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Microdomains, Lipid Rafts and Caveolae (San Feliu de Guixols, Spain, 19–24 May 2001)

2001; Wiley; Volume: 2; Issue: 9 Linguagem: Inglês

10.1034/j.1600-0854.2001.20909.x

1600-0854

Deborah A. Brown, Ken Jacobson,

Glycosylation and Glycoproteins Research

TrafficVolume 2, Issue 9 p. 668-672 Free Access Microdomains, Lipid Rafts and Caveolae (San Feliu de Guixols, Spain, 19–24 May 2001) Deborah A. Brown, Corresponding Author Deborah A. Brown Department of Biochemistry and Cell Biology, SUNY at Stony Brook, Stony Brook, NY 11794–5215, USA *Corresponding author: Deborah A. Brown, debrown@ms.cc.sunysb.eduSearch for more papers by this authorKen Jacobson, Ken Jacobson Department of Cell and Developmental Biology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill 27599–7090, USASearch for more papers by this author Deborah A. Brown, Corresponding Author Deborah A. Brown Department of Biochemistry and Cell Biology, SUNY at Stony Brook, Stony Brook, NY 11794–5215, USA *Corresponding author: Deborah A. Brown, debrown@ms.cc.sunysb.eduSearch for more papers by this authorKen Jacobson, Ken Jacobson Department of Cell and Developmental Biology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill 27599–7090, USASearch for more papers by this author First published: 18 September 2008 https://doi.org/10.1034/j.1600-0854.2001.20909.xCitations: 14AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat The first full-length meeting on membrane rafts and caveolae, organized by Klaus Fiedler and Gerrit van Meer and sponsored by EURESCO, was held in the spectacularly situated Eden Roc hotel in San Feliu de Guixols, Spain, overlooking the rugged Costa Brava coastline. Rafts and caveolae remain uncertain bedfellows. Although rafts (lipid microdomains defined by tight acyl chain packing) have a high affinity for caveolae (plasma membrane pits formed by caveolin proteins), the two are distinguishable; rafts can exist and function outside of caveolae. Similarly, it is not yet clear how rafts are involved in caveolar function. At least some functions of caveolae appear to be mediated by binding of caveolins to other proteins, with no obvious requirement for the unique raft lipid environment. We will focus here on the following themes, which were especially prominent at the meeting: raft structure, the function of rafts and caveolae in transport along the exocytic and endocytic pathways, the role of rafts in signaling, and the function and dynamics of caveolin proteins. Structure and Dynamics of Rafts/Caveolae The conference provided new insights into the chemical and physical basis of raft structure and dynamics. Gerrit van Meer reviewed the origin of the raft hypothesis in the preferential transport of sphingolipids to the apical surface of epithelial cells and some of the structural bases of lipid domain formation, including how hydrophobic mismatch between the raft domain and the surrounding bilayer might influence what components may occupy the domain. Philippe Devaux reviewed the history of boundary layer lipid and transbilayer flip-flop of lipids. He pointed out that even with rapid exchange with the bulk membrane lipids (the lipid annulus is not seen on the slower nmr time scale), lipids in the annulus may show considerable specificity for the protein they surround. In addition, the endocytosis of sphingolipids is delayed, possibly reflecting their tendency to be in rafts. Peter Slotte suggested that the physical basis of the preferential interaction of sphingomyelin with cholesterol is likely to depend on a hydrogen-bonding network between these components at the surface of the membrane. Interestingly, sphingomyelin alone is less detergent resistant than the corresponding phosphatidylcholines, indicating that its interaction with cholesterol must be a major factor in conferring detergent resistance. Massimo Masserini showed how domain formation in artificial bilayer membranes prepared with natural lipids could be studied by differential scanning calorimetry, and that the domains are characterized by a small cooperative unit of only ∼ 200 molecules. Following on this theme, Ken Jacobson discussed how the structural tenets of the raft hypothesis – including raft dependence on cholesterol, detergent resistance, and preferential partitioning of glycosphingolipids and GPI-anchored proteins (GPIAPs) and certain cross-linked components – could be remarkably recapitulated in various model membrane systems and visualized in the fluorescence microscope. This confirmation of the raft hypothesis strongly supports its tenability, but raises the issue of why domains are so difficult to visualize in cell membranes. Indeed, the challenge for the microscopist is to determine the