Dupree, P., R. G. Parton, G. Raposo, T. V. Kurzchalia, and K. Simons. Caveolae and sorting in the trans-Golgi network of epithelial cells. EMBO J. 12: 1597-1605, 1993[Medline].

16.   Feron, O., L. Belhassen, L. Kobzik, T. W. Smith, R. A. Kelly, and T. Michel. Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J. Biol. Chem. 271: 22810-22814, 1996[Abstract/Free Full Text].

17.   Feron, O., F. Saldana, J. B. Michel, and T. Michel. The endothelial nitric-oxide synthase-caveolin regulatory cycle. J. Biol. Chem. 273: 3125-3128, 1998[Abstract/Free Full Text].

18.   Feron, O., T. W. Smith, T. Michel, and R. A. Kelly. Dynamic targeting of the agonist-stimulated m2 muscarinic acetylcholine receptor to caveolae in cardiac myocytes. J. Biol. Chem. 272: 17744-17748, 1997[Abstract/Free Full Text].

19.   Fiedler, K., R. G. Parton, R. Kellner, T. Etzold, and K. Simons. VIP36, a novel component of glycolipid rafts and exocytic carrier vesicles in epithelial cells. EMBO J. 13: 1729-1740, 1994[Medline].

20.   Fielding, C. J., A. Bist, and P. E. Fielding. Caveolin mRNA levels are up-regulated by free cholesterol and down-regulated by oxysterols in fibroblast monolayers. Proc. Natl. Acad. Sci. USA 94: 3753-3758, 1997[Abstract/Free Full Text].

21.   Fra, A. M., E. Williamson, K. Simons, and R. G. Parton. De novo formation of caveolae in lymphocytes by expression of VIP21-caveolin. Proc. Natl. Acad. Sci. USA 92: 8655-8659, 1995[Abstract/Free Full Text].

22.   Fujimoto, T. Calcium pump of the plasma membrane is localized in caveolae. J. Cell Biol. 120: 1147-1157, 1993[Abstract/Free Full Text].

23.   Fujimoto, T., S. Nakade, A. Miyawaki, K. Mikoshiba, and K. Ogawa. Localization of inositol 1,4,5-trisphosphate receptor-like protein in plasmalemmal caveolae. J. Cell Biol. 119: 1507-1513, 1992[Abstract/Free Full Text].

24.   Garcia-Cardena, G., R. Fan, D. F. Stern, J. W. Liu, and W. C. Sessa. Endothelial nitric oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1. J. Biol. Chem. 271: 27237-27240, 1996[Abstract/Free Full Text].

25.   Garcia-Cardena, G., P. Martasek, B. S. Masters, P. M. Skidd, J. Couet, S. Li, M. P. Lisanti, and W. C. Sessa. Dissecting the interaction between nitric oxide synthase and caveolin. J. Biol. Chem. 272: 25437-25440, 1997[Abstract/Free Full Text].

26.   Garcia-Cardena, G., P. Oh, J. Liu, J. E. Schnitzer, and W. C. Sessa. Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. Proc. Natl. Acad. Sci. USA 93: 6448-6453, 1996[Abstract/Free Full Text].

27.   Glenney, J. R. Two related but distinct forms of the M_r 36,000 tyrosine kinase substrate (calpactin) that interact with phospholipid and actin in a Ca²⁺-dependent manner. Proc. Natl. Acad. Sci. USA 83: 4258-4262, 1986[Abstract/Free Full Text].

28.   Glenney, J. R. Tyrosine phosphorylation of a 22-kDa protein is correlated with transformation by Rous sarcoma virus. J. Biol. Chem. 264: 20163-20166, 1989[Abstract/Free Full Text].

29.   Glenney, J. R. The sequence of human caveolin reveals identity with VIP21, a component of transport vesicles. FEBS Lett. 314: 45-48, 1992[Medline].

30.   Glenney, J. R., and L. Zokas. Novel tyrosine kinase substrates from Rous sarcoma virus-transformed cells are present in the membrane skeleton. J. Cell Biol. 108: 2401-2408, 1989[Abstract/Free Full Text].

