Caveolin
Encyclopedia
Caveolins are a family of integral membrane protein
s which are the principal components of caveolae
membranes and involved in receptor-independent endocytosis
. Caveolins may act as scaffolding proteins within caveolar membranes by compartmentalizing and concentrating signaling molecules. Various classes of signaling molecules, including G-protein subunits, receptor and non-receptor tyrosine kinase
s, endothelial nitric oxide synthase
(eNOS), and small GTPase
s, bind Cav-1 through its 'caveolin-scaffolding domain'.
The caveolin gene
family has three members in vertebrate
s: CAV1, CAV2, and CAV3, coding for the proteins caveolin-1, caveolin-2 and caveolin-3, respectively. All three members are membrane proteins with similar structure. Caveolin forms oligomers and associates with cholesterol and sphingolipids in certain areas of the cell membrane
, leading to the formation of caveolae
.
ic side of the membrane. There are two isoforms of caveolin-1: caveolin-1α and caveolin-1β, the latter lacking a part of the N-terminus.
Caveolins are found in the majority of adherent
, mammal
ian cells.
s of the plasma membrane, called caveolae. Oligomer
s of caveolin form the coat of these domains. Cells that lack caveolins also lack caveolae. Many functions are ascribed to these domains, ranging from endocytosis
and transcytosis
to signal transduction
.
Caveolin-1 has also been shown to play a role in the integrin
signaling. The tyrosine
phosphorylated
form of caveolin-1 colocalizes with focal adhesion
s, suggesting a role for caveolin-1 in migration
. Indeed, downregulation of caveolin-1 leads to less efficient migration in vitro
.
Genetically engineered
mice that lack caveolin-1 and caveolin-2 are viable and fertile, showing that neither the caveolins, nor caveolae are essential in embryonic development or reproduction of these animals. However, knock-out
animals do develop abnormal, hypertrophic lungs and cardiac myopathy, leading to a reduction in life span. Mice lacking caveolins also suffer from impaired angiogenic
responses as well as abnormal responses to vasoconstrictive stimuli. In zebrafish, lack of caveolins leads to embryonic lethal
ity, suggesting that higher vertebrate
s (as exemplified by mice) have developed compensation or redundancy for the functions of caveolins.
and oncogenesis. High expression
of caveolins leads to inhibition of cancer-related pathways, such as growth factor
signaling pathways
. However, certain cancer cells that express caveolins have been shown to be more aggressive and metastatic
, because of a potential for anchorage-independent growth.
.
).
Integral membrane protein
An integral membrane protein is a protein molecule that is permanently attached to the biological membrane. Proteins that cross the membrane are surrounded by "annular" lipids, which are defined as lipids that are in direct contact with a membrane protein...
s which are the principal components of caveolae
Caveolae
In biology, caveolae , which are a special type of lipid raft, are small invaginations of the plasma membrane in many vertebrate cell types, especially in endothelial cells and adipocytes....
membranes and involved in receptor-independent endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
. Caveolins may act as scaffolding proteins within caveolar membranes by compartmentalizing and concentrating signaling molecules. Various classes of signaling molecules, including G-protein subunits, receptor and non-receptor tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
s, endothelial nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
(eNOS), and small GTPase
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
s, bind Cav-1 through its 'caveolin-scaffolding domain'.
The caveolin gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
family has three members in vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s: CAV1, CAV2, and CAV3, coding for the proteins caveolin-1, caveolin-2 and caveolin-3, respectively. All three members are membrane proteins with similar structure. Caveolin forms oligomers and associates with cholesterol and sphingolipids in certain areas of the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
, leading to the formation of caveolae
Caveolae
In biology, caveolae , which are a special type of lipid raft, are small invaginations of the plasma membrane in many vertebrate cell types, especially in endothelial cells and adipocytes....
.
Structure and expression
The caveolins are similar in structure. They all form hairpin loops that are inserted into the cell membrane. Both the C-terminus and the N-terminus face the cytoplasmCytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic side of the membrane. There are two isoforms of caveolin-1: caveolin-1α and caveolin-1β, the latter lacking a part of the N-terminus.
