Caveolas - biologia PDF

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Figure 1 Caveola formation requires membrane-inserted caveolin-1 and cytoplasmic PTRF

Nassar, Z. D. et al. (2013) Caveola-forming proteins caveolin-1 and PTRF in prostate cancer Nat. Rev. Urol. doi:10.1038/nrurol.2013.168

Caveolae are invaginations of the plasma membrane that measure 60–80 nm in diameter. In the absence of PTRF, caveola formation is lost and caveolin-1 is found on noncaveolar plasma membrane. Prostate cancer cells secrete caveolin-1, which is found in the circulatory system in lipoprotein-like particles. Abbreviation: PTRF, polymerase I and transcript release factor.

Caveola-forming proteins caveolin-1 and PTRF in prostate cancer Zeyad D. Nassar, Michelle M. Hill, Robert G. Parton & Marie-Odile Parat About the authors topof pageAbstract The expression of caveola-forming proteins is dysregulated in prostate cancer. Caveolae are flask-shaped invaginations of the plasma membrane that have roles in membrane trafficking and cell signalling. Members of two families of proteins—caveolins and cavins—are known to be required for the formation and functions of caveolae. Caveolin-1, the major structural protein of caveolae, is overexpresssed in prostate cancer and has been demonstrated to be involved in prostate cancer angiogenesis, growth and metastasis. Polymerase I and transcript release factor (PTRF) is the only cavin family member necessary for caveola formation. When exogenously expressed in prostate cancer cells, PTRF reduces aggressive potential, probably via both caveola-mediated and caveolaindependent mechanisms. In addition, stromal PTRF expression decreases with progression of the disease. Evaluation of caveolin-1 antibodies in the clinical setting is underway and it is hoped that future studies will reveal the mechanisms of PTRF action, allowing its targeting for therapeutic purposes.

Caveolae are invaginations of the plasma membrane that measure 60– 80 nm in diameter and have been observed in most cell types but are particularly abundant in terminally differentiated cells, such as adipocytes, endothelial cells, fibroblasts and muscle cells (both smooth and striated).1 Caveolae have membrane trafficking, mechanotransducing and signalling functions.1 Like other lipid rafts, caveolae are enriched in cholesterol, glycosphingolipids and lipidanchored proteins, but their discrete morphology and signature proteins—caveolin-1 and polymerase I and transcript release factor (PTRF)—are unique

Electron microscopy has revealed that caveolae are present in prostate tissue, in both stromal cells (smooth muscle cells of normal rat prostate tissue)3, 4 and epithelial cells (basal but not luminal epithelial cells of dog prostate tissue).5 Analysis of caveola content in cultured primary human prostate stromal and epithelial cells has shown that prostatic stromal cells have about twice as many caveolae per micron of the cell membrane as prostatic epithelial cells.6

2. Caveolae-mediated endocytosis:

A schematic illustration shows the structure of a caveola, which is a pit in the plasma membrane that is composed of lipids and caveolin protein. View Full-Size ImageFigure 4: The main features of caveolae and caveolins Caveolin is inserted into the caveolar membrane, with the N and C termini facing the cytoplasm and a putative \"hairpin\" intramembrane domain embedded within the membrane bilayer. The scaffolding domain, a highly conserved region of caveolin, might have a role in cholesterol interactions through conserved basic (+) and bulky hydrophobic residues (red circles). The C-terminal domain, which is close to the intramembrane domain, is modified by palmitoyl groups that insert into the lipid bilayer. The complex structures that are formed by interconnected caveolae can occupy a large area of the plasma membrane. © 2007 Nature Publishing Group Parton, R. G. & Simons, K. The multiple faces of caveolae. Nature Reviews

Caveolae are small invaginations of the cell's plasma membrane. Under the electron microscope, caveolae look to be flask-shape pits about 5080 nm across. They are composed of lipids (such as cholesterol and sphingolipids) and caveolin. A small dimeric protein called caveolin forms the shape and structure of the caveolae. Caveolin proteins insert in the plasma membrane and self-associate, forming a caveolin coat on the surface of the membrane (Figure 4). Both the SV40 virus (a virus found in monkeys and humans) and the papillomavirus (which may cause genital warts and is associated with cervical cancer) use caveolae-mediated endocytosis to infect cells. How do we know? In one case, researchers were able to block SV40 entry into monkey and human cells by preventing the formation of caveolae using a drug called nystatin. As a control, they inhibited the formation of clathrin-coated vesicles, and as they expected, the virus remained fully infective to the cells (Anderson et al. 1996). Using the same strategy together with dominant negative caveolin mutants, Jessica Smith and her group showed that papillomavirus also uses the caveolae-mediated entry pathway (Smith, Campos & Ozbun 2007).

