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PubMed2006

Shift syndecan-2 from RACK1 to caveolin-2 upon transformation with oncogenic ras.

Syndecan-2 was found to detach from RACK1 and associate with caveolin-2 and Ras in cells transformed with oncogenic ras. Most of syndecan-2 from transformed cells was revealed with negligible phosphorylations at tyrosine residues. We experimented with HeLa cells transfected with plasmids encoding syndecan-2 and its mutants (syndecan-2(Y180F), syndecan-2(Y192F), and syndecan-2(Y180,192F)) to provide evidences that PY180 of syndecan-2 is a binding site for RACK1 and is deprived in cells transfected with oncogenic ras. However, in HeLa cells transfected with syndecan-2(Y180F), RACK1 was found to sustain its reactions with syndecan-2 independent of phosphorylation. The finding of syndecan-2 reactive with caveolin-2/Ras suggests the molecular complex most likely to obstruct RACK1 for functional attachment at syndecan-2, as revealed in cells transfected with oncogenic ras. We provided evidences to reinforce the view that molecular rearrangements upon transformation are specific and interesting.

Animals↗
PubMed2005

Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii.

Rickettsia conorii, a strictly intracellular and category C priority bacterial pathogen (NIAID), invades different mammalian cells. Although some signaling events involved in bacterial entry have been documented, the bacterial and host proteins mediating entry were not known. We report the identification of the Ku70 subunit of DNA-dependent protein kinase (DNA-PK) as a receptor involved in R. conorii internalization. Ku70 is recruited to R. conorii entry sites, and inhibition of Ku70 expression impairs R. conorii internalization. Bacterial invasion is dependent on the presence of cholesterol-enriched microdomains containing Ku70. R. conorii infection stimulates the ubiquitination of Ku70. In addition, the ubiquitin ligase c-Cbl is recruited to R. conorii entry foci, and downregulation of endogenous c-Cbl blocks bacterial invasion and Ku70 ubiquitination. An affinity chromatography approach identified the rickettsial protein rOmpB as a ligand for Ku70. This is the first report of a receptor-ligand interaction involved in the internalization of any rickettsial species.

Actins↗
PubMed2006

Roscovitine differentially affects CaV2 and Kv channels by binding to the open state.

Roscovitine potently inhibits cyclin-dependent kinases (CDK) and can independently slow the closing of neuronal (CaV2.2) calcium channels. We were interested if this drug could affect other ion channels similarly. Using whole cell recordings, we found that roscovitine specifically slows deactivation of all CaV2 channels (N, P/Q and R) by binding to the open state. This effect had a rapid onset and EC(50)=54, 120 and 54microM for N-, P/Q-, and R-type channels, respectively. Deactivation of other channel types was not slowed, including L-type calcium channels (CaV1.2, CaV1.3), potassium channels (native, Kv4.2, Kv2.1 and Kv1.3), and native sodium channels. However, most of the channels tested were inhibited by roscovitine. The inhibition was characterized by slow development and a lower affinity (EC(50)=100-300microM). Surprisingly, potassium channels were rapidly inhibited with an EC(50)=23microM, which is similar to the EC(50) for roscovitine block of cell division [Meijer, L., Borgne, A., Mulner, O., Chong, J., Blow, J., Inagaki, N., Inagaki, M., Delcros, J., Moulinoux, J., 1997. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem. 243, 527-536]. Potassium current inhibition seemed to result from open channel block. The high potency of these two rapid onset effects makes them complicating factors for ongoing clinical trials and research using roscovitine. Thus, the physiology and pharmacology of slow CaV2 deactivation and potassium channel block must be explored.

Calcium Channels, L-Type↗
PubMed2006

Separation and characterization of caveolae subclasses in the plasma membrane of primary adipocytes; segregation of specific proteins and functions.

