- Email: [email protected]
Caveolae
Current Biology Vol 22 No 4 R114
few key dynamic shapes, or as some physicists say, universal patterns. Highly aligned groups, rotating mills and dynamic figure-of-eights are key examples. These types of patterns are observed not only in moving animal groups, but also in cell migration, bacteria populations, and even in many physical and chemical systems. The question is whether a few key mechanisms could explain similarities between these patterns. Identifying common features in different simulation models and in diverse biological systems may allow us to one day provide a direct link between interaction asymmetries and these universal patterns. That starlings and other birds characterise these universal patterns so well may explain our fascination with flocking. It could explain why during just two weeks in November, 5.3 million people watched Sophie Windsor Clive’s Vimeo upload of her and her friend’s sighting of a murmuration (http://vimeo.com/31158841). An evening murmuration is more than just the dance of starlings; it is a glimpse in to one of the fundamental motions of life. Where can I find out more?
Ballerini, M., Cabibbo, N., Candelier, R., Cavagna, A., Cisbani, E., Giardina, I., Lecomte, V., Orlandi, A., Parisi, G., Procaccini, A., et al. (2008). Interaction ruling animal collective behaviour depends on topological rather than metric distance: evidence from a field study. Proc. Natl. Acad. Sci. USA 105, 1232–1237. Feare, C. (1999). Starlings and Mynas (Princeton University Press). Herbert-Read, J.E., Pernab, A., Mann, R.P., Schaerfa, T.M., Sumpter, D.J.T., and Ward, A.J.W. (2011) Inferring the rules of interaction of shoaling fish. Proc. Natl. Acad. Sci. USA 108, 18726–18731. Procaccini, A., Orlandi, A., Cavagna, A., Giardina, I., Zorattoe, F., Santuccie, D., Chiarottie, F., Hemelrijk, C.K., Allevae, E., Parisib, G., and Carereb, C. (2011). Propagating waves in starling, Sturnus vulgaris, flocks under predation. Anim. Behav. 82, 759–765. Sumpter, D.J.T. (2010). Collective Animal Behavior (Princeton University Press). Usherwood, J.R., Stavrou, M., Lowe, J.C., Roskilly, K., and Wilson, A.M. (2011). Flying in a flock comes at a cost in pigeons. Nature 474, 494–497. Vicsek, T., and Zafiris, A. (2010). Collective motion, arXiv:1010.5017, 2010 - arxiv.org.
1Structure
and Motion Laboratory, Royal Veterinary College, Hatfield, Hertfordshire, AL9 7TA, UK. 2Evolutionary Ecology Group, Department of Zoology, University of Cambridge, Downing Street, Cambridge, CB2 3EJ, UK. 3Department of Mathematics, Uppsala University, Uppsala, Sweden. E-mail: [email protected]; [email protected]
Caveolae Asier Echarri and Miguel A. Del Pozo* What are caveolae? Caveolae are invaginations of the plasma membrane with a defined omega (W) shape and a diameter of 60–80 nm (Figure 1). Caveolae, which can only be unambiguously identified by electron microscopy, were first noticed in 1953 by G.E. Palade and were described and named ‘caveola intracellularis’ by E. Yamada in 1955. However,��������� ����������������� it took almost��������������������������������� 40 years to identify caveolins, the main proteins responsible for this unique plasma membrane domain. There are three mammalian caveolin genes: caveolin-1, caveolin-2 and caveolin-3. Smooth muscle expresses all three isoforms, while skeletal and cardiac muscle express only caveolin-3. Caveolins 1 and 2 are also expressed in non-muscle cells. Caveolae formation is strictly dependent on caveolin-1 or caveolin-3, depending on the tissue. Caveolin-2 appears to contribute to caveolae formation in some cell lines but is dispensable in vivo. Another family of proteins, the cavins (see below) have recently been shown to participate in caveolae formation. Caveolae are also found in complex structures harboring multiple caveolae that can form raceme- or rosette-like structures (Figure 1). Compared with the surrounding membrane, the membrane of caveolae is enriched in cholesterol and certain sphingolipids. Not to be confused with... Lipid rafts. A consensus definition of lipid rafts was agreed at a Keystone meeting in 2006: “membrane rafts are small (10–200 nm), heterogeneous, highly dynamic, sterol- and sphingolipid-enriched domains that compartmentalize cellular processes. Small rafts can sometimes be stabilized to form larger platforms through protein–protein and protein–lipid interactions.” Based on this widely-accepted definition, membrane rafts and caveolae denote distinct membrane domains. Contrary to lipid rafts, caveolae are quite homogeneous in size and have a defined curvature. In addition, caveolae are normally quite static. However, lipid rafts and caveolae do have some features in common, such as their enrichment in cholesterol and certain sphingolipids.