31.   Goldberg, R. I., R. M. Smith, and L. Jarett. Insulin and alpha 2-macroglobulin-methylamine undergo endocytosis by different mechanisms in rat adipocytes. I. Comparison of cell surface events. J. Cell. Physiol. 133: 203-212, 1987[Medline].

32.   Hailstones, D., L. S. Sleer, R. G. Parton, and K. K. Stanley. Regulation of caveolin and caveolae by cholesterol in MDCK cells. J. Lipid Res. 39: 369-379, 1998[Abstract/Free Full Text].

33.   Hope, H. R., and L. J. Pike. Phosphoinositides and phosphoinositide-utilizing enzymes in detergent-insoluble lipid domains. Mol. Biol. Cell 7: 843-851, 1996[Abstract].

34.   Huang, C., J. R. Hepler, L. T. Chen, A. F. Gilman, R. G. Anderson, and S. M. Mumby. Organization of G proteins and adenylyl cyclase at the plasma membrane. Mol. Biol. Cell 8: 2365-2378, 1997[Abstract/Free Full Text].

35.   Hunter, T. Oncoprotein networks. Cell 88: 333-346, 1997[Medline].

36.   Isshiki, M., J. Ando, R. Korenaga, H. Kogo, T. Fujimoto, T. Fujita, and A. Kamiya. Endothelial Ca²⁺ waves preferentially originate at specific loci in caveolin-rich cell edges. Proc. Natl. Acad. Sci. USA 95: 5009-5014, 1998[Abstract/Free Full Text].

37.   Ju, H., R. Zou, V. J. Venema, and R. C. Venema. Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity. J. Biol. Chem. 272: 18522-18525, 1997[Abstract/Free Full Text].

38.   Keller, G. A., M. W. Siegel, and I. W. Caras. Endocytosis of glycophospholipid-anchored and transmembrane forms of CD4 by different endocytic pathways. EMBO J. 11: 863-874, 1992[Medline].

39.   Kurzchalia, T. V., P. Dupree, and S. Monier. VIP21-caveolin, a protein of the trans-Golgi network and caveolae. FEBS Lett. 346: 88-91, 1994[Medline].

40.   Kurzchalia, T. V., P. Dupree, R. G. Parton, R. Kellner, H. Virta, M. Lehnert, and K. Simons. VIP21, a 21-kDa membrane protein is an integral component of trans-Golgi-network-derived transport vesicles. J. Cell Biol. 118: 1003-1014, 1992[Abstract/Free Full Text].

41.   Lander, H. M., A. T. Jacovina, R. J. Davis, and J. M. Tauras. Differential activation of mitogen-activated protein kinases by nitric oxide-related species. J. Biol. Chem. 271: 19705-19709, 1996[Abstract/Free Full Text].

42.   Li, S., J. Couet, and M. P. Lisanti. Src tyrosine kinases, Galpha 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[Abstract/Free Full Text].

43.   Li, S., T. Okamoto, M. Chun, M. Sargiacomo, J. E. Casanova, S. H. Hansen, I. Nishimoto, and M. P. Lisanti. Evidence for a regulated interaction between heterotrimeric G proteins and caveolin. J. Biol. Chem. 270: 15693-15701, 1995[Abstract/Free Full Text].

44.   Li, S., K. S. Song, and M. P. Lisanti. Expression and characterization of recombinant caveolin. Purification by polyhistidine tagging and cholesterol-dependent incorporaton into defined lipid membranes. J. Biol. Chem. 271: 568-573, 1996[Abstract/Free Full Text].

45.   Lisanti, M. P., P. E. Scherer, J. Vidugiriene, Z. Tang, A. Hermanowski-Vosatka, Y. H. Tu, R. F. Cook, and M. Sargiacomo. Characterization of caveolin-rich membrane domains isolated from an endothelial-rich source: implications for human disease. J. Cell Biol. 126: 111-126, 1994[Abstract/Free Full Text].

46.   Lisanti, M. P., Z. L. Tang, and M. Sargiacomo. Caveolin forms a hetero-oligomeric protein complex that interacts with an apical GPI-linked protein: implications for the biogenesis of caveolae. J. Cell Biol. 123: 595-604, 1993[Abstract/Free Full Text].