Caveolae are nearly ubiquitous plasma membrane domains that in adipocytes vary in size between 25 and 150 nm. They constitute sites of entry into the cell as well as platforms for cell signalling. We have previously reported that plasma membrane-associated caveolae that lack cell surface access can be identified by electron microscopy. We now report the identification, after density gradient ultracentrifugation, of a subclass of very high-density apparently closed caveolae that were not labelled by cell surface protein labelling of intact cells. These caveolae contained caveolin-1 and caveolin-2. Another class of high-density caveolae contained caveolin-1, caveolin-2 and specifically fatty acid transport protein-1, fatty acid transport protein-4, fatty acyl-CoA synthetase, hormone-sensitive lipase, perilipin, and insulin-regulated glucose transporter-4. This class of caveolae was specialized in fatty acid uptake and conversion to triacylglycerol. A third class of low-density caveolae contained the insulin receptor, class B scavenger receptor-1, and insulin-regulated glucose transporter-4. Small amounts of these proteins were also detected in the high-density caveolae. In response to insulin, the insulin receptor autophosphorylation and the amount of insulin-regulated glucose transporter-4 increased in these caveolae. The molar ratio of cholesterol to phospholipid in the three caveolae classes varied considerably, from 0.4 in very high-density caveolae to 0.9 in low-density caveolae. There was no correlation between the caveolar contents of caveolin and cholesterol. The low-density caveolae, with the highest cholesterol concentration, were particularly enriched with the cholesterol-rich lipoprotein receptor class B scavenger receptor-1, which mediated cholesteryl ester uptake from high-density lipoprotein and generation of free cholesterol in these caveolae, suggesting a specific role in cholesterol uptake/metabolism. These findings demonstrate a segregation of functions in caveolae subclasses.

Acyl Coenzyme A↗
PubMed2005

Caveolin-1 is not essential for biosynthetic apical membrane transport.

Caveolin-1 has been implicated in apical transport of glycosylphosphatidylinositol (GPI)-anchored proteins and influenza virus hemagglutinin (HA). Here we have studied the role of caveolin-1 in apical membrane transport by generating caveolin-1-deficient Madin-Darby canine kidney (MDCK) cells using retrovirus-mediated RNA interference. The caveolin-1 knockdown (cav1-KD) MDCK cells were devoid of caveolae. In addition, caveolin-2 was retained in the Golgi apparatus in cav1-KD MDCK cells. However, we found no significant alterations in the apical transport kinetics of GPI-anchored proteins or HA upon depletion of caveolin-1. Similar results were obtained using embryonic fibroblasts from caveolin-1-knockout mice. Thus, we conclude that caveolin-1 does not play a major role in lipid raft-mediated biosynthetic membrane trafficking.

Adenoviridae↗
PubMed2006

Caveolin-1 and -2 in airway epithelium: expression and in situ association as detected by FRET-CLSM.

BACKGROUND: Caveolae are involved in diverse cellular functions such as signal transduction, cholesterol homeostasis, endo- and transcytosis, and also may serve as entry sites for microorganisms. Hence, their occurrence in epithelium of the airways might be expected but, nonetheless, has not yet been examined. METHODS: Western blotting, real-time quantitative PCR analysis of abraded tracheal epithelium and laser-assisted microdissection combined with subsequent mRNA analysis were used to examine the expression of cav-1 and cav-2, two major caveolar coat proteins, in rat tracheal epithelium. Fluorescence immunohistochemistry was performed to locate caveolae and cav-1 and -2 in the airway epithelium of rats, mice and humans. Electron-microscopic analysis was used for the identification of caveolae. CLSM-FRET analysis determined the interaction of cav-1alpha and cav-2 in situ. RESULTS: Western blotting and laser-assisted microdissection identified protein and transcripts, respectively, of cav-1 and cav-2 in airway epithelium. Real-time quantitative RT-PCR analysis of abraded tracheal epithelium revealed a higher expression of cav-2 than of cav-1. Immunoreactivities for cav-1 and for cav-2 were co-localized in the cell membrane of the basal cells and basolaterally in the ciliated epithelial cells of large airways of rat and human. However, no labeling for cav-1 or cav-2 was observed in the epithelial cells of small bronchi. Using conventional double-labeling indirect immunofluorescence combined with CLSM-FRET analysis, we detected an association of cav-1alpha and -2 in epithelial cells. The presence of caveolae was confirmed by electron microscopy. In contrast to human and rat, cav-1-immunoreactivity and caveolae were confined to basal cells in mice. Epithelial caveolae were absent in cav-1-deficient mice, implicating a requirement of this caveolar protein in epithelial caveolae formation. CONCLUSION: These results show that caveolae and caveolins are integral membrane components in basal and ciliated epithelial cells, indicating a crucial role in these cell types. In addition to their physiological role, they may be involved in airway infection.

Animals↗
PubMed2007

Reciprocal negative regulation between thyrotropin/3',5'-cyclic adenosine monophosphate-mediated proliferation and caveolin-1 expression in human and murine thyrocytes.