in vivo correlates of detergent-resistant membranes (DRM) and, in particular, the identity of the smallest 'building blocks' of rafts. In this respect, the conference succeeded in suggesting how divergent views of rafts derived from various advanced light microscopic techniques may be reconciled. Satyajit Mayor suggested from homotransfer fluorescence resonance energy transfer (FRET) experiments that a fundamental unit structure may be a GPIAP-cholesterol-dependent cluster that includes only a few molecules of GPIAPs and lipids (< 200). The fact that homotransfer is more sensitive to such small clusters than conventional FRET may explain why clusters are not seen by that method. Such clusters may accommodate different GPIAPs. If so, it would indicate that the GPI moiety is important in forming these putative structures. In fact, a very small condensed-cholesterol complex formed with certain phosphatidylcholines (PC) was proposed to account for the PC-cholesterol phase diagram in a poster by Arun Radhakrishnan, lending further credence to the Mayor notion. Akihiro Kusumi presented new gold labeling single-particle tracking data showing that the GPIAP CD59 undergoes hop-diffusion between adjacent 100 nm domains. This is very similar to the diffusion behavior of a simple lipid, DOPC, which is proposed to escape to the next domain by passing through a 'membrane picket fence' defined by transmembrane proteins attached the underlying membrane-associated cytoskeleton. Since CD59 is a resident raft protein, as defined by detergent insolubility, Kusumi proposed that the elementary raft in which the protein is contained must have a lifetime of less than 25 ms in order to pass through the 'pickets' to the adjacent compartment. Kusumi demonstrated that when CD59 is cross-linked, it enters so-called transient confinement zones that both he and Jacobson showed are cholesterol dependent. Such zones, which can be separated by 100's of nanometers and are stable for 10's of seconds, are apparent specializations of the plasma membrane in which even lightly cross-linked components can congregate. Heinrich Hoerber showed how thermally driven diffusion within a laser trap can be used to characterize that bit of the membrane, presumably the elementary raft, that is attached by appropriate antibodies to the 200-nm latex bead trapped within the focused laser beam. The stable drag experienced by the bead–raft complex diffusing within the trap is consistent with a raft domain size of ∼ 50 nm (∼ 3500 molecules) and long (10's of seconds) lifetimes. Overall, what is emerging is a small elementary raft unit ranging in size from less than 100 molecules to several thousand molecules. There is more doubt about the lifetime of such entities; they may exist as extremely short-lived units (∼ ms) or much more stable domains (lifetimes of minutes). Certainly, especially when particle methods are employed, the ability of the particle to aggregate and stabilize these elementary raft units must be considered. In general, only when we can reconcile the different microscopic views of rafts will we have a complete picture of raft size and dynamics. In this regard, a number of speakers (including Kai Simons) stressed how small rafts with limited biological activity may come together to provide larger, fully active microdomains. This is particularly evident in studies of T-cell receptor function. Another view of rafts may be inferred from differential detergent extraction. As one example, Wieland Huttner examined prominin, a pentaspan microvillar protein with no known connections to the cytoskeleton. Prominin can be strongly labeled with photo-activatable cholesterol, and localization of the protein to microvilli is cholesterol dependent. Although prominin is fully soluble in cold Triton X-100, it associates with membranes isolated by their insolubility in Lubrol WX. Huttner suggested that prominin localizes to microvilli because it partitions strongly into novel Lubrol-insoluble rafts present there. He proposed that these rafts are specialized to accommodate the extremely tight radii of curvature found in microvilli. Roger Morris used electron microscopy and different detergents to show that loosely clustered Thy-1 and tightly clustered prion protein (both GPIAPs) are in different rafts or different regions of the same raft in cultured neurons. Hai-Tao He used a Brij detergent to isolate 'small' rafts (in ∼ 70-nm diameter vesicles by EM) at 37 °C that contained the T-cell receptor and some of its signal transduction partners. These proteins were signaling competent in the insoluble membranes. This begins to suggest that certain complexes might be cleanly excised as DRMs without extensive detergent-induced rearrangement. He suggested that the small