47.   Liu, J., P. Oh, T. Horner, R. A. Rogers, and J. E. Schnitzer. Organized endothelial cell surface signal transduction in caveolae distinct from glycosylphosphatidylinositol-anchored protein microdomains. J. Biol. Chem. 272: 7211-7222, 1997[Abstract/Free Full Text].

48.   Liu, P., and R. G. Anderson. Compartmentalized production of ceramide at the cell surface. J. Biol. Chem. 270: 27179-27185, 1995[Abstract/Free Full Text].

49.   Liu, P., Y. Ying, and R. G. Anderson. Platelet-derived growth factor activates mitogen-activated protein kinase in isolated caveolae. Proc. Natl. Acad. Sci. USA 94: 13666-13670, 1997[Abstract/Free Full Text].

50.   Liu, P., Y. Ying, Y. G. Ko, and R. G. Anderson. Localization of platelet-derived growth factor-stimulated phosphorylation cascade to caveolae. J. Biol. Chem. 271: 10299-10303, 1996[Abstract/Free Full Text].

51.   Marshall, C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80: 179-185, 1995[Medline].

52.   Mastick, C. C., M. J. Brady, and A. R. Saltiel. Insulin stimulates the tyrosine phosphorylation of caveolin. J. Cell Biol. 129: 1523-1531, 1995[Abstract/Free Full Text].

53.   McDonald, K. K., S. Zharikov, E. R. Block, and M. S. Kilberg. A caveolar complex between the cationic amino acid transporter 1 and endothelial nitric-oxide synthase may explain the "arginine paradox." J. Biol. Chem. 272: 31213-31216, 1997[Abstract/Free Full Text].

54.   Michel, J. B., O. Feron, D. Sacks, and T. Michel. Reciprocal regulation of endothelial nitric-oxide synthase by calcium-calmodulin and caveolin. J. Biol. Chem. 272: 15583-15586, 1997[Abstract/Free Full Text].

55.   Michel, J. B., O. Feron, K. Sase, P. Prabhakar, and T. Michel. Caveolin versus calmodulin. Counterbalancing allosteric modulators of endothelial nitric oxide synthase. J. Biol. Chem. 272: 25907-25912, 1997[Abstract/Free Full Text].

56.   Mineo, C., R. G. Anderson, and M. A. White. Physical association of ras enhances activation of membrane-bound raf (RafCAAX). J. Biol. Chem. 272: 10345-10348, 1997[Abstract/Free Full Text].

57.   Mineo, C., G. L. James, E. J. Smart, and R. G. Anderson. Localization of epidermal growth factor-stimulated Ras/Raf-1 interaction to caveolae membrane. J. Biol. Chem. 271: 11930-11935, 1996[Abstract/Free Full Text].

58.   Monier, S., D. J. Dietzen, W. R. Hastings, D. M. Lublin, and T. V. Kurzchalia. Oligomerization of VIP21-caveolin in vitro is stabilized by long chain fatty acylation or cholesterol. FEBS Lett. 388: 143-149, 1996[Medline].

59.   Morgan, B. P., C. W. van den Berg, E. V. Davies, M. B. Hallett, and V. Horejsi. Cross-linking of CD59 and of other glycosyl phosphatidylinositol-anchored molecules on neutrophils triggers cell activation via tyrosine kinase. Eur. J. Immunol. 23: 2841-2850, 1993[Medline].

60.   Mulder, A. B., J. W. Smit, V. J. Bom, N. R. Blom, M. R. Halie, and J. Vandermeer. Association of endothelial tissue factor and thrombomodulin with caveolae. Blood 88: 3667-3670, 1996[Free Full Text].

61.   Muller, G., and K. Geisen. Characterization of the molecular mode of action of the sulfonylurea, glimepiride, at adipocytes. Horm. Metab. Res. 28: 469-487, 1996[Medline].

62.   Murata, M., J. Peranen, R. Schreiner, F. Wieland, T. V. Kurzchalia, and K. Simons. VIP21/caveolin is a cholesterol-binding protein. Proc. Natl. Acad. Sci. USA 92: 10339-10343, 1995[Abstract/Free Full Text].

