Focal adhesion

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Immunofluorescence coloration of actin (green) and the focal adhesion protein vinculin (red) in a fibroblast. Focal adhesion are visible as red dots at the end of the green bundles.

In cell biology, 'Focal Adhesions' (aka 'Cell-Matrix adhesions', or just 'FAs') are specific types of large macromolecular assemblies through which both mechanical force and regulatory signals are transmitted. More precisely, FAs can be considered as sub-cellular macromolecules that mediate the regulatory effects (e.g. cell anchorage) of extracellular matrix (ECM) adhesion on cell behavior.^[1]

FAs serve as the mechanical linkages to the ECM, and as a biochemical signalling hub to concentrate and direct numerous signaling proteins at sites of integrin binding and clustering.

Focal Adhesions are complicated macromolecular assemblies

[edit] In depth

FA are large, dynamic protein complexes through which the cytoskeleton of a cell connects to the extracellular matrix, or ECM. They are limited to clearly defined ranges of the cell, at which the plasma membrane closes to within to 15nm of the ECM substrate.^[2] 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. FAs can contain over 100 different proteins, which suggests a considerable functional diversity.^[3] 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.^[4] In sessile cells, focal adhesions are quite stable under normal conditions, while moving cells their stability is diminished: this is because in motile cells, FAs 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, in which white blood cells migrate along the connective endothelium following cellular signals and to damaged biological tissue.

[edit] Focal Adhesion Morphology

The morphology of focal adhesion, particularly the connection to proteins of the ECM, generally involves the integral membrane protein Integrin. Integrin binds to extra-cellular proteins via a specific amino acid sequence, known as R-G-D motifs. (These motifs are found in proteins such as Fibronectin, Laminin, Vitronectin or collagen.) 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 and Vinculin. 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.

[edit] Adhesion dynamics with migrating cells

The dynamic assembly and disassembly of FAs plays a central role in cell migration. During cell migration, both the composition and the morphology of the FA changes. Initially, small (0.25μm²) FAs called "focal complexes" are formed at the leading edge of the cell in Lamellipodia : they consist of integrin, and some of the adapter proteins, such as Talin and Paxilin. Many of these focal complexes fail to mature and are disassembled as the lamellipodia withdraws. However, some focal complexes mature into larger and stable FAs, and recruit many more proteins such as Zyxin. 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 FA, moves closer and closer to the trailing edge of the cell. At the trailing edge of the cell the FA must be dissolved. The mechanism of this is poorly understood and is probably instigated by a variety of different methods depending of the circumstances of the cell. One possibility is that the Calcium dependent protease Calpain is involved: it has been shown that the inhibition of Calpain leads to the inhibition of FA-ECM separation. Focal adhesion components are amongst the known calpain substrates, and it is possible that Calpain degrades these components to aid in the FA disassembly^[5]

[edit] Natural biomechanical sensor

Extracellular Mechanical forces, which are exerted through FAs, can activate Src kinase and stimulate the growth of the adhesions. This indicates that FAs may function as mechaniscal sensors , and suggests that force generated from myosin fibers could contribute to maturing the focal complexes.^[6]

[edit] See also

• Actin
• Fibronectin
• Integrin
• Vinculin
• TES

[edit] References

[edit] External links

• Intercellular Connections