domains may preassemble the early T cell receptor (TCR) signaling pathways for signal initiation before they coalesce into larger domains for sustained biological activity. The relative dearth of knowledge concerning the specifics of the interaction of detergents with membranes resulted in considerable support for more involvement of lipid chemists and biophysicists in the raft field, particularly with respect to fully characterizing the action of various detergents used to isolate DRMs. New Technology Important new technology was showcased at the conference. Indeed, Kai Simons declared that the ability to image single events – for example, the fusion of individual vesicles with membranes – would be one of the key future thrusts in molecular cell biology. Several groups (Gerhard Schuetz, Piet Lommmerse) demonstrated in posters how the diffusion of single fluorescent lipids on the outer monolayer of the plasma membrane, or GPI-anchored enhance yellow fluorescent protein (EYFP) on the inner monolayer, could be tracked at the single molecule level using ultra-sensitive fluorescence microscopes. Akihiro Kusumi went a step further, showing how when individual GFP-H-Ras molecules encountered their signal transduction partners, in this case an Alexa-labeled Ras binding domain of Raf-1, Ras mobility was reduced and a FRET signal was observed for several hundreds of ms. Heinrich Hoerber demonstrated that the laser tweezers, employed as a photonic force microscope, could be used to map the energy landscape of the cell surface to nanometer resolution based on plotting the distribution of particle positions within the laser tweezers. Thus, the degree to which the particle is localized in a given region (that is, a domain) could be correlated with the local diffusion coefficient of the particle-tagged molecule. Sandor Damjanovich showed how FRET could be used to deduce, via triangulation with several energy transfer pairs, spatial relationships in protein clusters important in IL-15 signaling in T cells. Using FRET in combination with high-resolution near-field scanning fluorescence microscopy, spatial co-localization could be distinguished from true short-range molecular associations that result in FRET. Rafts in the Exocytic Pathway Important roles for rafts have emerged in exocytic membrane traffic in yeast as well as mammalian cells. Kai Simons showed that Pma1p, the plasma membrane ATPase in Saccharomyces cerevisiae, associates with rafts in the Golgi, although rafts themselves form in the ER in yeast. New data suggest that Pma1p is recruited to rafts by a second protein, Ast1p, and that this interaction is required for cell-surface delivery of Pma1p. Howard Riezman showed that different populations of ER-derived transport vesicles, separable on sucrose gradients, carry the GPIAP, Gas1p and the transmembrane protein Gap1p (1). Riezman showed that several proteins previously known to participate in tethering ER-derived vesicles to the Golgi apparatus are also important for sorting of Gas1p from Gap1p-containing transport vesicles. He showed that the tethering and sorting functions are separable. In a poster, Kyohei Umebayashi showed that the Trp transporter Tat2p, whose trafficking is regulated by Trp levels, associates with rafts during transport to the plasma membrane of Saccharomyces cerevisiae. In a Δerg6 mutant, which accumulates zymosterol instead of ergosterol, Tat2p is missorted in the multivesicular body pathway and degraded when Trp is lowered. In mammalian cells, Miguel Alonso used an antisense strategy to show that the proteolipid MAL is required for apical sorting of several proteins, as well as for association of one of these (influenza hemagglutinin) with rafts. Chiara Zurzolo showed that apical transport of GPIAPs in MDCK and FRT cells correlated with raft association and with the ability to form high-molecular weight oligomers. Rafts in the Endocytic Pathway Increasing attention surrounds internalization of raft-associated proteins and lipids via non-clathrin-mediated endocytic mechanisms. Kirsten Sandvig, who along with Bo van Deurs has pioneered this field in studies of toxin internalization, showed that internalization of cholera toxin, which binds the raft-associated ganglioside GM1, does not depend on caveolae and depends only partially on clathrin-coated pits. She used an assay measuring transport of ricin from the endosome to the trans-Golgi network, examining sulfation of ricin. Cholesterol depletion with methyl β-cyclodextrin (MBCD) inhibited this transport, as did (surprisingly) cholesterol loading with MBCD-cholesterol complexes. Transport was independent of Rab9, a protein that regulates transport of the mannose 6-phosphate receptor from late endosomes to the Golgi (2). Tony Futerman showed