63.   Neubig, R. R. Membrane organization in G-protein mechanisms. FASEB J. 8: 939-946, 1994[Abstract].

64.   Oka, N., M. Yamamoto, C. Schwencke, J. Kawabe, T. Ebina, S. Ohno, J. Couet, M. P. Lisanti, and Y. Ishikawa. Caveolin interaction with protein kinase C. Isoenzyme-dependent regulation of kinase activity by the caveolin scaffolding domain peptide. J. Biol. Chem. 272: 33416-33421, 1997[Abstract/Free Full Text].

65.   Oram, J. F., and S. Yokoyama. Apolipoprotein-mediated removal of cellular cholesterol and phospholipids. J. Lipid Res. 37: 2473-2491, 1996[Abstract].

66.   Palade, G. E. Fine structure of blood capillaries. J. Appl. Physics 24: 1424, 1953.

67.   Parpal, S., J. Gustavsson, and P. Stralfors. Isolation of phosphooligosaccharide/phospho-sphoinositol glycan from caveolae and cytosol of insulin-stimulated cells. J. Cell Biol. 131: 125-135, 1995[Abstract/Free Full Text].

68.   Parton, R. G., M. Way, N. Zorzi, and E. Stang. Caveolin-3 associates with developing T-tubules during muscle differentiation. J. Cell Biol. 136: 137-154, 1997[Abstract/Free Full Text].

69.   Peters, K. R., W. W. Carley, and G. E. Palade. Endothelial plasmalemmal vesicles have a characteristic striped bipolar surface structure. J. Cell Biol. 101: 2233-2238, 1985[Abstract/Free Full Text].

70.   Pike, L. J., and L. Casey. Localization and turnover of phosphatidylinositol 4,5-bisphosphate in caveolin-enriched membrane domains. J. Biol. Chem. 271: 26453-26456, 1996[Abstract/Free Full Text].

71.   Rechardt, L., and H. Hervonen. Cytochemical demonstration of adenylate cyclase activity with cerium. Histochemistry 82: 501-505, 1985[Medline].

72.   Ritter, T. E., O. Fajardo, H. Matsue, R. G. Anderson, and S. W. Lacey. Folate receptors targeted to clathrin-coated pits cannot regulate vitamin uptake. Proc. Natl. Acad. Sci. USA 92: 3824-3828, 1995[Abstract/Free Full Text].

73.   Robbins, S. M., N. A. Quintrell, and J. M. Bishop. Myristoylation and differential palmitoylation of the HCK protein-tyrosine kinases govern their attachment to membranes and association with caveolae. Mol. Cell. Biol. 15: 3507-3515, 1995[Abstract].

74.   Roettger, B. F., R. U. Rentsch, D. Pinon, E. Holicky, E. Hadac, J. M. Larkin, and L. J. Miller. Dual pathways of internalization of the cholecystokinin receptor. J. Cell Biol. 128: 1029-1041, 1995[Abstract/Free Full Text].

75.   Rothberg, K. G., J. E. Heuser, W. C. Donzell, Y. S. Ying, J. R. Glenney, and R. G. Anderson. Caveolin, a protein component of caveolae membrane coats. Cell 68: 673-682, 1992[Medline].

76.   Rothberg, K. G., Y. S. Ying, B. A. Kamen, and R. G. Anderson. Cholesterol controls the clustering of the glycophospholipid-anchored membrane receptor for 5-methyltetrahydrofolate. J. Cell Biol. 111: 2931-2938, 1990[Abstract/Free Full Text].

77.   Sargiacomo, M., M. Sudol, Z. Tang, and M. P. Lisanti. Signal transducing molecules and glycosyl-phosphatidylinositol-linked proteins form a caveolin-rich insoluble complex in MDCK cells. J. Cell Biol. 122: 789-807, 1993[Abstract/Free Full Text].

78.   Scherer, P. E., T. Okamot, M. Chun, I. Nishimoto, H. F. Lodish, and M. P. Lisanti. Identification, sequence, and expression of caveolin-2 defines a caveolin gene family. Proc. Natl. Acad. Sci. USA 93: 131-135, 1996[Abstract/Free Full Text].