Are caveolae present in all cells and organisms? Caveolae have been identified in several mammals and in zebrafish, but not in Caenorhabditis elegans, despite the presence of caveolins in this organism. Honeybee caveolin is able to form caveolae but surprisingly no caveolin gene has been identified in the fruit fly. Caveolins are restricted to metazoans, and are absent from fungi, plants and non-metazoan parasites. In humans, caveolae are abundant in endothelial cells, adipocytes, smooth muscle cells and fibroblasts but are absent from red blood cells, platelets and lymphocytes. The fact that mice lacking caveolin-1, 2 or 3 are viable but show phenotypes in multiple tissues strongly suggests that caveolae represent an advantage for certain cells, but that life can go on without caveolae. What regulates caveolae formation? Cholesterol plays a major role in caveolae formation, as its depletion flattens caveolae. Caveolae are also flattened by physical stretching of cells or inflation by placing cells in hyposmotic medium, suggesting a role in mechanosensing ������������������� and mechanotransduction���������������� . Caveolae have only been observed at the plasma membrane and there is no evidence for their formation in endomembranes, despite the presence of multioligomerized caveolin-1 complexes in the Golgi. Therefore, specific factors needed for caveolae formation must be present or active only at the plasma membrane. A second family of proteins, the cavins (a family of four proteins), has recently been shown to be important in caveolae formation. Reduction in the levels of cavin-1 (also known as PTRF), cavin-2 (SDPR) or cavin-3 (SRBC) correlates with reduced caveolae density. Cavin-4 (MURC) is expressed predominantly in muscle and is probably a caveolae component, but its role is unclear. Although few studies have examined the role of cavins, direct or indirect interaction between cavins and caveolins appears to be important for caveolae formation, stability and possibly trafficking. However, more studies are needed to define the role of each cavin. It is very possible that other, as yet unidentified factors are needed for caveolae formation. A recently identified candidate is the membrane curvature regulator pacsin2, which has been implicated in sculpting caveolae.
Magazine R115
Caveolae in rosette-like structures Single caveolae
Flattened caveolae
Actin-linked caveolae
Plasma membrane
out in
Actin fibers 60–80 nm Dynamin2 Filamin A
Src Filamin A
Caveolins
PKCα
Cavins
Actin Endocytic caveolin carrier
Caveolin in endomembranes
70 nm
70 nm
Current Biology
Figure 1. Scheme showing single caveolae, flattened caveolae and complex rosette-like structures decorated with caveolae. Actin fiber-linked caveolae regulated by filamin A are depicted. The caveolae marker caveolin-1 can be translocated from the plasma membrane to different endomembranes. Cavins are shown in plasma membrane caveolae. Representative EM photographs show a single caveolae and caveolae rosettes in adherent HeLa cells.