that cholera toxin internalization in cultured hippocampal neurons, which lack caveolae, is inhibited by inhibitors of clathrin-coated pit-mediated endocytosis, but not by MBCD, which disrupts rafts and caveolae (3). Consistent with Sandvig's results, he found that transport from endosomes to the Golgi, and to lysosomes for degradation, was inhibited by MBCD. The MBCD-sensitive step was shown to be early in the pathway; internalization of CT for 15 min before addition of MBCD significantly reduced the effect of MBCD on toxin degradation. Alice Dautry-Varsat showed that the raft-associated interleukin 2 receptor is internalized in T cells and fibroblasts by a dynamin-dependent, non-clathrin-dependent pathway (4). In a poster, Benjamin Nichols showed that GPI-GFP as well as toxins accumulate in the Golgi apparatus in a clathrin- and Rab5-independent, but cholesterol-dependent, manner (5). In addition to their role in internalization, rafts are also important in transport steps further along the endocytic pathway. Jean Gruenberg reported that cholesterol-laden endosomes, which accumulate in cells containing a mutated Niemann–Pick Type C1 (NPC1) protein and in normal cells after treatment with the drug U18666A, have abnormally low mobility. He found that this low mobility results from abnormally high amounts of Rab7 bound to the cholesterol-loaded endosomes, due to impaired extraction of Rab7 by Rab GDI. He also reported cross-talk between the p38 MAP kinase-dependent stress response and endocytosis. MAP kinase phosphorylates and activates Rab GDI, stimulating endocytosis. Using aerolysin toxin as a probe, Gisou van der Goot found that GPIAPs accumulate in recycling endosomes (as well as the plasma membrane) in CHO cells, but in late endosomes and the Golgi in BHK cells, suggesting cell type-specific trafficking mechanisms for these proteins. Internalization of Caveolae Several talks focused on internalization of caveolae. The process is especially well studied in endothelial cells. Maya Simionescu showed that albumin and low density lipoprotein (LDL) are transported across endothelial monolayers by transcytosis via caveolae. Klaus Fiedler also observed LDL transcytosis in these cells, and suggested that internalization of caveolae is regulated by binding to the actin cytoskeleton. Romeo Cecchelli established an in vitro model of the blood–brain barrier using endothelial cells from brain, and showed that LDL is transported across the monolayer in caveolae. Jan Schnitzer showed that internalization of caveolae in lung endothelial cells is regulated. Endothelin-1 stimulates tyrosine phosphorylation of the endothelin receptor subunit ETB, caveolin-1, and the caveolar G protein Gq, and also stimulates caveolar budding. Internalization of caveolae may be much less common in non-endothelial cells. Bo van Deurs examined caveolae dynamics in several cultured fibroblast and epithelial cell lines using photobleaching of GFP-tagged caveolin. Caveolae at the cell surface had very low mobility, although mobility was increased by disruption of the actin cytoskeleton or cholesterol depletion. Internalization of caveolae was not detected. A repeated photobleaching protocol showed that separate pools of caveolin, which did not exchange in the time course of the experiment (up to 1 h) were present in cell-surface caveolae and in the interior of the cell. In the following discussion, both Teymuras Kurzchalia and Lucas Pelkmans also reported that they did not observe internalization of caveolae in unstimulated cells. However, in a poster, Pelkmans reported that SV40 enter cells via caveolae, and are transported to a novel compartment termed a caveosome (6). Here, virions are sorted into tubules that extend from caveosomes, and eventually to the ER, while caveolin appears to recycle to the plasma membrane. In addition, electron microscopy studies by Peter Peters documented internalization of the GPIAP prion protein in caveolae in transfected chinese hamster ovary (CHO) cells, and subsequent transport to the late endocytic pathway. Rafts and Signaling Two groups showed roles for CD44, which interacts both with rafts and the cytoskeleton, in signaling pathways leading to cell motility. Lukas Huber showed that binding of CD44 to its ligand hyaluronic acid induces formation of lamellopodia. This process is inhibited by dominant-negative N17Rac (7). Frederick Maxfield showed that CD43 and CD44 redistribute to the rear when neutrophils are induced to migrate. Detergent-insoluble DiC16 (a raft-preferring lipid probe) was also concentrated at the rear of the cells. As CD44 binds both rafts and the cytoskeleton, Maxfield suggested that chemotactic signals cause cytoskeletal changes that pull CD44 toward the rear of the cell. Rafts are dragged