79.   Schmid, S. Clathrin-coated vesicle formation and protein sorting: an integrated process. Annu. Rev. Biochem. 66: 511-548, 1997[Medline].

80.   Schnitzer, J. E., P. Oh, B. S. Jacobson, and A. M. Dvorak. Caveolae from luminal plasmalemma of rat lung endothelium: microdomains enriched in caveolin, Ca(2+)-ATPase, and inositol trisphosphate receptor. Proc. Natl. Acad. Sci. USA 92: 1759-1763, 1995[Abstract/Free Full Text].

81.   Sessa, W. C., G. Garcia-Cardena, J. Liu, A. Keh, J. S. Pollock, J. Bradley, S. Thiru, I. M. Braverman, and K. M. Desai. The Golgi association of endothelial nitric oxide synthase is necessary for the efficient synthesis of nitric oxide. J. Biol. Chem. 270: 17641-17644, 1995[Abstract/Free Full Text].

82.   Sevinsky, J. R., L. V. Rao, and W. Ruf. Ligand-induced protease receptor translocation into caveolae: a mechanism for regulating cell surface proteolysis of the tissue-factor dependent coagulation pathway. J. Cell Biol. 133: 293-304, 1996[Abstract/Free Full Text].

83.   Shaul, P. W., E. J. Smart, L. J. Robinson, Z. German, I. S. Yuhanna, Y. Ying, R. G. Anderson, and T. Michel. Acylation targets endothelial nitric-oxide synthase to plasmalemmal caveolae. J. Biol. Chem. 271: 6518-6522, 1996[Abstract/Free Full Text].

84.   Shenoy-Scaria, A. M., D. J. Dietzen, J. Kwong, D. C. Link, and D. M. Lublin. Cysteine3 of Src family protein tyrosine kinase determines palmitoylation and localization in caveolae. J. Cell Biol. 126: 353-363, 1994[Abstract/Free Full Text].

85.   Simionescu, N. Cellular aspects of transcapillary exchange. Physiol. Rev. 63: 1536-1560, 1983[Free Full Text].

86.   Slezak, J., and S. A. Geller. Cytochemical studies of myocardial adenylate cyclase after its activation and inhibition. J. Histochem. Cytochem. 32: 105-113, 1984[Abstract].

87.   Smart, E. J., D. C. Foster, Y. S. Ying, B. A. Kamen, and R. G. Anderson. Protein kinase C activators inhibit receptor-mediated potocytosis by preventing internalization of caveolae. J. Cell Biol. 124: 307-313, 1994[Abstract/Free Full Text].

88.   Smart, E. J., C. Mineo, and R. G. Anderson. Clustered folate receptors deliver 5-methyltetrahydrofolate to cytoplasm of MA104 cells. J. Cell Biol. 134: 1169-1177, 1996[Abstract/Free Full Text].

89.   Smart, E. J., Y.-S. Ying, and R. G. Anderson. Hormonal regulation of caveolae internalization. J. Cell Biol. 131: 929-938, 1995[Abstract/Free Full Text].

90.   Smart, E. J., Y. S. Ying, P. A Conrad, and R. G. Anderson. Caveolin moves from caveolae to the Golgi apparatus in response to cholesterol oxidation. J. Cell Biol. 127: 1185-1197, 1994[Abstract/Free Full Text].

91.   Smart, E. J., Y. S. Ying, W. C. Donzell, and R. G. Anderson. A role for caveolin in transport of cholesterol from endoplasmic reticulum to plasma membrane. J. Biol. Chem. 271: 29427-29435, 1996[Abstract/Free Full Text].

92.   Smart, E. J., Y. S. Ying, C. Mineo, and R. G. Anderson. A detergent-free method for purifying caveolae membrane from tissue culture cells. Proc. Natl. Acad. Sci. USA 92: 10104-10108, 1995[Abstract/Free Full Text].

93.   Smith, R. M., and L. Jarett. Receptor-mediated endocytosis and intracellular processing of insulin: ultrastructural and biochemical evidence for cell-specific heterogeneity and distinction from nonhormonal ligands. Lab. Invest. 58: 613-629, 1988[Medline].

