Changes in expression patterns of intermediate filaments are often associated with cancer progression, in particular with phenotypes leading to increased cellular migration and invasion. In this review we will describe the role of vimentin intermediate filaments in cancer cell migration, cell adhesion structures, and metastasis formation.
Full Answer
What are intermediate filaments?
Intermediate filaments constitute a complex family of polypeptides that are classified into six groups differentially expressed in various tissues. Types I and II intermediate filament proteins, the cytokeratins, are found in epithelial cells. Type I corresponds to the acidic keratins and type II to the neutral basic keratins.
What is the function of interstitial fluid filaments in metastatic tumors?
First, as polymerized filaments, IF proteins provide mechanical elements that enable cells to invade and migrate through their surrounding tissues during initial stages of tumor metastasis.
What is the function of intermediate protofilaments?
This is made possible by extensive interactions between the constituent protofilaments of an intermediate filament, which enhance its resistance to compression, twisting, stretching and bending forces.
What are intermediate filaments in metazoans?
Intermediate filaments (IFs) are a diverse, integral, and ubiquitous component of the nuclear and cytoplasmic cytoskeleton in metazoans. More than 70 genes, partitioned in six major classes, encode IF-forming proteins and are regulated in a tissue-specific and differentiation-dependent fashion.
Why are intermediate filaments important?
The main function of intermediate filaments is to provide support and structure for cells. The intermediate filaments are a permanent part of the cytoskeleton and help provide structure for the cell. They are also essential in anchoring the cell to other cells, called cell cohesion, and to the extracellular matrix.
What are intermediate filaments associated with?
the cytoskeletonIn addition, intermediate filaments can associate not only with the plasma membrane but also with the other elements of the cytoskeleton, actin filaments and microtubules. Intermediate filaments thus provide a scaffold that integrates the components of the cytoskeleton and organizes the internal structure of the cell.
Which disorder is caused by abnormal intermediate filaments?
A common feature of many intermediate filament–related disorders, including skin disorders, liver disease, desmin myopathy, and Alexander disease, is the occurrence of cytoplasmic inclusion bodies.
What do intermediate filaments do in neurons?
Intermediate filaments (IFs) are one such cytoskeletal polymer and include different classes that are expressed in a variety of tissues. Neurofilaments (NFs) are a specific IF class expressed in neurons that provide structural support for the establishment of axon caliber in large-diameter myelinated axons (3, 4).
What diseases are associated with microfilaments?
These findings support the proposal that giant axonal neuropathy is a generalized disorder of cytoplasmic microfilaments and that segmental demyelination occurs concomitantly with axonal and Schwann cell disease.
What is the main function of intermediate filaments quizlet?
Intermediate filaments have great tensile strength, and their main function is to enable cells to withstand the mechanical stress that occurs when cells are stretched.
What disease or condition is associated with damage of the microtubules?
Reduced microtubule stability has been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and tauopathies like Progressive Supranuclear Palsy.
What diseases are caused by cytoskeleton malfunction?
Consequently, a variety of inherited diseases are accompanied by cytoskeletal malfunctions, including spastic paraplegias, spinocerebellar ataxias, and mental retardation.
What diseases affect the cytoskeleton?
Indeed, many diseases have now been associated with abnormalities in cytoskeletal and nucleoskeletal proteins, including several cardiovascular disease syndromes, neurodegeneration, cancer (invasion), liver cirrhosis, pulmonary fibrosis, and blistering skin diseases.
How do intermediate filaments maintain cell shape?
Microfilaments thicken the cortex around the inner edge of a cell; like rubber bands, they resist tension. Microtubules are found in the interior of the cell where they maintain cell shape by resisting compressive forces. Intermediate filaments are found throughout the cell and hold organelles in place.
What is an example of an intermediate filament?
The intermediate filaments comprise the major component of the cytoskeleton and consist of five major subgroups—vimentin, keratins, desmin, neurofilaments, and glial fibrillary acidic protein (GFAP)—and a small number of minor subgroups (e.g., nestin, peripherin).