Do caveolae endocytose? Although there is still some debate regarding the ability of caveolae to endocytose, numerous studies clearly show translocation of caveolin-1 from the plasma membrane to internal compartments. Whether single caveolae ‘pinch off’ in a similar manner to clathrin-coated pits and whether they endocytose specific cargo remains unclear. The literature also suggests that cell detachment or harsh treatments, such as phosphatase inhibition, induce caveolae to translocate towards the endomembrane system, mainly in the form of clusters or rosettes. This type of caveolae translocation thus might co-exist with less frequent budding of individual caveolae. The fact that no specific cargo has been unambiguously identified for caveolae endocytosis after 60 years of research suggests that caveolae may not be designed to specifically transport membrane residents or solutes. Several
proposed cargos, including cholera toxin B subunit and SV40, have also been shown to enter the cell via other pathways. Proteins reported to be required for proper translocation of caveolae from the plasma membrane to different compartments include dynamin2, Src kinase, PKCa, and filamins A and B. The actin cytoskeleton is also required in this process. A role for caveolae in transcytosis in endothelial cells has also been described. Opinion is divided on this issue, but considering the ability of caveolae to cluster into tubulovesicular-like structures (Figure 1), a role for caveolae in regulating transcytosis seems quite possible. Are caveolae linked to the cytoskeleton? Abundant evidence suggests that a pool of caveolae is intimately linked to the actin cytoskeleton. Early immunofluorescence and electron microscopy observations showed
caveolae and caveolins close to actin fibers, and several studies show a functional and biochemical interaction between actin-crosslinking filamin proteins and caveolae/caveolin, indicating that filamins are likely to link caveolae to actin fibers. The reason for this intimate connection remains unclear. An appealing possibility is that the role of caveolae in mechanosensing needs to be coordinated with actin fibers, whose strength ought to be coupled to force-induced plasma membrane modifications. The regulation of caveolae trafficking by integrins may have a role in this interplay. Microtubules are involved in the trafficking of caveolin-1-positive vesicles to different organelles and may also regulate the density of caveolae. Sophisticated electron microscopy techniques suggest that microtubules are tightly associated with caveolae.
Current Biology Vol 22 No 4 R116
Do caveolae regulate signaling pathways? The broad spectrum of signaling pathways sensitive to caveolae or caveolins is remarkable, with impacts on gene expression, cell proliferation, anchorage dependence of cell growth, directional cell migration, extracellular matrix remodeling, and so on. Since caveolins are also found outside of caveolae, some of the functions assigned to caveolin may not be related to caveolae, but it is clear that caveolae directly regulate numerous signaling pathways. Two types of mechanism have been described by which caveolae finetune or activate/deactivate signaling cascades. One is the differential lateral plasma membrane distribution of signaling molecules within or outside of caveolae. The second is the movement of caveolae residents between the cell surface and interior due to the translocation of caveolae between the plasma membrane and the endomembrane ��������������������������� system, where caveolae presumably lose their characteristic shape. In both cases, the change in localization results in different signaling outputs. Signaling molecules (membrane receptors, non-receptor kinases and adaptors) can be recruited to caveolae through direct binding to caveolins or by caveolin-independent mechanisms.
role in human cardiovascular disorders. Clearly, caveolae are needed for a healthy organism. What remains to be explored? The central question we cannot yet answer is why it is advantageous for certain cells to contain caveolae. In other words, what is the physiological function of this unique plasma membrane domain? Although caveolae are implicated in many signaling cascades and cellular processes, the reason for the shape of this membrane domain is unclear. The mechanosensory and mechanotransduction capability of caveolae may be an important specific function that differentiates caveolae from other membrane domains. A �� clearer understanding of how caveolae sense and transmit physical forces will undoubtedly shed light on their physiological role. It ������������������������ is currently unclear whether other functions of caveolae, such as their role in cholesterol homeostasis or specific roles in a given signaling pathway, are related to their role in mechanosensing. Experimental models for exploring the connections between apparently unrelated and diverse caveolae functions will help us to draw a clear picture of the true function of caveolae. Where can I find out more?
