Caveolins, liquid-ordered domains, and signal transduction - PubMed (original) (raw)

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Caveolins, liquid-ordered domains, and signal transduction

E J Smart et al. Mol Cell Biol. 1999 Nov.

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FIG. 1

FIG. 1

Caveolae and caveola-related domains. A diagram summarizing the various biochemical, morphological, and functional features of these plasma membrane-associated microdomains is shown. See text for details. DIGs, detergent-insoluble glycolipid-rich membranes; GEMs, glycolipid-enriched membranes; GPCRs, G-protein-coupled receptors; RTKs, receptor tyrosine kinases; NRTKs, nonreceptor tyrosine kinases; PLDs, phospholipase D.

FIG. 2

FIG. 2

Dynamin localizes to caveolae in cultured epithelial cells. (A) Fluorescence micrographs representing laser scanning confocal microscopy of cultured hepatocytes that were double-labeled with a monoclonal anti-caveolin-1 antibody as a marker for caveolae (a) and a polyclonal antibody to dynamin to label the endogenous dynamin (b). A significant number of vesicular structures are labeled with both antibodies (arrows and outlined areas), indicating colocalization of dynamin and caveolin-1. Bar, 8.0 μm. (B) Horseradish peroxidase-cholera toxin B is sequestered within caveolae in dynamin-inhibited cells. Electron micrographs showing hepatocytes that were injected with an inhibitory dynamin antibody and incubated with peroxidase-conjugated cholera toxin are shown. Most of the toxin, represented by the peroxidase reaction product, has not been internalized but instead resides on the plasma membrane grape-like caveolar clusters. Bars, 0.2 μm.

FIG. 2

FIG. 2

Dynamin localizes to caveolae in cultured epithelial cells. (A) Fluorescence micrographs representing laser scanning confocal microscopy of cultured hepatocytes that were double-labeled with a monoclonal anti-caveolin-1 antibody as a marker for caveolae (a) and a polyclonal antibody to dynamin to label the endogenous dynamin (b). A significant number of vesicular structures are labeled with both antibodies (arrows and outlined areas), indicating colocalization of dynamin and caveolin-1. Bar, 8.0 μm. (B) Horseradish peroxidase-cholera toxin B is sequestered within caveolae in dynamin-inhibited cells. Electron micrographs showing hepatocytes that were injected with an inhibitory dynamin antibody and incubated with peroxidase-conjugated cholera toxin are shown. Most of the toxin, represented by the peroxidase reaction product, has not been internalized but instead resides on the plasma membrane grape-like caveolar clusters. Bars, 0.2 μm.

FIG. 3

FIG. 3

The caveolin gene family. An alignment of the protein sequences of murine caveolin-1, -2, and -3 is shown. Identical residues are boxed and highlighted. Note that caveolin-1 and -3 are most closely related, while caveolin-2 is divergent. Translation initiation sites are circled. In addition, the positions of the membrane-spanning segment (green) and the oligomerization domain (purple) are indicated.

FIG. 4

FIG. 4

Caveolins negatively regulate signaling along the p42/44 MAPK cascade. Caveolae have been implicated in signaling through the p42/44 MAPK pathway. Caveolin-1 can inhibit signal transduction from the p42/44 MAPK cascade both in vitro and in vivo by acting as a natural endogenous inhibitor of EGF-R, MEK, and ERK (31). Conversely, when NIH 3T3 cells are used, antisense-mediated reductions in caveolin-1 protein expression are sufficient to constitutively activate the p42/44 MAPK cascade and drive oncogenic transformation (49). In normal NIH 3T3 cells, caveolin-1 expression levels are downregulated in rapidly dividing cells and dramatically upregulated at confluency. Thus, upregulation of caveolin-1 expression levels may be important in mediating normal contact inhibition and in negatively regulating the activation state of the p42/44 MAPK cascade. In accordance with these findings, the caveolin-1 gene is localized to a suspected tumor suppressor locus that is deleted in many forms of human cancer (7q31.1/D7S 522 locus) (34, 36).

FIG. 5

FIG. 5

Detailed organization of the human caveolin-1 and -2 locus and its relationship to D7S 522, a microsatellite marker that is deleted in many forms of human cancer. The sizes of the exons and the distances between them are indicated. Note that the marker D7S 522 is located ∼67 kb upstream of the caveolin-2 gene and that the caveolin-2 gene is located ∼19 kb upstream of the caveolin-1 gene.

FIG. 6

FIG. 6

Schematic diagram summarizing the signaling pathways that down-regulate caveolin-1 gene expression via transcriptional control. The points of control that are affected by oncogenic activating mutations (Ras, Raf, Src, and Abl) and pharmacological agents (PD 98059, forskolin, and IBMX) are as indicated. RTKs, receptor tyrosine kinases; cAMP, cyclic AMP; NRTKs, nonreceptor tyrosine kinases; GPCRs, G-protein-coupled receptors; PDE, cyclic nucleotide phosphodiesterase. The overall structure of the murine caveolin-1 gene is as we described previously (–36).

FIG. 7

FIG. 7

Caveolae mediate SR-BI-dependent uptake of cholesterol esters from HDL. HDL cholesterol esters are initially associated with plasma membrane caveolae. While in caveolae, cholesterol esters may either efflux back to HDL or translocate to nonreversible pools within the plasma membrane or an intracellular membrane compartment. The mechanism for internalization of caveolar cholesterol esters remains unknown.

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