Disease relevance of Caveolae

• Clathrin- and caveolin-1-independent endocytosis: entry of simian virus 40 into cells devoid of caveolae [1].
• Caveolin, a 22-kD integral membrane protein, is an important structural component of caveolae that was first identified as a major v-Src substrate in Rous sarcoma virus transformed cells [2].
• Caveolin-3 is another skeletal muscle membrane protein which is important in the formation of caveolae and whose mutations cause dominantly inherited limb girdle muscular dystrophy type 1C (LGMD1C) [3].
• We show here that E. coli K1 infection of human BMEC (HBMEC) results in activation of caveolin-1 for bacterial uptake via caveolae [4].
• Impairment of caveolae formation and T-system disorganization in human muscular dystrophy with caveolin-3 deficiency [5].

High impact information on Caveolae

• The caveolin proteins (caveolin-1, -2, and -3) serve as the structural components of caveolae, while also functioning as scaffolding proteins, capable of recruiting numerous signaling molecules to caveolae, as well as regulating their activity [6].
• The recent colocalization of the cationic amino acid transporter CAT-1 (system y(+)), nitric oxide synthase (eNOS), and caveolin-1 in endothelial plasmalemmal caveolae provides a novel mechanism for the regulation of NO production by L-arginine delivery and circulating hormones such insulin and 17beta-estradiol [7].
• Caveolin-1, the primary coat protein of caveolae, has been implicated as a regulator of signal transduction through binding of its "scaffolding domain" to key signaling molecules [8].
• Dynamin, a 100-kDa GTPase, is an essential component of vesicle formation in receptor-mediated endocytosis, synaptic vesicle recycling, caveolae internalization, and possibly vesicle trafficking in and out of the Golgi [9].
• In this membrane, microinvaginations termed caveolae are organized in band-like domains, which were highly sensitive to filipin (and therefore cholesterol-rich) compared with the surrounding non-caveolar inter-band regions (assumed to be cholesterol-poor) [10].

Chemical compound and disease context of Caveolae

• In a search for 5-HT(2A) receptor-interacting proteins, we discovered that caveolin-1 (Cav-1), a scaffolding protein enriched in caveolae, complexes with 5-HT(2A) receptors in a number of cell types including C6 glioma cells, transfected HEK-293 cells, and rat brain synaptic membrane preparations [11].
• We have shown that foot-and-mouth disease virus (FMDV) infection mediated by the integrin alphavbeta6 takes place through clathrin-dependent endocytosis but not caveolae or other endocytic pathways that depend on lipid rafts [12].
• Caveolin-1, a structural component of caveolae, is overexpressed in metastatic and androgen-resistant prostate cancer and highly expressed in tumor-associated endothelial cells [13].
• Here we show that pretreatment of Caco-2 cell monolayers with filipin III, which disrupts caveolae by chelating cholesterol, significantly reduces the ability of Campylobacter jejuni to enter these cells [14].
• Further, the interactions among eNOS, cholesterol, oxidated LDL and caveola membranes are probably involved in some molecular changes observed in vascular diseases [15].

Biological context of Caveolae

• The plasma membrane pits known as caveolae have been implicated both in cholesterol homeostasis and in signal transduction [16].
• Addition of platelet-derived growth factor to either the intact cell or caveolae isolated from these cells stimulates tyrosine phosphorylation and activates mitogen-activated protein kinases in caveolae [17].
• Cyclooxygenase-2 inhibition sensitizes human colon carcinoma cells to TRAIL-induced apoptosis through clustering of DR5 and concentrating death-inducing signaling complex components into ceramide-enriched caveolae [18].
• The glycolipid precursor of these putative second messengers, as well as the receptor for insulin, appear to be localized in caveolae microdomains of the plasma membrane, and glucose transporters accumulate in caveolae in response to insulin treatment, suggesting a focal role for caveolae in insulin signalling [19].
• However, its remains unknown whether down-regulation of caveolin-1 protein and caveolae organelles contributes to their transformed phenotype [20].

