Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Caveolin-1, a structural protein of caveolae, is cleared unusually slowly from the Golgi apparatus during biosynthetic transport. Furthermore, several caveolin-1 mutant proteins accumulate in the Golgi apparatus. We examined this behavior further in this mutant study. Golgi accumulation probably resulted from loss of Golgi exit information, not exposure of cryptic retention signals, because several deletion mutants accumulated in the Golgi apparatus. Alterations throughout the protein caused Golgi accumulation. Thus, most probably acted indirectly, by affecting overall conformation, rather than by disrupting specific Golgi exit motifs. Consistent with this idea, almost all the Golgi-localized mutant proteins failed to oligomerize normally (even with an intact oligomerization domain), and they showed reduced raft affinity in an in vitro detergent-insolubility assay. A few mutant proteins formed unstable oligomers that migrated unusually slowly on blue native gels. Only one mutant protein, which lacked the first half of the N-terminal hydrophilic domain, accumulated in the Golgi apparatus despite normal oligomerization and raft association. These results suggested that transport of caveolin-1 through the Golgi apparatus is unusually difficult. The conformation of caveolin-1 may be optimized to overcome this difficulty, but remain very sensitive to mutation. Disrupting conformation can coordinately affect oligomerization, raft affinity, and Golgi exit of caveolin-1.
Mol Biol Cell 2004 Oct
PMID:Conformational defects slow Golgi exit, block oligomerization, and reduce raft affinity of caveolin-1 mutant proteins. 1530 21

Binding of echovirus 1 (EV1, a nonenveloped RNA virus) to the alpha2beta1 integrin on the cell surface is followed by endocytic internalization of the virus together with the receptor. Here, video-enhanced live microscopy revealed the rapid uptake of fluorescently labeled EV1 into mobile, intracellular structures, positive for green fluorescent protein-tagged caveolin-1. Partial colocalization of EV1 with SV40 (SV40) and cholera toxin, known to traffic via caveosomes, demonstrated that the vesicles were caveosomes. The initiation of EV1 infection was dependent on dynamin II, cholesterol, and protein phosphorylation events. Brefeldin A, a drug that prevents SV40 transport, blocked the EV1 infection cycle, whereas drugs that disrupt the cellular cytoskeleton had no effect. In situ hybridization revealed the localization of viral RNA with endocytosed viral capsid proteins in caveosomes before initiation of viral replication. Thus, both the internalization of EV1 to caveosomes and subsequent events differ clearly from caveolar endocytosis of SV40 because EV1 uptake is fast and independent of actin and EV1 is not sorted further to sER from caveosomes. These results shed further light on the cell entry of nonenveloped viral pathogens and illustrate the use of viruses as probes to dissect caveolin-associated endocytic pathways.
Mol Biol Cell 2004 Nov
PMID:Echovirus 1 endocytosis into caveosomes requires lipid rafts, dynamin II, and signaling events. 1535 70

Caveolin-1, an integral membrane protein of caveolae found in many cell types, has been suggested as a candidate tumor suppressor. However, the mechanism underlying caveolin-1 decreased expression is not fully understood. The purpose of this study is to investigate the role of aberrant promoter methylation in the regulation of caveolin-1 gene in breast cancer correlated with clinical findings. We used methylation specific PCR, direct sequencing and immunohistochemistry stain methods to explore the role of caveolin-1 gene in the development of breast cancer. We demonstrated that 14 of 55 cases (25.5%) and 4 of 55 cases (7.3%) had methylated CpG-island on caveolin-1 promoter in cancerous and non-cancerous cells, respectively. The frequency of aberrant promoter methylation of breast cancer tissues was significant higher than non-cancerous tissues (p<0.05). There were four types of methylation pattern of caveolin-1 gene in the breast cancer tissues. No mutation but one polymorphism GAC right curved arrow GAT at codon 82 was found in the whole exonic sequences of caveolin-1 gene. The methylation status of caveolin-1 gene had no clear relationship with age, cell grade, stage of tumor, and status of estrogen receptor, p53 and c-erbB2 in the breast cancer tissues. However, in breast tissue with aberrant promoter methylation of caveolin-1 gene, the presence of progesterone receptor showed borderline statistic difference compared to unmethylated promoter (p=0.11). Immunohistochemistry demonstrated that expression of caveolin-1 gene correlated with aberrant promoter methylation status in sporadic breast cancer tissues. Our findings suggest that aberrant promoter methylation of caveolin-1 gene is associated with inactivation of expression. This process occurs in the precancerous stage and may play an important role in the development of breast cancer.
Int J Mol Med 2004 Oct
PMID:Mutational, epigenetic and expressional analyses of caveolin-1 gene in breast cancers. 1537 84

