in Undergraduate Research - Issue 1
Role of Caveolae and the Caveolins in Mammalian Physiology
Dr. Babak Razani and Dr. Michael Lisanti
Albert Einstein College of Medicine
Dept. of Molecular Pharmacology
Caveolae are 50-100 nm invaginations of the plasma membrane that have
captured the interest of scientists for many decades. However, the wide-ranging
and physiologically important roles of these curious structures have
only recently been addressed. Among the important milestones in the
understanding of caveolae is the discovery of a family of proteins that
are intimately involved in caveolar function (the caveolins). It has
become clear now that caveolae and their caveolin "marker proteins"
are involved in a variety of cellular processes including endocytosis,
lipid homeostasis, signal transduction, and tumorigenesis. In this review,
we will highlight the current view of caveolae in cell biology and discuss
the relevance of these structures to mammalian physiology.
Examination of a cell at the ultrastructural level reveals numerous
intricate components that contribute to its appropriate function. Since
the advent of electron microscopy in the 1940s and 50s, structures such
as the mitochondrion, endoplasmic reticulum, golgi apparatus, and clathrin-coated
endocytic vesicles were discovered for the first time and their distinct
functions in cells speculated upon. In this same period, another cellular
entity, a 50-100 nm vesicle that was found to be either directly invaginated
from or in close proximity to the plasma membrane was also described
(Figure 1A). Based on this conspicuous "cave-like" morphology
at the membrane, these structures were named "caveolae"
and were added to the growing list of newly discovered cellular organelles
(Palade, 1953; Yamada, 1955).
In the ensuing decades and with the incipience of cellular and molecular
biology, research on many of these cellular organelles led to a precise
understanding of their function (e.g. implication of mitochondria in
ATP production, the ER/golgi in protein synthesis and sorting, and clathrin-coated
pits in endocytosis). Unfortunately, due to difficulty in characterizing
their biochemical and molecular nature, caveolae remained enigmatic
structures with no definitive function(s). Based on their structural
resemblance to clathrin-coated vesicles and their seemingly dynamic
movement between the plasma membrane and intracellular compartments,
caveolae were initially thought to serve solely an endocytic role akin
to clathrin-coated pits (Palade, 1953; Simionescu et al., 1975).
Now, based on work in the last decade, caveolae are being recognized
as rather complex organelles with important roles not only in endocytosis
but also lipid homeostasis, signal transduction, and tumorigenesis.
In addition, they seem to play very specific roles in distinct cell
types, making these structures one of the most interesting and multi-functional
entities in cells. In this review, we will discuss the salient features
of these structures and the current understanding of their function
in mammalian organisms.
1. Caveolae, a unique "cellular organelle" with a unique
Electron micrograph of an endothelial cell showing caveolae, 50-100
nm structures that are either direct invaginations or in close proximity
to the plasma membrane. Caveolae are estimated to make-up an estimated
30-70% of the plasma membrane area in certain cells such as endothelial
cells, adipocytes, or Type I pneumocytes .
B) Diagram comparing the biochemical composition of lipid
rafts and caveolae (adapted from (Galbiati et al., 2001)). Lipid
rafts form via a coalescence of cholesterol and sphingolipids; as
a result, these microdomains have vastly different biochemical properties
than the bulk phospholipids bilayer. Caveolae are generally considered
to be "invaginated" lipid rafts primarily due to an enrichment
in a family or proteins known as the caveolins. Here, the caveolin
oligomer is depicted as a dimer for simplicity.
nature of caveolae: introduction to the caveolins
Based on numerous biophysical and biochemical analyses of plasma membranes,
it is now known that the traditional view of a lipid bilayer as a
"fluid mosaic" is not entirely accurate (Brown and London,
1998). Although a membrane solely made of phospholipids does indeed
act as a fluid-mosaic, cell membranes which are also composed of cholesterol,
sphingolipids, and various lipid-modified and transmembrane proteins,
behave differently (Brown and London, 1998). In cell membranes, depending
on the local concentration of cholesterol, sphingolipids, and some
phospholipids, more rigid patches of membrane can form. Floating among
the bulk phospholipids bilayer, these biochemically distinct patches
of membrane have now been termed lipid rafts, the study
of which is an active area of research (see (Simons and Toomre, 2000)
for review) (Figure 1B).
Interestingly, research in the past decade has shown that caveolae
are biochemically indistinguishable from lipid rafts and are composed
of a similar local enrichment of cholesterol and sphingolipids (Simons
and Toomre, 2000) (Figure 1B). The primary difference between these
two entities is the invaginated, vesicular morphology of caveolae.