Is the lack of caveolae associated with human disease? Many oncogenes induce a marked reduction in caveolin-1 expression, resulting in loss of caveolae from transformed cells. This correlates with increased proliferation and anchorage-independent cell growth, but in certain cancers caveolin-1 expression is advantageous for cancer progression and promotes metastasis. Understanding the role of caveolae in cancer progression will require comprehensive knowledge about the role of caveolae and/or caveolin in regulating pathways essential for cell adhesion, proliferation and migration. Mutations in caveolin-1 and cavin-1 have been linked to lipodystrophy in humans, suggesting that the proposed function of caveolae in lipid homeostasis is altered in affected individuals. Similarly, mutations in caveolin-3 have been linked to various muscular disorders, including limb girdle muscular dystrophy and rippling muscle disease. The predominantly cardiovascular phenotypes of caveolindeficient mice also suggest a potential
Bastiani, M. and Parton R.G. (2010). Caveolae at a glance. J. Cell Sci. 123, 3831–3836. Goetz, J.G., Minguet, S., Navarro-Lérida, I., Lazcano, J.J., Samaniego, R., Calvo, E., Tello, M., Osteso-Ibañéz, T., Pellinen, T., Echarri, A., et al. (2011). Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146, 148����� –���� 163. Hansen, C.G. and Nichols, B.J. (2010). Exploring the caves: cavins, caveolins and caveolae. Trends Cell Biol. 20, 177–186. Hill, M.M., Bastiani, M., Luetterforst, R., Kirkham, M., Kirkham, A., Nixon, S.J., Walser, P., Abankwa, D., Oorschot, V.M., Martin, S., et al. (2008). PTRFCavin, a conserved cytoplasmic protein required for caveola formation and function. Cell 132, 113����� –���� 124. Parton, R.G. and Simons, K. (2007). The multiple faces of caveolae. Nat. Rev. Mol. Cell Biol. 8, 185–194. Pilch, P.F., and Liu, L. (2011). Fat caves: caveolae, lipid trafficking and lipid metabolism in adipocytes. Trends Endocrinol. Metab. 22, 318–324. Sinha B., Köster D., Ruez R., Gonnord P., Bastiani M., Abankwa D., Stan R.V., Butler-Browne G., Vedie B., Johannes L., et al. (2011). Cells respond to mechanical stress by rapid disassembly of caveolae. Cell 144, 402–413.
Integrin Signaling Laboratory, Vascular Biology and Inflammation Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain. *E-mail: [email protected]
Primer
The ESCRT machinery Oliver Schmidt and David Teis* The endosomal sorting complexes required for transport (ESCRT) assemble into a multisubunit machinery that performs a topologically unique membrane bending and scission reaction away from the cytoplasm. This evolutionarily highly conserved process is required for the multivesicular body (MVB) pathway, cytokinesis and HIV budding. The modular setup of the machinery with five distinct ESCRT complexes (ESCRT-0, -I, -II, -III and the Vps4 complex) that have a clear division of tasks — from interaction with ubiquitinated membrane proteins to membrane deformation and abscission — allows them to be flexibly integrated into these three very different biological processes (Figure 1). In the first of these processes, the MVB pathway delivers ubiquitinated membrane proteins and lipids into lysosomes for degradation. During MVB sorting the entire ESCRT machinery sequentially assembles on endosomes, where it generates MVB vesicles by budding the limiting endosomal membrane away from the cytoplasm. An ESCRT-mediated membrane scission step finally releases the mature MVB vesicle into the lumen of the organelle. Since this process is required for membrane protein turnover, it is critical for the regulation of cell surface receptor signaling in cells and during development. In the second process, at the end of cytokinesis, ESCRT complexes coordinate membrane abscission with microtubule disassembly at the midbody to physically separate the two daughter cells. Finally, in the third process ESCRT complexes are hijacked during HIV budding at the surface of infected host cells where they catalyze the scission of the membrane stalk that connects the budding virus with the host cell. Despite fundamental differences, all three processes require a topologically equivalent membrane budding and scission reaction — away from the cytoplasm — which is catalyzed by the coordinated action of the ESCRT
few key dynamic shapes, or as some physicists say, universal patterns. Highly aligned groups, rotating mills and dynamic figure-of-eights are key examples. These types of patterns are observed not only in moving animal groups, but also in cell migration, bacteria populations, and even in many physical and chemical systems. The question is whether a few key mechanisms could explain similarities between these patterns. Identifying common features in different simulation models and in diverse biological systems may allow us to one day provide a direct link between interaction asymmetries and these universal patterns. That starlings and other birds characterise these universal patterns so well may explain our fascination with flocking. It could explain why during just two weeks in November, 5.3 million people watched Sophie Windsor Clive’s Vimeo upload of her and her friend’s sighting of a murmuration (http://vimeo.com/31158841). An evening murmuration is more than just the dance of starlings; it is a glimpse in to one of the fundamental motions of life. Where can I find out more?