We have recently shown that stimulation of endothelial cells with vascular endothelial growth factor (VEGF) induces dissociation of caveolin-1 from the VEGFR-2 receptor, followed by Src family kinase-dependent tyrosine phosphorylation of the protein (Labrecque, L., Royal, I., Surprenant, D. S., Patterson, C., Gingras, D., and Beliveau, R. (2003) Mol. Biol. Cell 14, 334-347). In this study, we provide evidence that the VEGF-dependent tyrosine phosphorylation of caveolin-1 induces interaction of the protein with the membrane-type 1 matrix metalloproteinase (MT1-MMP). This interaction requires the phosphorylation of caveolin-1 on tyrosine 14 by members of the Src family of protein kinases, such as Src and Fyn, because it is completely abolished by expression of a catalytically inactive Src mutant or by site-directed mutagenesis of tyrosine 14 of caveolin-1. Most interestingly, the association of MT1-MMP with phosphorylated caveolin-1 induced the recruitment of Src and a concomitant inhibition of the kinase activity of the enzyme, suggesting that this complex may be involved in the negative regulation of Src activity. The association of MT1-MMP with phosphorylated caveolin-1 occurs in caveolae membranes and involves the cytoplasmic domain of MT1-MMP because it was markedly reduced by mutation of Cys574 and Val582 residues of the cytoplasmic tail of the enzyme. Most interestingly, the reduction of the interaction between MT1-MMP and caveolin-1 by using these mutants also decreases MT1-MMP-dependent cell locomotion. Overall these results indicate that MT1-MMP associates with tyrosine-phosphorylated caveolin-1 and that this complex may play an important role in MT1-MMP regulation and function.
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PMID:Src-mediated tyrosine phosphorylation of caveolin-1 induces its association with membrane type 1 matrix metalloproteinase. 1546 65

Continuous microvascular endothelium constitutively transfers protein from vessel lumen to interstitial space. Compelling recent biochemical, ultrastructural, and physiological evidence reviewed herein demonstrates that protein transport is not the result of barrier "leakiness" but, rather, is an active process occurring primarily in a transendothelial vesicular pathway. Protein accesses the vesicular pathway by means of caveolae open to the vessel lumen. Vascular tracer proteins appear in free cytoplasmic vesicles within minutes; contents of transport vesicles are rapidly deposited into the subendothelial matrix by exocytosis. Caveolin-1 deficiency eliminates caveolae and abolishes vesicular protein transport; interestingly, exchange vessels develop a compensatory transport mode through the opening of a paracellular permeability pathway. The evidence supports the transcytosis hypothesis and the concept that transcytosis is a fundamental component of transendothelial permeability of macromolecules.
Am J Physiol Lung Cell Mol Physiol 2004 Nov
PMID:Functional and morphological studies of protein transcytosis in continuous endothelia. 1547 92

A fraction of the nuclear estrogen receptor alpha (ERalpha) is localized to the plasma membrane region of 17beta-estradiol (E2) target cells. We previously reported that ERalpha is a palmitoylated protein. To gain insight into the molecular mechanism of ERalpha residence at the plasma membrane, we tested both the role of palmitoylation and the impact of E2 stimulation on ERalpha membrane localization. The cancer cell lines expressing transfected or endogenous human ERalpha (HeLa and HepG2, respectively) or the ERalpha nonpalmitoylable Cys447Ala mutant transfected in HeLa cells were used as experimental models. We found that palmitoylation of ERalpha enacts ERalpha association with the plasma membrane, interaction with the membrane protein caveolin-1, and nongenomic activities, including activation of signaling pathways and cell proliferation (i.e., ERK and AKT activation, cyclin D1 promoter activity, DNA synthesis). Moreover, E2 reduces both ERalpha palmitoylation and its interaction with caveolin-1, in a time- and dose-dependent manner. These data point to the physiological role of ERalpha palmitoylation in the receptor localization to the cell membrane and in the regulation of the E2-induced cell proliferation.
Mol Biol Cell 2005 Jan
PMID:Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol. 1549 58

Estrogen receptor regulation of nitric oxide production by vascular endothelium may involve rapid, membrane-initiated signaling pathways in addition to classic genomic mechanisms. In this study, we demonstrate using intact cerebral blood vessels that 17beta-estradiol rapidly activates endothelial nitric-oxide synthase (eNOS) via a phosphoinositide-3 (PI-3) kinase-dependent pathway. The effect is mediated by estrogen receptors (ERs), consistent with colocalization of ERalpha and caveolin-1 immunoreactivity at the plasma membrane of endothelial cells lining cerebral arteries. Treatment with 10 nM 17beta-estradiol for 30 min increased NO production, as measured by total nitrite assay, in cerebral vessels isolated from ovariectomized rats. This effect was significantly decreased by membrane cholesterol depletion with beta-methyl-cyclodextrin, the ER antagonist ICI 182,780 [fulvestrant (Faslodex)], and two inhibitors of PI-3 kinase: wortmannin and LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride]. In parallel with NO production, 17beta-estradiol treatment rapidly increased phosphorylation of both eNOS (p-eNOS) and Akt (p-Akt). PI-3 kinase inhibitors also blocked the latter effects; together, these data are consistent with ER activation of the PI-3 kinase-p-Akt-p-eNOS pathway. ERalpha protein (66 and 50 kDa) coimmunoprecipitated with eNOS as well as with the p85alpha regulatory subunit of PI-3 kinase, further implicating ERalpha in kinase activation of eNOS. Little is known regarding the effects of estrogen on cellular kinase pathways in vivo; therefore, we compared cerebral blood vessels isolated from ovariectomized rats that were either untreated or given estrogen replacement for 4 weeks. Long-term estrogen exposure increased levels of cerebrovascular p-Akt and p-eNOS as well as basal NO production. Thus, in addition to the rapid activation of PI-3 kinase, p-Akt, and p-eNOS, estrogen signaling via nontranscriptional, kinase mechanisms has long-term consequences for vascular function.
Mol Pharmacol 2005 Jan
PMID:Estrogen receptor activation of phosphoinositide-3 kinase, akt, and nitric oxide signaling in cerebral blood vessels: rapid and long-term effects. 1549 4