The expression of caveolins is down-regulated in tissue samples of human thyroid autonomous adenomas and in the animal model of this disease. Because several cell types present in thyroid express caveolins, it remained unclear if this down-regulation occurs in thyrocytes and which are the mechanism and role of this down-regulation in the tumor context. Here we show that prolonged stimulation of isolated human thyrocytes by TSH/cAMP/cAMP-dependent protein kinase inhibits caveolins' expression. The expression of caveolins is not down-regulated by activators of other signaling pathways relevant to thyroid growth/function. Therefore, the down-regulation of caveolins' expression in autonomous adenomas is a direct consequence of the chronic activation of the TSH/cAMP pathway in thyrocytes. The down-regulation of caveolin-1 occurs at the mRNA level, with a consequent protein decrease. TSH/cAMP induces a transcription-dependent, translation-independent destabilization of the caveolin-1 mRNA. This effect is correlated to the known proliferative role of that cascade in thyrocytes. In vivo, thyrocytes of caveolin-1 knockout mice display enhanced proliferation. This demonstrates, for the first time, the in vivo significance of the specific caveolin-1 down-regulation by one mitogenic cascade and its relation to a human disease.

Animals↗
PubMed2005

Germ cells and fatty acids induce translocation of CD36 scavenger receptor to the plasma membrane of Sertoli cells.

The CD36 scavenger receptor is involved in the uptake and transport of fatty acids, as well as the phagocytosis process in macrophages. We show here that the CD36 protein is expressed by Sertoli cells in the seminiferous epithelium, mainly during the stages where phagocytosis takes place. Using a Sertoli-derived cell line, we show that addition of germ cells and residual bodies triggers a re-localization of CD36 from the cytoplasm to the plasma membrane of the cells, while latex beads do not. Moreover, Sertoli cell phagocytosis of germ cells, but not of latex beads, is reduced by the presence of fatty acids in the culture medium. In the testis, CD36 plays a key role in both phagocytosis and lipid recycling, for constant production of mature spermatozoa.

Animals↗
PubMed2007

Caveolin-1(-/-)- and caveolin-2(-/-)-deficient mice both display numerous skeletal muscle abnormalities, with tubular aggregate formation.

Here, we examine the role of "non-muscle" caveolins (Cav-1 and Cav-2) in skeletal muscle biology. Our results indicate that skeletal muscle fibers from male Cav-1(-/-) and Cav-2(-/-) mice show striking abnormalities, such as tubular aggregates, mitochondrial proliferation/aggregation, and increased numbers of M-cadherin-positive satellite cells. Notably, these skeletal muscle defects were more pronounced with increasing age. Because Cav-2-deficient mice displayed normal expression levels of Cav-1, whereas Cav-1-null mice exhibited an almost complete deficiency in Cav-2, these skeletal muscle abnormalities seem to be due to loss of Cav-2. Thus, Cav-2(-/-) mice represent a novel animal model-and the first genetically well-defined mouse model-that can be used to study the pathogenesis of tubular aggregate formation, which remains a poorly understood age-related skeletal muscle abnormality. Finally, because Cav-1 and Cav-2 were not expressed within mature skeletal myofibers, our results indicate that development of these abnormalities probably originates in stem/precursor cells, such as satellite cells or myoblasts. Consistent with this hypothesis, skeletal muscle isolated from male Cav-3(-/-) mice did not show any of these abnormalities. As such, this is the first study linking stem cells with the genesis of these intriguing muscle defects.

Animals↗
PubMed2006

Immunohistochemical study of caveolin-1 and -2 in the rat retina.

The expression of caveolin-1 and -2 in the retina was examined; Western blot analysis showed that both were present. Immunohistochemistry indicated that caveolin-1 was expressed in the majority of retinal layers, including the ganglion cell layer, inner plexiform layer, outer plexiform layer, and in the vascular endothelial cells of the retina. Caveolin-2 was primarily immunostained in the vessels, but in a few other elements as well. This is the first demonstration of caveolin differential expression in the retina of rats, and suggests that caveolin plays an important role in signal transduction in glial cells and neuronal cells.

Animals↗
PubMed2006

PV-1 is negatively regulated by VEGF in the lung of caveolin-1, but not caveolin-2, null mice.