Ballerini, M., Cabibbo, N., Candelier, R., Cavagna, A., Cisbani, E., Giardina, I., Lecomte, V., Orlandi, A., Parisi, G., Procaccini, A., et al. (2008). Interaction ruling animal collective behaviour depends on topological rather than metric distance: evidence from a field study. Proc. Natl. Acad. Sci. USA 105, 1232–1237. Feare, C. (1999). Starlings and Mynas (Princeton University Press). Herbert-Read, J.E., Pernab, A., Mann, R.P., Schaerfa, T.M., Sumpter, D.J.T., and Ward, A.J.W. (2011) Inferring the rules of interaction of shoaling fish. Proc. Natl. Acad. Sci. USA 108, 18726–18731. Procaccini, A., Orlandi, A., Cavagna, A., Giardina, I., Zorattoe, F., Santuccie, D., Chiarottie, F., Hemelrijk, C.K., Allevae, E., Parisib, G., and Carereb, C. (2011). Propagating waves in starling, Sturnus vulgaris, flocks under predation. Anim. Behav. 82, 759–765. Sumpter, D.J.T. (2010). Collective Animal Behavior (Princeton University Press). Usherwood, J.R., Stavrou, M., Lowe, J.C., Roskilly, K., and Wilson, A.M. (2011). Flying in a flock comes at a cost in pigeons. Nature 474, 494–497. Vicsek, T., and Zafiris, A. (2010). Collective motion, arXiv:1010.5017, 2010 - arxiv.org.
1Structure
and Motion Laboratory, Royal Veterinary College, Hatfield, Hertfordshire, AL9 7TA, UK. 2Evolutionary Ecology Group, Department of Zoology, University of Cambridge, Downing Street, Cambridge, CB2 3EJ, UK. 3Department of Mathematics, Uppsala University, Uppsala, Sweden. E-mail: [email protected]; [email protected]
Caveolae Asier Echarri and Miguel A. Del Pozo* What are caveolae? Caveolae are invaginations of the plasma membrane with a defined omega (W) shape and a diameter of 60–80 nm (Figure 1). Caveolae, which can only be unambiguously identified by electron microscopy, were first noticed in 1953 by G.E. Palade and were described and named ‘caveola intracellularis’ by E. Yamada in 1955. However,��������� ����������������� it took almost��������������������������������� 40 years to identify caveolins, the main proteins responsible for this unique plasma membrane domain. There are three mammalian caveolin genes: caveolin-1, caveolin-2 and caveolin-3. Smooth muscle expresses all three isoforms, while skeletal and cardiac muscle express only caveolin-3. Caveolins 1 and 2 are also expressed in non-muscle cells. Caveolae formation is strictly dependent on caveolin-1 or caveolin-3, depending on the tissue. Caveolin-2 appears to contribute to caveolae formation in some cell lines but is dispensable in vivo. Another family of proteins, the cavins (see below) have recently been shown to participate in caveolae formation. Caveolae are also found in complex structures harboring multiple caveolae that can form raceme- or rosette-like structures (Figure 1). Compared with the surrounding membrane, the membrane of caveolae is enriched in cholesterol and certain sphingolipids. Not to be confused with... Lipid rafts. A consensus definition of lipid rafts was agreed at a Keystone meeting in 2006: “membrane rafts are small (10–200 nm), heterogeneous, highly dynamic, sterol- and sphingolipid-enriched domains that compartmentalize cellular processes. Small rafts can sometimes be stabilized to form larger platforms through protein–protein and protein–lipid interactions.” Based on this widely-accepted definition, membrane rafts and caveolae denote distinct membrane domains. Contrary to lipid rafts, caveolae are quite homogeneous in size and have a defined curvature. In addition, caveolae are normally quite static. However, lipid rafts and caveolae do have some features in common, such as their enrichment in cholesterol and certain sphingolipids.