Alternate endocytic pathways: Besides the previously described, well-established endocytosis processes, there are a number of endocytic pathways that do not involve clathrin and caveolin. In these alternate endocytic pathways, the specific coat protein or pinching-off systems have not yet been identified. Scientists have learned that some viruses — including the rotavirus (the most common cause of diarrhea in infants), lymphocytic choriomeningitis virus (a rodent virus that may infect humans), and, in some cell types, the influenza (flu) virus — enter cells through these alternate pathways (Rojek, Perez & Kunz 2008; Sanchez-San Martin et al. (2004).

Allen Nature Reviews Neuroscience 8, 128–140 (February 2007) | doi:10.1038/nrn2059

During neurotransmitter signalling, many G-protein-coupled receptors (GPCRs) undergo agonist-induced endocytosis, leading to receptor recycling, receptor sequestration and receptor downregulation. Clathrin-independent lipid raft mechanisms might contribute to this process. Both caveolae and planar lipid rafts can facilitate clathrin-independent endocytosis from the plasma membrane40, 42, although the precise components and intracellular trafficking pathways that are involved have yet to be definitively determined40, 41. Caveolae or raft endocytosis can be assessed using fluorescence microscopy, and cellular uptake of cholera toxin B is often used to distinguish clathrin-independent, raft-mediated endocytosis; however, this toxin can also be taken up by other pathways41. a | Several GPCRs have been reported to be internalized through the caveolae pathway (Table 2). A signal-dependent event leads to dynamin-dependent fission of the invaginated caveola and subsequent endocytosis and vesicle trafficking to caveolin-containing caveosomes40. The molecular mechanisms responsible for GPCR internalization through caveolae are largely undefined and warrant further investigation. b | Planar lipid rafts can also facilitate endocytosis; however, less evidence is available for this route of GPCR internalization. c | Neurotransmitter signalling can also result in the movement of receptors into or out of lipid rafts. This translocation and lateral movement in the membrane could either activate or diminish neurotransmitter signalling by altering the coupling of receptors with G proteins and/or other signalling effectors.

Allen Nature Reviews Neuroscience 8, 128–140 (February 2007) | doi:10.1038/nrn2059

Lipid rafts are cholesterol- and sphingolipid-enriched, highly dynamic, submicroscopic (25–100 nm diameter) assemblies, which float in the liquid-disordered lipid bilayer in cell membranes2, 4, 40. a | There are two common raft domains in mammalian cells: planar lipid rafts and caveolae. Both possess a similar lipid composition. Planar rafts are essentially continuous with the plane of the plasma membrane and lack distinguishing morphological features. By contrast, caveolae are small, flask-shaped membrane invaginations of the plasma membrane that contain caveolins. Caveolin molecules can oligomerize and are thought to be essential in forming these invaginated membrane structures108. Caveolins and flotillin can recruit signalling molecules into lipid rafts. Many neurotransmitter receptors (both ionotropic and G-protein-coupled), G proteins, and signalling effectors such as second-messengergenerating enzymes are found in lipid rafts. Neurotransmitters might activate receptors that are located both within and outside lipid rafts. b | The lipid raft signalling hypothesis proposes that these microdomains spatially organize signalling molecules at the membrane, perhaps in complexes, to promote kinetically favourable interactions that are necessary for signal transduction. c | Alternatively, lipid raft microdomains might inhibit interactions by separating signalling molecules, thereby dampening signalling responses.

Allen Nature Reviews Neuroscience 8, 128–140 (February 2007) | doi:10.1038/nrn2059

a | Actin and tubulin associate with lipid rafts and caveolae either as polymerized structures or their building block components (actin monomers or tubulin dimers). These cytoskeletal elements might help to organize lipid raft domains and the neurotransmitter molecules that are present in these structures (G-protein-coupled receptors, ionotropic receptors, effectors, G proteins). b | Disruption of actin filaments or microtubules reorganizes certain receptors or G proteins present in lipid rafts, as described in the main text. It is suggested that tubulin-binding or actin-binding drugs could compromise the association between dimeric tubulin and receptors or G proteins. Depending on the system, cytoskeletal elements present in rafts would be expected to facilitate or inhibit neurotransmitter signalling by contributing to the raft organization of the signalling molecules. Adapted, with permission, from Ref. 87 (2006) American Society for Biochemistry and Molecular Biology....