rearward along with CD44, leaving the leading edge relatively depleted of rafts. Maxfield showed that Rac is recruited to the membrane at the leading edge to stimulate actin polymerization and lamellopodia formation, in a manner that requires cholesterol but not rafts. The role of rafts in T-cell signaling is especially well established. Hannes Stockinger showed that CD147 negatively regulates T-cell activation and provided evidence that this inhibition is accompanied by modulation of rafts. Stockinger proposed that engagement of CD147 affects T-cell membrane organization, inhibiting the immune response. As described above, Hai-Tao He showed that the TCR is present in DRMs isolated from resting cells under appropriate conditions. TCR ligation in these isolated DRMs causes tyrosine phosphorylation of several important substrates. Vaclav Horejsi has identified the 80-kDa protein raft-associated protein phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG) (8) (also called Cbp (9)) that, when tyrosine phosphorylated, serves as a membrane docking site for the cytoplasmic protein C-terminal Src kinase (Csk). After recruitment to the plasma membrane, CSK tyrosine phosphorylates and inhibits Src-family kinases present in the rafts. A two-hybrid screen with PAG as bait yielded EBP50, which also binds the actin-binding protein ezrin. PAG may thus link rafts to the actin cytoskeleton. Tony Magee's group has shown that cholera toxin B (CTB)-mediated clustering of GM1 in T cells (which lack caveolae) causes co-clustering of other raft markers, and activates cells (10). He now reports that wild-type and activated K-Ras, but not wild-type H-Ras, co-cluster with CTB in these cells, indicating raft association. As the polybasic domain of K-Ras is known to be required for membrane association, Magee and his colleagues used EGFP-linked PH domain constructs to visualize PIP2 and PIP3. Both PIP2 and PIP3 (after activation with CTB) co-patched with CTB, indicating raft enrichment of these molecules and coupling of lipids in rafts in opposite leaflets of the bilayer. The raft association of the two Ras proteins contrasts with results of Parton, Hancock, and colleagues in caveolae-containing cells, as discussed below. Caveolins: Function and Trafficking As caveolins are the only known structural proteins of caveolae, characterizing these proteins should provide important clues to caveolar function. Caveolae have been proposed to act in signal transduction and in cholesterol transport. Robert Parton has suggested a link between these functions by showing that expression of a mistargeted dominant negative caveolin mutant reduces plasma membrane cholesterol levels, presumably disrupting rafts (11). The protein inhibits signaling through H-Ras but not K-Ras, suggesting that raft association of the former is required for signaling. Modification of H-Ras, but not K-Ras, with two palmitate chains is presumed to be important in its raft targeting. Further work showed that H-Ras must move out of rafts to signal (12). Two groups reported new findings on the role of tyrosine phosphorylated caveolin-1 in signaling. Filippo Giancotti has shown that caveolin-1 is required for signaling through the α5β1 integrin when cells are plated on fibronectin (13). He now showed that integrin binding to fibronectin induces tyrosine phosphorylation of caveolin, and that tyrosine-phosphorylated caveolin localizes to focal complexes and focal adhesions (14). Mark McNiven also found tyrosine-phosphorylated caveolin in novel dynamin and cortactin-dependent waves that sweep across the dorsal surface of cells as they start to migrate in response to growth factors. These waves are associated with actin stress fiber disassembly. Viable and fertile mice deficient in caveolin-1 and the muscle-specific caveolin-3 were reported by Teymuras Kurzchalia and Michael Lisanti, respectively, showing that caveolins are not essential proteins. Caveolin-1-deficient mice had defects in vascular and myogenic tone consistent with the reported regulatory effects of caveolin-1 on eNOS, and showed a hyperproliferation of undifferentiated endothelial progenitors and fibrosis in the lung. These mice suffered from premature exhaustion in a novel long-term swim test. Lisanti showed that mice deficient in caveolin-3 lacked caveolae in muscle and showed a mild myopathy (15), as reported earlier by another group (16). Dystrophin was no longer targeted to DRMs in caveolin-3–/– mice, and two normally caveolar muscle proteins had a diffuse scattered appearance. In addition, T tubules appeared misformed and immature. Caveolin trafficking is likely to be important in function, particularly in the proposed role of caveolae in cholesterol transport. Three groups reported a novel localization