Are caveolae present in all cells and organisms? Caveolae have been identified in several mammals and in zebrafish, but not in Caenorhabditis elegans, despite the presence of caveolins in this organism. Honeybee caveolin is able to form caveolae but surprisingly no caveolin gene has been identified in the fruit fly. Caveolins are restricted to metazoans, and are absent from fungi, plants and non-metazoan parasites. In humans, caveolae are abundant in endothelial cells, adipocytes, smooth muscle cells and fibroblasts but are absent from red blood cells, platelets and lymphocytes. The fact that mice lacking caveolin-1, 2 or 3 are viable but show phenotypes in multiple tissues strongly suggests that caveolae represent an advantage for certain cells, but that life can go on without caveolae. What regulates caveolae formation? Cholesterol plays a major role in caveolae formation, as its depletion flattens caveolae. Caveolae are also flattened by physical stretching of cells or inflation by placing cells in hyposmotic medium, suggesting a role in mechanosensing ������������������� and mechanotransduction���������������� . Caveolae have only been observed at the plasma membrane and there is no evidence for their formation in endomembranes, despite the presence of multioligomerized caveolin-1 complexes in the Golgi. Therefore, specific factors needed for caveolae formation must be present or active only at the plasma membrane. A second family of proteins, the cavins (a family of four proteins), has recently been shown to be important in caveolae formation. Reduction in the levels of cavin-1 (also known as PTRF), cavin-2 (SDPR) or cavin-3 (SRBC) correlates with reduced caveolae density. Cavin-4 (MURC) is expressed predominantly in muscle and is probably a caveolae component, but its role is unclear. Although few studies have examined the role of cavins, direct or indirect interaction between cavins and caveolins appears to be important for caveolae formation, stability and possibly trafficking. However, more studies are needed to define the role of each cavin. It is very possible that other, as yet unidentified factors are needed for caveolae formation. A recently identified candidate is the membrane curvature regulator pacsin2, which has been implicated in sculpting caveolae.
Magazine R115
Caveolae in rosette-like structures Single caveolae
Flattened caveolae
Actin-linked caveolae
Plasma membrane
out in
Actin fibers 60–80 nm Dynamin2 Filamin A
Src Filamin A
Caveolins
PKCα
Cavins
Actin Endocytic caveolin carrier
Caveolin in endomembranes
70 nm
70 nm
Current Biology
Figure 1. Scheme showing single caveolae, flattened caveolae and complex rosette-like structures decorated with caveolae. Actin fiber-linked caveolae regulated by filamin A are depicted. The caveolae marker caveolin-1 can be translocated from the plasma membrane to different endomembranes. Cavins are shown in plasma membrane caveolae. Representative EM photographs show a single caveolae and caveolae rosettes in adherent HeLa cells.