An N-glycosylated 60-kDa PV-1 protein that binds heparin was detected in mouse lung from a single mRNA transcript. In the absence of disulfide bond reduction PV-1 is detected as a dimer or large molecular weight oligomer. In the lung of Cav-1, but not Cav-2, null mice the amount of PV-1 protein is diminished, with no detectable change in mRNA level. PV-1 does not fractionate with caveolae on a sucrose density gradient, but the Cav-1 protein is detected in fractions following immunoprecipitation with PV-1 antibodies. Both PV-1 and Cav-1 localize to alveolar endothelial cells, but PV-1 is concentrated at the abluminal and Cav-1 at the luminal cell surface with minimal colocalization. In the Cav-1 null lungs, PV-1 is nearly undetectable in endothelial cells, but remains unchanged in pneumocytes and bronchial epithelial cells. Injection of a VEGF-R2 inhibitor increased PV-1 protein in lung of Cav-1 null, but not Cav-2 or wild-type mice. These data indicate that the PV-1 protein is negatively regulated in pulmonary endothelial cells by VEGF-R2 signaling.

Amino Acid Motifs↗
PubMed2004

Computational methods for the analysis of differential conservation in groups of similar DNA sequences.

Multiple sequence alignments are a powerful tool for identifying the regions of DNA which have been constrained in evolutionary divergence, presumably due to their functional role. However, such constraints rarely manifest themselves as perfect conservation of a site clearly standing out in its broader environment, as they reflect the species-specific differences in proteins, as well as the ability of some proteins to interact with multiple variants of their binding sequence. In this paper we explore the use of alignment column uncertainty as an aid in locating differential phylogenetic footprints, which refer to the sites in DNA where groups of related species exhibit sequence conservation, but where the pattern may vary between the groups. We use efficient, linear-time algorithms to locate such sites. We have performed a study of the mammalian CAV2-CAV1 gene region using our software, and we conclude with several observations concerning the differential conservation and the use of computational methods for its detection. The software developed for this project is available, free of charge, by contacting the author.

Animals↗
PubMed1998

Spatial determinants of specificity in insulin action.

Insulin is a potent stimulator of intermediary metabolism, however the basis for the remarkable specificity of insulin's stimulation of these pathways remains largely unknown. This review focuses on the role compartmentalization plays in insulin action, both in signal initiation and in signal reception. Two examples are discussed: (1) a novel signalling pathway leading to the phosphorylation of the caveolar coat protein caveolin, and (2) a recently identified scaffolding protein, PTG, involved directly in the regulation of enzymes controlling glycogen metabolism.

Animals↗
PubMed2003

A phospholipase D-dependent process forms lipid droplets containing caveolin, adipocyte differentiation-related protein, and vimentin in a cell-free system.

We developed a microsome-based, cell-free system that assembles newly formed triglyceride (TG) into spherical lipid droplets. These droplets were recovered in the d </= 1.055 g/ml fraction by gradient ultracentrifugation and were similar in size and appearance to those isolated from rat adipocytes and 3T3-L1 cells. Caveolin 1 and 2, vimentin, adipocyte differentiation-related protein, and the 78-kDa glucose regulatory protein were identified on the droplets from the cell-free system. The caveolin was soluble in 1% Triton X-100, as was the caveolin on lipid droplets from 3T3-L1 cells. The lipid droplets from the cell-free system, like those from 3T3-L1 cells, contained TG, diacylglycerol, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. The assembly of these TG-containing structures was dependent on the rate of TG biosynthesis and required an activator present in the 160,000 x g supernatant from homogenized rat adipocytes. The activator induced phospholipase D (PLD) activity, and its effect on the release of the TG-containing structures from the microsomes was inhibited by 1-butanol (but not 2-butanol) or 2,3-diphosphoglycerate. The activator could be replaced by a constitutively active PLD or phosphatidic acid. These results indicate that PLD and the formation of phosphatidic acid are important in the assembly of the TG-containing structures.

3T3 Cells↗
PubMed2004

Caveolin-1 regulates matrix metalloproteinases-1 induction and CD147/EMMPRIN cell surface clustering.

CD147, a regulator of matrix metalloproteinase (MMP) production, showed highly specific association with caveolin-1 on the surface of multiple cell types. CD147-caveolin-1 complex formation was temperature and cholesterol dependent, reminiscent of associations seen within caveolae/lipid rafts. However, the subset of caveolin-1 associated with CD147 appeared exclusively within intermediate density sucrose gradient fractions, rather than in the low density fractions containing the bulk of caveolin-1. Mutagenesis experiments revealed that CD147 Ig domain 2 was required for caveolin-1 association. In contrast to CD147-caveolin-1 complexes, CD147-alpha(3) integrin association was not disrupted upon cholesterol depletion, occurred in high density sucrose fractions, and did not involve CD147 Ig domain 2. Overexpression of caveolin-1 caused a specific decrease in clustering of cell surface CD147, as detected by "cluster specific" mAb M6/13. Conversely, a mutant CD147 deficient in caveolin-1 association showed enhanced spontaneous cell surface clustering (detected by mAb M6/13), and did not show decreased clustering in response to caveolin-1 overexpression. Furthermore, the same CD147 mutant yielded an elevated induction of MMP-1. In conclusion, caveolin-1 associates with CD147, in a complex distinct from CD147-alpha(3) integrin complexes, thereby diminishing both CD147 clustering and CD147-dependent MMP-1-inducing activity.