Where do you find intermediate filaments?
Intermediate filaments are therefore found in particularly durable structures such as hair, scales and fingernails. The primary function of intermediate filaments is to create cell cohesion and prevent the acute fracture of epithelial cell sheets under tension.
How do intermediate filaments differ from microtubules?
Intermediate filaments differ from both microtubules and microfilaments in that reversible association and dissociation of intermediate filament dimers can occur all along the length of the filament, whereas association and dissociation of microtubules and microfilaments occur only at their ends.
How many nm are intermediate filaments?
Intermediate filaments are approximately 10 nm in diameter with wavy profiles in electron micrographs of thin sections of cells (see Fig. 35.1B) or after negative staining of isolated filaments (see Fig. 35.3B). In some cases, such as neurofilaments, parts of the head domains and most of the tail domains project radially from the filament core, forming a type of bottlebrush (see Fig. 35.3C ). The most carefully studied intermediate filaments are built from octameric complexes (ie, two laterally associated molecular dimers) that associate end to end to form protofibrils like the strands of a rope (see Fig. 35.3D). In cross section, a standard intermediate filament has up to 16 coiled-coils, but their exact internal arrangement is not known. Because the molecular dimers lack polarity, intermediate filaments are considered to be apolar (ie, both ends of the filament are equivalent; see Fig. 35.3D). This is a striking difference from actin filaments (see Fig. 33.8) and microtubules (see Fig. 34.4), which depend on their polarity for many functions, including the unidirectional motion of motor proteins. Furthermore, the number of protofilaments can vary along a single filament, making them much more heterogeneous than actin filaments or microtubules.
How do IFs assemble?
IFs assemble by entirely distinct mechanisms compared to the assembly of actin or tubulin. Unlike actin or tubulin polymers, IFs are symmetric in their longitudinal direction and the assembly of IFs does not require hydrolysis of nucleotides. The initial step in IF assembly is formation of parallel coiled-coil homodimer or heterodimer pairs of IF proteins, depending on the class of IF. The dimers then assemble head-to-head in a partly staggered lateral arrangement to form symmetric tetramers (Figure 4 ). Tetramers then assemble into an intermediate state called the unit length filament (ULF), 54 a structure that is observed during IF polymerization in vitro, that might relate to punctate IF structures termed squiggles 55 observed in cells, and that helps explain the kinetics of IF polymerization. 50,56 The ULF is thought to be a complex of eight roughly parallel IF tetramers bound in approximately the orientation that the tetramers will maintain in the mature filaments and with significant disorder at the ends.
What is intermediate filament turnover?
Intermediate filament turnover is a highly dynamic process required to maintain tissue integrity and is implicated in degenerative and regenerative processes. Despite these essential roles, little is known about the mechanisms that cause the degradation of intermediate filaments. Nevertheless, the last decade has seen the emergence of the ubiquitin proteasome system, in particular E3 ubiquitin ligases, as important regulators. Here, we will focus on the first identified factor controlling the degradation of the entire intermediate filament family, the gigaxonin-E3 ligase. We will present the scientific achievements and the methodologies to study gigaxonin and its crucial role in intermediate filament turnover.
How long does it take for an intermediate filament to exchange?
35.4). Nevertheless, intermediate filaments in some cells exchange their subunits within minutes to hours during interphase.
What is the IF of a metazoan?
Intermediate filaments (IFs) are a diverse, integral, and ubiquitous component of the nuclear and cytoplasmic cytoskeleton in metazoans. More than 70 genes, partitioned in six major classes, encode IF-forming proteins and are regulated in a tissue-specific and differentiation-dependent fashion.
What is the role of cytokeratins in epithelial cells?
Some intermediate filament types (e.g., cytokeratins) may strengthen epithelial cells against mechanical stress.
What is the primary function of intermediate filaments?
The primary function of intermediate filaments is to create cell cohesion and prevent the acute fracture of epithelial cell sheets under tension. This is made possible by extensive interactions between the constituent protofilaments of an intermediate filament, which enhance its resistance to compression, twisting, stretching and bending forces.