94.   Song, S. K., S. Li, T. Okamoto, L. A. Quilliam, M. Sargiacomo, and M. P. Lisanti. Copurification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent-free purification of caveolae microdomains. J. Biol. Chem. 271: 9690-9697, 1996[Abstract/Free Full Text].

95.   Stan, R. V., W. G. Roberts, D. Predescu, K. Ihida, L. Saucan, L. Ghitescu, and G. E. Palade. Immunoisolation and partial characterization of endothelial plasmalemmal vesicles (caveolae). Mol. Biol. Cell 8: 595-605, 1997[Abstract].

96.   Stefanova, I., V. Horejsi, I. J. Ansotegui, W. Knapp, and H. Stockinger. GPI-anchored cell-surface molecules complexed to protein tyrosine kinases. Science 254: 1016-1019, 1991[Abstract/Free Full Text].

97.   Stralfors, P. Insulin second messagers. Bioessays 19: 327-335, 1997[Medline].

98.   Sugi, H., S. Suzuki, and T. Daimon. Intracellular calcium translocation during contraction in vertebrate and invertebrate smooth muscles as studied by the pyroantimonate method. Can. J. Physiol. Pharmacol. 60: 576-587, 1982[Medline].

99.   Tachibana, T., and T. Nawa. Ultrastructural localization of Ca²⁺-ATPases in Meissner's corpuscle of the Mongolian gerbil. Arch. Histol. Cytol. 55: 375-379, 1992[Medline].

100.   Tang, Z., P. E. Scherer, T. Okamoto, K. Song, C. Chu, D. S. Kohtz, I. Nishimoto, H. F. Lodish, and M. P. Lisanti. Molecular clonng of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle. J. Biol. Chem. 271: 2255-2261, 1996[Abstract/Free Full Text].

101.   Uittenbogaard, A., Y.-S. Ying, and E. J. Smart. Characterization of a cytosolic heat-shock protein-caveolin chaperone complex. J. Biol. Chem. 273: 6525-6532, 1998[Abstract/Free Full Text].

102.   Van den Berg, C. W., T. Cinek, M. B. Hallett, V. Horejsi, and B. P. Morgan. Exogenous glycosyl phosphatidylinositol-anchored CD59 associates with kinases in membrane clusters on U937 cells and becomes Ca(2+)-signaling competent. J. Cell Biol. 131: 669-677, 1995[Abstract/Free Full Text].

103.   Venema, V. J., H. Ju, R. Zou, and R. C. Venema. Interaction of neuronal nitric-oxide synthase with caveolin-3 in skeletal muscle. J. Biol. Chem. 272: 28187-28190, 1997[Abstract/Free Full Text].

104.   Vepa, S., W. M. Scribner, and V. Natarajan. Activation of protein phosphorylation by oxidants in vascular endothelial cells: identification of tyrosine phosphorylation of caveolin. Free Radic. Biol. Med. 22: 25-35, 1997[Medline].

105.   Wagner, R. C., P. Kreiner, R. J. Barrnett, and M. W. Bitensky. Biochemical characterization and cytochemical localization of a catecholamine-sensitive adenylate cyclase in isolated capillary endothelium. Proc. Natl. Acad. Sci. USA 69: 3175-3179, 1972[Abstract/Free Full Text].

106.   Way, M., and R. G. Parton. M-caveolin, a muscle-specific caveolin-related protein. FEBS Lett. 378: 108-112, 1996[Medline].

107.   Wu, C. B., S. Butz, Y. Ying, and R. G. Anderson. Tyrosine kinase receptors concentrated in caveolae-like domains from neuronal plasma membrane. J. Biol. Chem. 272: 3554-3559, 1997[Abstract/Free Full Text].

108.   Yamada, E. The fine structure of the gall bladder epithelium of the mouse. J. Biophys. Biochem. Cytol. 1: 445-458, 1955.[Abstract/Free Full Text]

109.   Zhang, F., B. Crise, B. Su, Y. Hou, J. K. Rose, A. Bothwell, and K. Jacobson. Lateral diffusion of membrane spanning and glycosylphosphatidylinositol-linked proteins: toward establishing rules governing the lateral mobility of membrane proteins. J. Cell Biol. 115: 75-84, 1991[Abstract/Free Full Text].