Antigens, CD↗
PubMed1996

Identification, sequence, and expression of caveolin-2 defines a caveolin gene family.

Caveolin, a 21- to 24-kDa integral membrane protein, is a principal component of caveolae membranes. Caveolin interacts directly with heterotrimeric guanine nucleotide binding proteins (G proteins) and can functionally regulate their activity. Here, an approximately 20-kDa caveolin-related protein, caveolin-2, was identified through microsequencing of adipocyte-derived caveolin-enriched membranes; caveolin was retermed caveolin-1. Caveolins 1 and 2 are similar in most respects. mRNAs for both caveolin-1 and caveolin-2 are most abundantly expressed in white adipose tissue and are induced during adipocyte differentiation. Caveolin-2 colocalizes with caveolin-1, indicating that caveolin-2 also localizes to caveolae. However, caveolin-1 and caveolin-2 differ in their functional interactions with heterotrimeric G proteins, possibly explaining why caveolin-1 and -2 are coexpressed within a single cell.

3T3 Cells↗
PubMed2004

Caveolae localization and caveolin expressions in Schwann cells of mature rat spinal nerves.

Caveolae are a specific plasmalemmal microdomain which appear as flask-like invaginations and/or vesicles attaching just beneath the plasmalemma. Caveolae are present in many cell types and are found in the Schwann cells that ensheath myelinated and unmyelinated nerve fibers of the peripheral nervous tissues. However, the precise distribution in the Schwann cell plasmalemma and the functional properties of these caveolae remains obscure. The present study revealed: (1) Caveolae are most commonly observed in the Schwann cell plasmalemma of myelinated nerve fibers. (2) Caveolae are principally located in the perikaryal plasmalemma of Schwann cells of the myelinated nerves. (3) Caveolin-1 is expressed strongly in Schwann cell caveolae. (4) Caveolin 2 and 3 are also immunohistochemically detected in Schwann cell caveolae, although the immunoreactivities are slight. The results suggested that caveolae of the peripheral nervous system are involved in cellular activities specific to Schwann cells in myelinated nerve fibers. These caveolae may contain receptors for signaling molecules that could affect the myelinated nerve fibers, and/or proteins related to ion transfer activity. Further studies are necessary in order to clarify the types of proteins associated with Schwann cell caveolae.

Animals↗
PubMed1999

Localization of the human caveolin-3 gene to the D3S18/D3S4163/D3S4539 locus (3p25), in close proximity to the human oxytocin receptor gene. Identification of the caveolin-3 gene as a candidate for deletion in 3p-syndrome.

Caveolin-3, a muscle-specific caveolin-related protein, is the principal structural protein of caveolae membrane domains in striated muscle cell types (cardiac and skeletal). Recently, we identified an autosomal dominant form of limb girdle muscular dystrophy in humans that is due to mutations within exon 2 of the caveolin-3 gene (3p25). However, the detailed location of the human caveolin-3 gene and its position with regard to neighboring genes remains unknown. Here, we have isolated three independent BAC clones containing the human caveolin-3 gene. Using a PCR-based approach, we determined that these clones contain both exons 1 and 2 of the human caveolin-3 gene. In addition, we performed microsatellite marker analysis of these BAC clones, using a panel of 13 markers that are known to map within the 3p25 region. Our results indicate that these BAC clones contain the following three markers: D3S18, SHGC-1079 (also known as D3S4163) and D3S4539. Interestingly, D3S18 is a marker for two known human diseases, von Hippel-Lindau disease and 3p-syndrome. As D3S4163 and D3S4539 are known to map in the vicinity of the 3' end of the human oxytocin receptor gene, we determined if these caveolin-3 positive BACs also contain the oxytocin receptor gene. We show that (i) these BACs contain all four exons of the oxytocin receptor gene and (ii) that the genes encoding caveolin-3 and the oxytocin receptor are located approximately 7-10 kb apart and in the opposite orientation. As 3p-syndrome is characterized by cardiac septal defects and caveolin-3 is expressed primarily in the heart and skeletal muscle, caveolin-3 is a candidate gene that may be deleted in 3p-syndrome.

Base Sequence↗