Caveolins are found in the majority of adherent
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
, mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian cells.
- Caveolin-1 is most prominently expressed in endothelialEndotheliumThe endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, fibrous and adiposeAdipose tissueIn histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
tissue. - The expression pattern of caveolin-2 is similar to that of caveolin-1; it seems to be co-expressedSynexpressionSynexpression is a type of non-random eukaryotic gene organization. Genes in a synexpression group may not be physically linked, but they are involved in the same process and they are coordinately expressed. It is expected that genes that function in the same process be regulated coordinately...
with caveolin-1. - The expression of caveolin-3 is restricted to striated and smooth muscleMuscleMuscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
.
Function
The functions of caveolins are still under intensive investigation. They are best known for their role in the formation of 50 nanometer-sized invaginationInvagination
Invagination means to fold inward or to sheath. In biology, this can refer to a number of processes.* Invagination is the morphogenetic processes by which an embryo takes form, and is the initial step of gastrulation, the massive reorganization of the embryo from a simple spherical ball of cells,...
s of the plasma membrane, called caveolae. Oligomer
Oligomer
In chemistry, an oligomer is a molecule that consists of a few monomer units , in contrast to a polymer that, at least in principle, consists of an unlimited number of monomers. Dimers, trimers, and tetramers are oligomers. Many oils are oligomeric, such as liquid paraffin...
s of caveolin form the coat of these domains. Cells that lack caveolins also lack caveolae. Many functions are ascribed to these domains, ranging from endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
and transcytosis
Transcytosis
Transcytosis is the process by which various macromolecules are transported across the interior of a cell. Vesicles are employed to intake the macromolecules on one side of the cell, draw them across the cell, and eject them on the other side. While transcytosis is most commonly observed in cells...
to signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
.
Caveolin-1 has also been shown to play a role in the integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
signaling. The tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
phosphorylated
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
form of caveolin-1 colocalizes with focal adhesion
Focal adhesion
In cell biology, focal adhesions are specific types of large macromolecular assemblies through which both mechanical force and regulatory signals are transmitted. More precisely, they can be considered as sub-cellular macromolecules that mediate the regulatory effects In cell biology, focal...
s, suggesting a role for caveolin-1 in migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
. Indeed, downregulation of caveolin-1 leads to less efficient migration in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
.
Genetically engineered
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...
mice that lack caveolin-1 and caveolin-2 are viable and fertile, showing that neither the caveolins, nor caveolae are essential in embryonic development or reproduction of these animals. However, knock-out
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
animals do develop abnormal, hypertrophic lungs and cardiac myopathy, leading to a reduction in life span. Mice lacking caveolins also suffer from impaired angiogenic
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
responses as well as abnormal responses to vasoconstrictive stimuli. In zebrafish, lack of caveolins leads to embryonic lethal
Lethal
Lethal is an adjective meaning capable of causing death.Lethal may also refer to:* Lethal , an American heavy metal band* Leigh Matthews, Australian rules footballer nicknamed "Lethal" or "Lethal" Leigh...
ity, suggesting that higher vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s (as exemplified by mice) have developed compensation or redundancy for the functions of caveolins.
Cancer
Caveolins have a paradoxical role in the development of this disease. They have been implicated in both tumor suppressionTumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
and oncogenesis. High expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of caveolins leads to inhibition of cancer-related pathways, such as growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
signaling pathways
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
. However, certain cancer cells that express caveolins have been shown to be more aggressive and metastatic
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
, because of a potential for anchorage-independent growth.
Cardiovascular diseases
Caveolins are thought to play an important role during the development of atherosclerosis. Furthermore, caveolin-3 has been associated with Long QT syndromeLong QT syndrome
The long QT syndrome is a rare inborn heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsade de pointes . These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation...
.
Muscular dystrophy
Caveolin-3 has been implicated in the development of certain types of muscular dystrophy (Limb-girdle muscular dystrophyLimb-girdle muscular dystrophy
Limb-girdle muscular dystrophy or Erb's muscular dystrophy is an autosomal class of muscular dystrophy that is similar but distinct from Duchenne muscular dystrophy and Becker's muscular dystrophy...
).