Do caveolae endocytose? Although there is still some debate regarding the ability of caveolae to endocytose, numerous studies clearly show translocation of caveolin-1 from the plasma membrane to internal compartments. Whether single caveolae ‘pinch off’ in a similar manner to clathrin-coated pits and whether they endocytose specific cargo remains unclear. The literature also suggests that cell detachment or harsh treatments, such as phosphatase inhibition, induce caveolae to translocate towards the endomembrane system, mainly in the form of clusters or rosettes. This type of caveolae translocation thus might co-exist with less frequent budding of individual caveolae. The fact that no specific cargo has been unambiguously identified for caveolae endocytosis after 60 years of research suggests that caveolae may not be designed to specifically transport membrane residents or solutes. Several
proposed cargos, including cholera toxin B subunit and SV40, have also been shown to enter the cell via other pathways. Proteins reported to be required for proper translocation of caveolae from the plasma membrane to different compartments include dynamin2, Src kinase, PKCa, and filamins A and B. The actin cytoskeleton is also required in this process. A role for caveolae in transcytosis in endothelial cells has also been described. Opinion is divided on this issue, but considering the ability of caveolae to cluster into tubulovesicular-like structures (Figure 1), a role for caveolae in regulating transcytosis seems quite possible. Are caveolae linked to the cytoskeleton? Abundant evidence suggests that a pool of caveolae is intimately linked to the actin cytoskeleton. Early immunofluorescence and electron microscopy observations showed
caveolae and caveolins close to actin fibers, and several studies show a functional and biochemical interaction between actin-crosslinking filamin proteins and caveolae/caveolin, indicating that filamins are likely to link caveolae to actin fibers. The reason for this intimate connection remains unclear. An appealing possibility is that the role of caveolae in mechanosensing needs to be coordinated with actin fibers, whose strength ought to be coupled to force-induced plasma membrane modifications. The regulation of caveolae trafficking by integrins may have a role in this interplay. Microtubules are involved in the trafficking of caveolin-1-positive vesicles to different organelles and may also regulate the density of caveolae. Sophisticated electron microscopy techniques suggest that microtubules are tightly associated with caveolae.
Current Biology Vol 22 No 4 R116
Do caveolae regulate signaling pathways? The broad spectrum of signaling pathways sensitive to caveolae or caveolins is remarkable, with impacts on gene expression, cell proliferation, anchorage dependence of cell growth, directional cell migration, extracellular matrix remodeling, and so on. Since caveolins are also found outside of caveolae, some of the functions assigned to caveolin may not be related to caveolae, but it is clear that caveolae directly regulate numerous signaling pathways. Two types of mechanism have been described by which caveolae finetune or activate/deactivate signaling cascades. One is the differential lateral plasma membrane distribution of signaling molecules within or outside of caveolae. The second is the movement of caveolae residents between the cell surface and interior due to the translocation of caveolae between the plasma membrane and the endomembrane ��������������������������� system, where caveolae presumably lose their characteristic shape. In both cases, the change in localization results in different signaling outputs. Signaling molecules (membrane receptors, non-receptor kinases and adaptors) can be recruited to caveolae through direct binding to caveolins or by caveolin-independent mechanisms.
role in human cardiovascular disorders. Clearly, caveolae are needed for a healthy organism. What remains to be explored? The central question we cannot yet answer is why it is advantageous for certain cells to contain caveolae. In other words, what is the physiological function of this unique plasma membrane domain? Although caveolae are implicated in many signaling cascades and cellular processes, the reason for the shape of this membrane domain is unclear. The mechanosensory and mechanotransduction capability of caveolae may be an important specific function that differentiates caveolae from other membrane domains. A �� clearer understanding of how caveolae sense and transmit physical forces will undoubtedly shed light on their physiological role. It ������������������������ is currently unclear whether other functions of caveolae, such as their role in cholesterol homeostasis or specific roles in a given signaling pathway, are related to their role in mechanosensing. Experimental models for exploring the connections between apparently unrelated and diverse caveolae functions will help us to draw a clear picture of the true function of caveolae. Where can I find out more?