This difference arises due to the presence of a set of proteins unique
to caveolae but absent from lipid rafts, the caveolins.
The caveolin protein family is composed of three distinct proteins,
caveolin-1, -2, and -3 (Cav-1, -2,-3) (Glenney, 1992; Rothberg et
al., 1992; Scherer et al., 1996; Tang et al., 1996). Not surprisingly,
these proteins are expressed in tissues with a high abundance in caveolae;
Cav-1 and -2 are co-expressed in many cell types with especially high
levels in endothelial cells, adipocytes, and type I pneumocytes, while
Cav-3 is exclusively expressed in skeletal and cardiac muscle cells
(Scherer et al., 1994; Scherer et al., 1996; Tang et al., 1996). The
main exception is smooth muscle cells, where intriguingly all three
proteins are expressed (Tang et al., 1996).
The caveolin proteins have several properties which are important
not only for selective localization to caveolae but also for driving
the invagination of these structures. Cav-1 has been shown to have
high binding affinity for cholesterol and sphingolipids (Fra et al.,
1995; Murata et al., 1995; Thiele et al., 2000). This property, along
with three carboxy-terminal lipid-modifications (palmitoylations),
stabilizes and targets Cav-1 to caveolae (Dietzen et al., 1995; Monier
et al., 1996). The caveolins can also oligomerize into a complex of
14-16 subunits and thereafter form even larger mega-complexes by oligomer-oligomer
interactions (Monier et al., 1995; Sargiacomo et al., 1995; Song et
al., 1997). Although it is still largely speculative, it is thought
that the high affinity for cholesterol, the oligomerization, and the
oligomer-oligomer interactions can together form an environment in
the lipid bilayer conducive for the creation of 50-100 nm caveolar
and endocytic processes
The observation that caveolae can exist as invaginations of the plasma
membrane, as completely enclosed vesicles, or as aggregates of several
vesicles, led investigators to infer that these structures were conduits
for the endocytosis of macromolecules (Simionescu et al., 1975). Indeed,
tracer studies and high resolution electron microscopy has revealed
that cells predominantly use caveolae for the selective uptake of
molecules as small as folate to full size proteins such as albumin
and alkaline phosphatase (Anderson et al., 1992; Parton et al., 1994;
Predescu et al., 1997; Schnitzer et al., 1994) (Figure 2A). In endothelial
cells, the uptake of such molecules is complicated by the fact that
the endocytosed caveolae seem to migrate from the luminal side to
the abluminal side, thereby transferring specific serum molecules
to the underlying tissue (a process referred to as transcytosis)
(Predescu et al., 1997; Simionescu et al., 1975) (Figure 2A).
Interestingly, several studies have also shown that caveolae-mediated
uptake of materials is not limited to macromolecules; in certain cell-types,
viruses (e.g. simian virus 40) and even entire bacteria (e.g. specific
strains of E. Coli) are engulfed and transferred to intracellular
compartments in a caveolae-dependant fashion (Anderson et al., 1996;
Montesano et al., 1982; Shin et al., 2000). Although the molecular
mechanism for these endocytic events are not completely understood,
there are indications that the same machinery operating traditional
vesicle budding and fusion processes is functional in this setting
(Henley et al., 1998; Oh et al., 1998; Schnitzer et al., 1995). Thus,
the cell utilizes similar endocytic techniques to differentially traffic
2. Proposed functions of caveolae and the caveolins (adapted from
(Razani and Lisanti, 2001))
A) Certain molecules have been shown to be predominantly
endocytosed via caveolae and not clathrin-coated vesicles. The
fate the cargo in a fully invaginated caveola is not entirely
understood; however, there is evidence to suggest that depending
on the cell type, caveolae can deliver their contents to the ER/golgi
compartments or to the abluminal side of a cell.
B) Intracellular cholesterol is thought to be transported
to plasma membrane caveolae via a golgi-independent caveolin-mediated
route. Caveolae then can serve as "relay stations" to
deliver the membrane cholesterol to the bulk plasma membrane or
to cholesterol-transporters such as HDL particles.
C) Caveolae are now thought to act as signalosomes, or
entities in which signal transduction events can take place efficiently.
