Focal adhesion
Encyclopedia
Cell biology
Cell biology is a scientific discipline that studies cells – their physiological properties, their structure, the organelles they contain, interactions with their environment, their life cycle, division and death. This is done both on a microscopic and molecular level...
, focal adhesions (also cell–matrix adhesions or FAs) 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 (e.g. cell anchorage) of extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
(ECM) adhesion on cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
behavior.
Focal adhesions serve as the mechanical linkages to the ECM, and as a biochemical signaling hub to concentrate and direct numerous signaling proteins at sites of 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....
binding and clustering.
Structure and function
Focal adhesions are large, dynamic protein complexes through which the cytoskeletonCytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
of a cell connects to the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
, or ECM. They are limited to clearly defined ranges of the cell, at which the plasma membrane closes to within 15nm of the ECM substrate. Focal adhesions are in a state of constant flux: proteins associate and disassociate with it continually as signals are transmitted to other parts of the cell, relating to anything from cell motility to cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
. Focal adhesions can contain over 100 different proteins, which suggests a considerable functional diversity. They actually serve for not only the anchorage of the cell, but can function beyond that as signal carriers (sensors), which inform the cell about the condition of the ECM and thus affect their behavior. In sessile cells, focal adhesions are quite stable under normal conditions, while in moving cells their stability is diminished: this is because in motile cells, focal adhesions are being constantly assembled and disassembled as the cell establishes new contacts at the leading edge, and breaks old contacts at the trailing edge of the cell. One example of their important role is in the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, in which white blood cells migrate along the connective endothelium
Endothelium
The 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...
following cellular signals to damaged biological tissue
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
.
Morphology
Connection between focal adhesions and proteins of the extracellular matrixExtracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
generally involves integrins. Integrins bind to extra-cellular proteins via short amino acid sequences, such as the R
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
-G
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
-D sequence motif
Sequence motif
In genetics, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and has, or is conjectured to have, a biological significance...
(found in proteins such as fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
, laminin
Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...
, or vitronectin
Vitronectin
Vitronectin also known as VTN is a protein that in humans is encoded by the VTN gene.The protein encoded by this gene is a member of the pexin family...
), or the DGEA and GFOGER motifs found in collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
. Integrins are heterodimers which are formed from one beta and one alpha subunit. These subunits are present in different forms, which differ in their specificity and affinity to the different ECM proteins. Within the cell, the intracellular domain of integrin binds to the cytoskeleton via adapter proteins such as talin, α-actinin, filamin
Filamin
Filamins are a class of proteins that hold two actin filaments at large angles.Types include:* FLNA* FLNB* FLNC...
and vinculin
Vinculin
In mammalian cells, vinculin is a membrane-cytoskeletal protein in focal adhesion plaques that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton...
. Many other intracellular signalling proteins, such as focal adhesion kinase, bind to and associate with this integrin-adapter protein–cytoskeleton complex, and this forms the basis of a focal adhesion.
Adhesion dynamics with migrating cells
The dynamic assembly and disassembly of focal adhesions plays a central role in cell migrationCell 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...
. During cell migration, both the composition and the morphology of the focal adhesion change. Initially, small (0.25μm²) focal adhesions called focal complexes (FXs) are formed at the leading edge of the cell in lamellipodia
Lamellipodia
The lamellipodium is a cytoskeletal protein actin projection on the mobile edge of the cell. It contains a quasi-two-dimensional actin mesh; the whole structure propels the cell across a substrate...
: they consist of integrin, and some of the adapter proteins, such as talin
Talin protein
Talin is a high-molecular-weight cytoskeletal protein concentrated at regions of cell–substratum contact and, in lymphocytes, at cell–cell contacts. Discovered in 1983 by Keith Burridge and colleagues, talin is a ubiquitous cytosolic protein that is found in high concentrations in focal adhesions...
and paxillin
Paxillin
Paxillin is a signal transduction adaptor protein discovered in 1990 in the laboratory of Keith Burridge and should not be confused with the neurotoxin paxilline. The C-terminal region of paxillin contains four LIM domains that target paxillin to focal adhesions, it is presumed through a direct...
. Many of these focal complexes fail to mature and are disassembled as the lamellipodia withdraw. However, some focal complexes mature into larger and stable focal adhesions, and recruit many more proteins such as zyxin
Zyxin
Zyxin is a protein that in humans is encoded by the ZYX gene.-Interactions:Zyxin has been shown to interact with ENAH, LASP1, LATS1, Actinin, alpha 1 and Vasodilator-stimulated phosphoprotein.-External links:* Info with links in the...
. Once in place, a focal adhesion remains stationary with respect to the extracellular matrix, and the cell uses this as an anchor on which it can push or pull itself over the ECM. As the cell progresses along its chosen path, a given focal adhesion moves closer and closer to the trailing edge of the cell. At the trailing edge of the cell the focal adhesion must be dissolved. The mechanism of this is poorly understood and is probably instigated by a variety of different methods depending on the circumstances of the cell. One possibility is that the calcium-dependent protease calpain
Calpain
A calpain is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS database...
is involved: it has been shown that the inhibition of calpain leads to the inhibition of focal adhesion-ECM separation. Focal adhesion components are amongst the known calpain substrates, and it is possible that calpain degrades these components to aid in focal adhesion disassembly
Natural biomechanical sensor
Extracellular mechanical forces, which are exerted through focal adhesions, can activate Src kinase and stimulate the growth of the adhesions. This indicates that focal adhesions may function as mechanical sensors, and suggests that force generated from myosinMyosin
Myosins comprise a family of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other eukaryotic motility processes. They are responsible for actin-based motility. The term was originally used to describe a group of similar...
fibers could contribute to maturing the focal complexes.
External links
- AdhesomeFAnetwork Database with all known focal adhesion proteins and their biochemical interactions
- Intercellular Connections
- Zaidel-Bar Cell Adhesion Lab