This review summarizes the highlights of the EB2004 symposium that dealt with the integrated aspects of the lung fluid balance. It is apparent that maintenance of lung fluid balance requires the proper functioning of vascular endothelial and alveolar epithelial barriers. Under physiological conditions, the transcytotic pathway requiring repeated fission-fusion events of the caveolar membrane with other caveolae solely transports albumin. Caveolin-1, which forms caveolae, and albumin-binding proteins play a central role in signaling the transcytosis of albumin. Signals responsible for increasing endothelial permeability in lung microvessels in response to inflammatory mediators were also described. These studies in gene knockout mouse models revealed the importance of Ca(2+) signaling via store-operated transient receptor channel 4 and the activation of endothelial myosin light chain kinase isoform in mediating the increase in microvessel permeability. Increases in the cytosolic Ca(2+) in situ in microvessel endothelia can occur by mitochondria-dependent as well as mitochondria-independent pathways (such as the endoplasmic reticulum). Both these pathways, by triggering endothelial cell activation, may result in lung microvascular injury. The resolution of alveolar edema, requiring clearance of fluid from the air space, is another area of intense investigation in animal models. Although beta-adrenergic agonists can activate alveolar fluid clearance, signaling pathways regulating these events in intact alveoli remain to be established. Development of mouse models in which the function of regulatory proteins (identified in cell culture studies) can be systematically analyzed will provide a better and more integrated picture of lung fluid balance. In vivo veritas!
Am J Physiol Lung Cell Mol Physiol 2004 Dec
PMID:Integrated control of lung fluid balance. 1553 57

Extracellular matrix remodeling occurs during development, tissue repair, and in a number of pathologies, including fibrotic disorders, hypertension, and atherosclerosis. Extracellular matrix remodeling involves the complex interplay between extracellular matrix synthesis, deposition, and degradation. Factors that control these processes are likely to play key roles in regulating physiological and pathological extracellular matrix remodeling. Our data show that fibronectin polymerization into the extracellular matrix regulates the deposition and stability of other extracellular matrix proteins, including collagen I and thrombospondin-1 (Sottile and Hocking, 2002. Mol. Biol. Cell 13, 3546). In the absence of continual fibronectin polymerization, there is a loss of fibronectin matrix fibrils, and increased levels of fibronectin degradation. Fibronectin degradation occurs intracellularly after endocytosis and can be inhibited by chloroquine, an inhibitor of lysosomal degradation, and by caveolae-disrupting agents. Down-regulation of caveolin-1 by RNAi inhibits loss of fibronectin matrix fibrils, fibronectin internalization, and fibronectin degradation; these processes can be restored by reexpression of caveolin-1. These data show that fibronectin matrix turnover occurs through a caveolin-1-dependent process. Caveolin-1 regulation of fibronectin matrix turnover is a novel mechanism regulating extracellular matrix remodeling.
Mol Biol Cell 2005 Feb
PMID:Fibronectin matrix turnover occurs through a caveolin-1-dependent process. 1556 5

A protein that constitutes a good marker for a type of cholesterol-rich domain in biological membranes is caveolin. A segment of this protein has a sequence that corresponds to a cholesterol recognition/interaction amino acid consensus (CRAC) motif; this motif has been suggested to cause the incorporation of proteins into cholesterol-rich domains. We have studied the interaction of two peptides containing the CRAC motif of caveolin-1 by differential scanning calorimetry, fluorescence, circular dichroism and magic angle spinning NMR. These peptides promote the segregation of cholesterol into domains from mixtures of the sterol with phosphatidylcholine, as shown by depletion of cholesterol from a portion of the membrane and enrichment of cholesterol in another domain. Cholesterol passes its solubility limit in the cholesterol-rich domain, resulting in the formation of cholesterol crystallites, suggesting that not all of the cholesterol recruited to this domain is bound to the peptide. NMR studies show that the peptides insert somewhat more deeply into membranes when cholesterol is present, but their strongest interaction takes place with the interfacial region of the membrane. We conclude that the peptides we studied containing CRAC sequences are more effective in promoting the formation of cholesterol-rich domains than are shorter peptides of this region of caveolin, which although they contain several aromatic amino acids, they have no CRAC motif. The presence or absence of a CRAC motif, however, is not a sufficient criterion to determine the extent to which a protein will promote the segregation of cholesterol in membranes.
J Mol Biol 2005 Jan 14
PMID:Caveolin scaffolding region and cholesterol-rich domains in membranes. 1557 26


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