A higher level of regulatory complexity is provided by the caveolins
where signaling molecules can be bound until extracellular ligands
relieve them of inhibition. Here, the dynamic regulation of a
receptor tyrosine kinase (e.g. EGF receptor) and a lipid-modified
kinase (e.g. the src-tyrosine kinase) in caveolae are shown.
and cholesterol homeostasis
Caveolae are highly enriched in cholesterol as compared to the bulk
plasma membrane and Cav-1 binds this cholesterol with high affinity
(estimated at 1 cholesterol molecule per caveolin molecule) (Murata
et al., 1995; Thiele et al., 2000). Furthermore, pharmacological depletion
of plasma membrane cholesterol leads to a loss of morphologically
identifiable caveolae (i.e. "flattening" against the membrane)
and dissipation of the caveolin-matrix (Rothberg et al., 1992). Due
to these observations, it was suggested that caveolae and caveolins
are involved in maintaining intracellular cholesterol balance; indeed,
there is evidence for such a role.
Cellular cholesterol is derived from two main sources, de novo production
or extracellular uptake (via low density lipoprotein (LDL) receptors
localized in clathrin-coated vesicles) (Fielding and Fielding, 1997;
Simons and Ikonen, 2000) (Figure 2B). Once inside, the caveolins seem
to function as intracellular escorts for the transport of this cholesterol
from the endoplasmic reticulum to plasma membrane caveolae (Smart
et al., 1996; Uittenbogaard et al., 1998) (Figure 2B). Upon delivery,
this cholesterol has three fates: (1) to remain as a component of
caveolar cholesterol, aiding in the invagination and proper function
of these structures, (2) to be siphoned into the bulk plasma membrane,
repleting the lipid bilayer with appropriate amounts of cholesterol,
or (3) to be effluxed to serum cholesterol-transporting units like
high density lipoproteins (HDLs) (Fielding et al., 1999; Fielding
and Fielding, 1995; Smart et al., 1996) (Figure 2B). In essence, the
caveolins deliver intracellular cholesterol to a "relay station"
wherein the overall fate of cholesterol is determined; the cholesterol
needs of the cell are met and excesses are effluxed.
and signal transduction
The intimate relationship between caveolae and their protein components,
the caveolins, is obvious. An important question that remained was
whether other plasma membrane proteins can also preferentially localize
to these structures. This issue has been addressed using biochemical
purification, wherein caveolae can be selectively isolated from other
cellular constituents and their protein components analyzed (Lisanti
et al., 1994; Sargiacomo et al., 1993).
Caveolae are highly enriched in numerous membrane-bound proteins,
especially signaling proteins with lipid-modified groups (e.g. H-ras,
src-family tyrosine kinases, heterotrimeric G-proteins, eNOS, etc)
(Lisanti et al., 1994; Smart et al., 1999) (Figure 2C). Furthermore,
it appears that the caveolins are not innocent by-standers in this
environment and can bind and functionally regulate (mostly inhibit)
several of these caveolae-localized molecules (Feron et al., 1996;
Garcia-Cardena et al., 1996; Li et al., 1996; Li et al., 1995; Song
et al., 1996; Song et al., 1997) (Figure 2C). The caveolins possess
a 20 amino acid juxtamembrane domain (now appropriately called the
scaffolding domain) that mediates this functional binding (Okamoto
et al., 1998).
The predilection for signaling proteins to localize to caveolae and
the capacity for the caveolins to regulate their function has led
some to refer to caveolae as "signalosomes" (or bodies where
signal transduction events and cross-talk between different signaling
pathways can take place efficiently and in regulated fashion) (Lisanti
et al., 1994; Smart et al., 1999). This aspect of caveolae is currently
an active area of research since it brings together the interests
of investigators conducting research in seemingly disparate areas.
An interesting corollary to the above-mentioned signalosome concept
arises during tumorigenesis. Several of the proteins localized to
caveolae and inhibited by Cav-1 (namely EGFR, Her2/Neu, and PDGF receptor
tyrosine kinases, components of the Ras/p42/44 MAP kinase cascade,
and members of the PI-3-kinase cascade) ) (Couet et al., 1997; Engelman
et al., 1998; Liu et al., 1996; Yamamoto et al., 1999; Zundel et al.,
2000) are extremely important in pro-proliferative/anti-apoptotic
signaling. If functionally deranged, such proteins can result in cells
with hyperactive cell cycles and eventually tumor formation. In this
regard, caveolae and Cav-1 might be expected to be essential members
of the cellular tumor suppressor repertoire, acting to dampen the
action of tumorigenic signals.
Interestingly, it has been observed that caveolae are absent or reduced
in number and Cav-1 is transcriptionally down-regulated in numerous
cancers (both cell-lines and in situ carcinomas) (Engelman et al.,
1998; Koleske et al., 1995; Lee et al., 1998; Razani et al., 2000).