Is the lack of caveolae associated with human disease? Many oncogenes induce a marked reduction in caveolin-1 expression, resulting in loss of caveolae from transformed cells. This correlates with increased proliferation and anchorage-independent cell growth, but in certain cancers caveolin-1 expression is advantageous for cancer progression and promotes metastasis. Understanding the role of caveolae in cancer progression will require comprehensive knowledge about the role of caveolae and/or caveolin in regulating pathways essential for cell adhesion, proliferation and migration. Mutations in caveolin-1 and cavin-1 have been linked to lipodystrophy in humans, suggesting that the proposed function of caveolae in lipid homeostasis is altered in affected individuals. Similarly, mutations in caveolin-3 have been linked to various muscular disorders, including limb girdle muscular dystrophy and rippling muscle disease. The predominantly cardiovascular phenotypes of caveolindeficient mice also suggest a potential
Bastiani, M. and Parton R.G. (2010). Caveolae at a glance. J. Cell Sci. 123, 3831–3836. Goetz, J.G., Minguet, S., Navarro-Lérida, I., Lazcano, J.J., Samaniego, R., Calvo, E., Tello, M., Osteso-Ibañéz, T., Pellinen, T., Echarri, A., et al. (2011). Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146, 148����� –���� 163. Hansen, C.G. and Nichols, B.J. (2010). Exploring the caves: cavins, caveolins and caveolae. Trends Cell Biol. 20, 177–186. Hill, M.M., Bastiani, M., Luetterforst, R., Kirkham, M., Kirkham, A., Nixon, S.J., Walser, P., Abankwa, D., Oorschot, V.M., Martin, S., et al. (2008). PTRFCavin, a conserved cytoplasmic protein required for caveola formation and function. Cell 132, 113����� –���� 124. Parton, R.G. and Simons, K. (2007). The multiple faces of caveolae. Nat. Rev. Mol. Cell Biol. 8, 185–194. Pilch, P.F., and Liu, L. (2011). Fat caves: caveolae, lipid trafficking and lipid metabolism in adipocytes. Trends Endocrinol. Metab. 22, 318–324. Sinha B., Köster D., Ruez R., Gonnord P., Bastiani M., Abankwa D., Stan R.V., Butler-Browne G., Vedie B., Johannes L., et al. (2011). Cells respond to mechanical stress by rapid disassembly of caveolae. Cell 144, 402–413.
Integrin Signaling Laboratory, Vascular Biology and Inflammation Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain. *E-mail: [email protected]
Primer
The ESCRT machinery Oliver Schmidt and David Teis* The endosomal sorting complexes required for transport (ESCRT) assemble into a multisubunit machinery that performs a topologically unique membrane bending and scission reaction away from the cytoplasm. This evolutionarily highly conserved process is required for the multivesicular body (MVB) pathway, cytokinesis and HIV budding. The modular setup of the machinery with five distinct ESCRT complexes (ESCRT-0, -I, -II, -III and the Vps4 complex) that have a clear division of tasks — from interaction with ubiquitinated membrane proteins to membrane deformation and abscission — allows them to be flexibly integrated into these three very different biological processes (Figure 1). In the first of these processes, the MVB pathway delivers ubiquitinated membrane proteins and lipids into lysosomes for degradation. During MVB sorting the entire ESCRT machinery sequentially assembles on endosomes, where it generates MVB vesicles by budding the limiting endosomal membrane away from the cytoplasm. An ESCRT-mediated membrane scission step finally releases the mature MVB vesicle into the lumen of the organelle. Since this process is required for membrane protein turnover, it is critical for the regulation of cell surface receptor signaling in cells and during development. In the second process, at the end of cytokinesis, ESCRT complexes coordinate membrane abscission with microtubule disassembly at the midbody to physically separate the two daughter cells. Finally, in the third process ESCRT complexes are hijacked during HIV budding at the surface of infected host cells where they catalyze the scission of the membrane stalk that connects the budding virus with the host cell. Despite fundamental differences, all three processes require a topologically equivalent membrane budding and scission reaction — away from the cytoplasm — which is catalyzed by the coordinated action of the ESCRT