What are intermediate filaments found in?
Intermediate filaments are therefore found in particularly durable structures such as hair, scales and fingernails.
What are the two main classes of keratin proteins?
Keratin proteins comprise the two largest classes of intermediate filament proteins. Historically, the two types of keratin were grouped as acidic (type I) or basic (type II) according to the overall physical properties of their composite amino acids. Keratin proteins first assemble into dimers, with one acidic and one basic chain, then into protofilaments and finally into IFs. In 2006, a universal nomenclature for each of the then known keratin genes and proteins, which totaled 54 (28 type I and 26 type II), was established to achieve international consensus for their naming and classification [3].
What is the structure that anchors skin cells to the extracellular matrix?
The keratin filaments anchor the skin cells to the extracellular matrix (ECM) at their base and to adjacent cells at their sides, through structures called hemidesmosomes and desmosomes, respectively. As these skin cells die, the layer of dead cells form an essential barrier to water loss.
How many classes of proteins are in the cytoplasm?
These filaments, which extend throughout the cytoplasm and inner nuclear membrane are composed from a large family of proteins that can be broadly grouped into five classes.
Do intermediate filaments bind nucleotides?
actin filaments, microtubules), intermediate filaments lack polarity, are more stable and their constituent subunits do not bind nucleotides (such as ATP) (as reviewed in [2] ).
What are intermediate filaments? What are their functions?
Unlike actin and microtubule cytoskeletons, the intermediate filaments are composed of a wide variety of structurally related proteins showing distinct expression patterns in tissues and cell types. Changes in the expression patterns of intermediate filaments are often associated with cancer progression; in particular with phenotypes leading to increased cellular migration and invasion. In this review we will describe the role of vimentin intermediate filaments in cancer cell migration, cell adhesion structures, and metastasis formation. The potential for targeting vimentin in cancer treatment and the development of drugs targeting vimentin will be reviewed.
What is the role of vimentin in metastasis?
Having discussed the diverse regulation of vimentin and its involvement in migration and invasion, the following two studies underline the crucial role vimentin plays in metastasis formation. In a study by Liu et al., metastatic and parental non-metastatic cell lines of the same origin—oral squamous cell carcinoma—were compared and vimentin was identified as the protein with the most increased expression in the metastatic cell line relative to the parental one. They also showed, by immunohistochemical staining of oral squamous cell carcinoma samples, that a high amount of lymph node metastases correlated with high vimentin expression [ 17 ].
How is vimentin expressed?
Vimentin is expressed from early stages of embryonic development in highly plastic mesenchymal cells. During later development, it becomes excluded from keratin-expressing epithelia. Following the same paradigm, the oncogenic transformation of epithelial cells results in an upregulation of vimentin and subsequent loss of keratin [ 8 ]. As the first step of becoming migratory, cells undergo EMT, a switch from epithelial polarity to front–rear polarity and loosen cell–cell junctions. Indeed, vimentin is widely used as a canonical marker of EMT reprogramming, associated with the acquisition of a migratory and invasive tumor cell phenotype [ 4 ]. As such, vimentin is abundantly expressed in many tumor types (for review see [ 9 ]), where its expression correlates with their aggressiveness and poor clinical outcome. Over-expression of vimentin in epithelial cells has been shown to be sufficient for cells to adopt the elongated shape typical of mesenchymal cells. This is followed by the reorganization of the actin and microtubule cytoskeletons [ 10 ], the internalization of desmosomes [ 11 ], and the rearrangement of keratin IFs [ 12 ]. Conversely, downregulation of vimentin not only hampers the migration of a large variety of tumor cell lines [ 4] but also partially restores their epithelial phenotype [ 13 ].
Does vimentin affect EMT?
Due to its role in EMT, it is not surprising that vimentin plays a pivotal role in the ability of cells to invade their surrounding matrix. This is of particular interest in relation to cancer, where acquisition of a mot ile phenotype and invasi ve capacity leads to metastases—the main cause of death in cancer patients.