Anatomical context of Caveolae

• Human T-lymphocytes extended pseudopodia into endothelial cells in caveolin- and F-actin-enriched areas, induced local translocation of ICAM-1 and caveolin-1 to the endothelial basal membrane and transmigrated through transcellular passages formed by a ring of F-actin and caveolae [21].
• Caveolin-1 is a protein component (of relative molecular mass 22, 000) of the striated coat that decorates the cytoplasmic surface of caveolae membranes [22].
• We recently showed that human skin fibroblasts internalize fluorescent analogues of the glycosphingolipids lactosylceramide and globoside almost exclusively by a clathrin-independent mechanism involving caveolae [23].
• Here, we further characterized the caveolar pathway for glycosphingolipids, showing that Golgi targeting of sphingolipids internalized via caveolae required microtubules and phosphoinositol 3-kinases and was inhibited in cells expressing dominant-negative Rab7 and Rab9 constructs [23].
• Analysis of endothelium in vivo by subcellular fractionation and immunomicroscopy shows that dynamin is concentrated on caveolae, primarily at the expected site of action, their necks [24].

Associations of Caveolae with chemical compounds

• These observations, which emphasize dependence on cell surface-associated receptors, provide evidence for the existence of a steroid receptor fast-action complex, or SRFC, in caveolae [25].
• Immunogold electron microscopy showed that ganglioside GM1-enriched caveolae associated with an annular plasmalemmal domain enriched in GPI-anchored proteins [26].
• These membrane fragments displayed light density on sucrose gradients characteristic of detergent insoluble glycosphingolipid-rich membrane domains (DIGs)/ caveolae, were solubilized by n-octyl glucoside (NOG, 1%) at 4 degrees C, and contained caveolin [27].
• Uptake of caveolae and degradation of PrPC was slow and sensitive to filipin [28].
• Introduction of Cys3 into p60src led to its palmitoylation. p59fyn but not p60src partitioned into Triton-insoluble complexes that contain caveolae, microinvaginations of the plasma membrane [29].

Gene context of Caveolae

• Caveolin-1 and -2 constitute a framework of caveolae in nonmuscle cells [30].
• Thus, the phosphorylation of caveolin-2 is a novel mechanism to regulate the dynamics of caveolae assembly [31].
• Inhibition of palmitoylation with tunicamycin and [(3)H]palmitic acid labeling demonstrated an estrogen-induced, palmitoylation-dependent plasma membrane ER46 recruitment, with reorganization into caveolae [32].
• Caveolin-2-deficient mice show evidence of severe pulmonary dysfunction without disruption of caveolae [33].
• Nystatin and filipin also affected the rate of internalization of CCR5, indicating a role for caveolae [34].

Analytical, diagnostic and therapeutic context of Caveolae

• Further, uPAR could be directly localized in caveolae by in vivo immunoelectron microscopy [35].
• Both uPAR and its ligand, uPA, were present in caveolae enriched low density Triton X-100 insoluble complexes, as shown by immunoblotting [35].
• Immunocytochemical studies carried out by immunodiffusion on rat lung with an anti-PV-1 polyclonal antibody directed against a COOH-terminal epitope reveal a specific localization of PV-1 to the stomatal diaphragms of rat lung endothelial caveolae and confirm the extracellular orientation of the PV-1 COOH terminus [36].
• Immunofluorescence staining revealed that caveolin, a marker protein for caveolae, is distributed heterogeneously in the cell and that Ca2+ waves preferentially originate at caveolin-rich cell edges [37].
• Here, we show that eNOS is found in Triton X-100-insoluble membranes prepared from cultured bovine aortic endothelial cells and colocalizes with caveolin, a coat protein of caveolae, in cultured bovine lung microvascular endothelial cells as determined by confocal microscopy [38].

References