In addition, both human CAV-1 and -2 genes map to 7q31.1 (a region
of the chromosome found to be frequently deleted in several epithelial
cancers - e.g. breast, lung, renal, and ovary) (Kerr et al., 1996;
Shridhar et al., 1997; Zenklusen et al., 1994). Such observations
provide strong evidence for a caveolin-mediated tumor surveillance
process and give impetus for researchers to include the caveolins
as important factors in the diagnosis and treatment of cancer.
In vivo relevance of
caveolar function in mammalian physiology
The current understanding of caveolae and caveolin function is based
on research conducted either in vitro (biochemical or cell culture
systems) or in vivo (namely, morphological assessment by electron
microscopy). Although such techniques are useful in providing insights
into the functions of these structures, a complete understanding of
their physiological relevance can only be attained by experiments
conducted in the whole organism (e.g. creation of transgenic or knockout
mice, wherein the expression of one or more caveolin proteins is perturbed).
Indeed, in the past year, several groups have reported on the phenotypes
of mice with targeted disruptions of the CAV-1, -2, and -3 loci, thereby
providing the first rigorous assessment of caveolae function in vivo
(Drab et al., 2001; Galbiati et al., 2001; Hagiwara et al., 2000;
Razani et al., 2002; Razani et al., 2001; Razani et al., 2002). Mice
deficient in Cav-1 or Cav-3 (but not Cav-2) lack morphologically identifiable
caveolae in tissues expressing those genes. This observation is important
in that it directly proves the importance of caveolin expression in
caveolae formation and provides a tool for the study of not only caveolins
but caveolae in a mammalian organism.
The phenotypes of Cav-1
null mice (Drab et al., 2001; Razani et al., 2002; Razani et al.,
- Loss of caveolae in cells
expressing Cav-1 (e.g. endothelial, epithelial, adipose cells)
- Dramatic reduction of
Cav-2 protein levels due to destabilization and degradation via the
proteosomal pathway - thus, Cav-1 null mice are in essence Cav-1 and
- Histologically abnormal
lungs - thickened alveolar septa due to endothelial cell hyper-proliferation
and increased deposition of extracellular matrix
- Cell cycle defects - fibroblasts
derived from these mice have increased S-phase fractions and proliferate
faster than their wild-type counterparts
- Defects in vasoregulation
- the aortas from these mice are hyper-responsive to vasodilatory
stimuli due to hyper-activation of the eNOS signaling cascade
- Defects in endocytosis
- the uptake of albumin by endothelial cells is drastically reduced
in these mice
- Defects in lipid homeostasis
- these mice are resistant to diet-induced obesity and have histological
abnormal adiposities with age. These mice are also hypertriglyceridemic
with a reduced capacity to clear serum lipids, a condition likely
related to the aberrant adipose function.
The phenotypes of Cav-2
null mice (Razani et al., 2002):
- Normal or slightly reduced
Cav-1 expression with no loss of caveolae - thus, these mice are extremely
useful for comparison with Cav-1 deficient mice in that they selectively
- Histologically abnormal
lungs - in fact, the lung defects in these mice are indistinguishable
from Cav-1 null mice, thereby for the first time demonstrating an
important role for Cav-2 independent of Cav-1
- Unperturbed vasoregulation
and lipid homeostasis - these observations were important in establishing
that Cav-1 and Cav-2 have distinct and non-overlapping roles in physiology
The phenotypes of Cav-3
null mice (Galbiati et al., 2001; Hagiwara et al., 2000):
- Loss of caveolae in cells
selectively expressing Cav-3 (i.e. skeletal and cardiac muscle)
- Histologically abnormal
skeletal muscle with necrotic muscle fibers and centralized nuclei
- indeed, this mild muscular dystrophy phenotype recapitulates the
pathology seen in a previously described group of patients with Limb-girdle
muscular dystrophy (type 1C) in which mutations in the CAV-3 gene
were found (Minetti et al., 1998).
- Defects in the myocyte
T-tubule network with irregularly-oriented tubules
As can be seen from the above description, the initial characterization
of these mice has provided a wealth of information ranging from the
predicted (e.g. involvement in endocytic processes and signaling cascades
such as eNOS) to the completely unexpected (e.g. lung hypercellularity
and defects in triglyceride rather than cholesterol homeostasis).
The study of caveolae and their marker proteins, the caveolins, has
been an exciting yet challenging endeavor. The ever-changing view of
their function in mammalian physiology is in part due to the difficulty
of working with such membrane domains and a lack of different but complementary
tools available for rigorous analyses. Caveolae and the caveolins have
thus far been implicated in endocytosis, lipid homeostasis, signal transduction,
and tumorigenesis. Now, with the availability of caveolin-deficient
mice, biochemical, cell culture, and genetic approaches can finally
be intermeshed to provide a more complete picture of caveolar function
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