for caveolins: intracellular lipid droplets (17–19). Robert Parton showed that a caveolin N-terminal truncation mutant accumulates in the droplets. The mutant induces accumulation of free cholesterol in late endosomes, and affects H-Ras signaling as described above. Toyoshi Fujimoto reported accumulation of caveolin-2 in lipid droplets in cells that express little caveolin-1, and suggested that they may support signal transduction. Fujimoto's EM studies indicated that the droplets are surrounded by a phospholipid monolayer, which is sometimes further surrounded by one or more bilayers. Deborah Brown showed that a mutant caveolin-1 with an ER retrieval signal accumulated in the droplets, as did endogenous caveolin after treatment with brefeldin A (BFA). This suggested that over-accumulation of caveolins in the ER leads to lipid droplet targeting. Lengthening the caveolin hydrophobic span prevented this accumulation, suggesting a role for the unusual topology of the protein (cytoplasmic domains flanking a relatively short hydrophobic domain) in lipid droplet targeting. Consistent with this idea, stomatin, which has the same topology as caveolin, also accumulated in lipid droplets after BFA treatment. Perspectives The last year has seen an explosion of reports on the function of rafts and caveolae in processes as diverse as signal transduction, membrane trafficking, and cell motility. This timely meeting highlighted many of these developments. Equally importantly, structural studies using new technologies are refining our understanding of how rafts exist in cell membranes. This rapid pace shows no signs of slowing, and we expect that the second EURESCO meeting on rafts and caveolae (to be held in Portugal in 2003) will be as exciting as the first. References 1 Muñiz M, Morsomme P, Riezman H. Protein sorting upon exit from the endoplasmic reticulum. Cell 2001; 104: 313– 320. 2 Iversen T-G, Skretting G, Llorente A, Nicoziani P, Van Deurs B, Sandvig K. Endosome to Golgi transport of ricin is independent of clathrin and of the Rab9- and Rab11-GTPases. Mol Biol Cellin press. 3 Shogomori H & Futerman AH. Cholera toxin is found in detergent-insoluble rafts/domains at the cell surface of hippocampal neurons but is internalized via a raft-independent mechanism. J Biol Chem 2001; 276: 9182– 9188. 4 Lamaze C, Dujeancourt A, Baba T, Lo CG, Benmerah A, Dautry-Varsat A. Interleukin 2 receptors and detergent-resistant membrane domains define a clathrin-independent endocytic pathway. Mol Cell 2001; 7: 661– 671. 5 Nichols BJ, Kenworthy AK, Polishchuk RS, Lodge R, Roberts TH, Hirschberg K, Phair RD, Lippincott-Schwartz J. Rapid cycling of lipid raft markers between the cell surface and Golgi complex. J Cell Biol 2001; 153: 529– 542. 6 Pelkmans L, Kartenbeck J, Helenius A. Caveolar endocytosis of simian virus 40 reveals a new two-step vesicular-transport pathway to the ER. Nat Cell Biol 2001; 3: 473– 483.DOI: 10.1038/35074539 7 Oliferenko S, Kaverina I, Small JV, Huber LA. Hyaluronic acid (HA) binding to CD44 activates Rac1 and induces lamellipodia outgrowth. J Cell Biol 2000; 148: 1159– 1164. 8 Brdicka T, Pavilstova D, Leo A, Bruyns E, Korinek V, Angelisova P, Scherer J, Shevchenko A, Shevchenko A, Hilgert I, Cerny J, Drbal K, Kuramitsu Y, Kornacker B, Horejsi V, et al. Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase Csk and is involved in regulation of T cell activation. J Exp Med 2000; 191: 1591– 1604. 9 Kawabuchi M, Satomi Y, Takao T, Shimonishi Y, Nada S, Nagai K, Tarakhovsky A, Okada M. Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature 2000; 404: 999– 1003.DOI: 10.1038/35010121 10 Janes PW, Ley SC, Magee AI. Aggregation of lipid rafts accompanies signaling via the T cell antigen receptor. 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Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex, and T-tubule abnormalities. J Biol Chem 2001; 276: 21425– 21433. 16 Hagiwara Y, Sasaoka T, Araishi K, Imamura M, Yorifuji H, Nonaka I, Ozawa E, Kikuchi T. Caveolin-3 deficiency causes muscle degeneration in mice. Hum Mol Genet 2000; 9: 3047– 3054. 17 Pol A, Luetterforst R, Lindsay M, Heino S, Ikonen E, Parton RG. A caveolin dominant negative mutant associates with lipid bodies and induces intracellular cholesterol imbalance. J Cell Biol 2001; 152: 1057– 1070. 18 Fujimoto T, Kogo H, Ishiguro K, Tauchi K, Nomura R. Caveolin-2 is targeted to lipid droplets, a new 'membrane domain' in the cell. J Cell Biol 2001; 152: 1079– 1086. 19 Ostermeyer AG, Paci JM, Zeng Y, Lublin DM, Munro S, Brown DA. Accumulation of caveolin in the endoplasmic reticulum redirects the protein to lipid storage droplets. J Cell Biol 2001; 152: 1071– 1078. Citing Literature Volume2, Issue9September 2001Pages 668-672 ReferencesRelatedInformation