In cell biology, 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 (ECM) adhesion on cell 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 binding and clustering.
Structure and function
Focal adhesions 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 15 nm 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. Focal adhesions can contain over 100 different proteins, which suggests a considerable functional diversity. More than anchoring the cell, they function 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, in which white blood cells migrate along the connective endothelium following cellular signals to damaged biological tissue.
Connection between focal adhesions and proteins of the extracellular matrix generally involves integrins. Integrins bind to extra-cellular proteins via short amino acid sequences, such as the R-G-D sequence motif (found in proteins such as fibronectin, laminin, or vitronectin), or the DGEA and GFOGER motifs found in 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.
Adhesion dynamics with migrating cells
The dynamic assembly and disassembly of focal adhesions plays a central role in cell migration. 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: they consist of integrin, and some of the adapter proteins, such as talin and paxillin. 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. 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 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 myosin fibers could contribute to maturing the focal complexes. This gains further support from the fact that inhibition of myosin-generated forces leads to slow disassembly of focal adhesions, by changing the turnover kinetics of the focal adhesion proteins.
- Chen CS, Alonso JL, Ostuni E, Whitesides GM and Ingber DE, 2003. Cell shape provides global control of focal adhesion assembly. Biochemical and Biophysical Research Communications, 307(2):355–61.
- Zaidel-Bar R, Cohen M, Addadi L and Geiger B, 2004. Hierarchical assembly of cell matrix adhesion complexes. Biochemical Society Transactions, 32(3):416–20.
- Zamir E and Geiger B, 2001. Molecular complexity and dynamics of cell–matrix adhesions. Journal of Cell Science, 114(20):3583–90.
- Riveline D, Zamir E, Balaban NQ, Schwarz US, Ishizaki T, Narumiya S, Kam Z, Geiger B and Bershadsky AD, 2001. Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism. Journal of Cell Biology, 153(6):1175–86
- Huttenlocher A, Palecek SP, Lu Q, Zhang W, Mellgren RL, Lauffenburger DA, Ginsberg MH and Horwitz AF, 1997. Regulation of cell migration by the calcium-dependent protease calpain. Journal of Biological Chemistry, 272(52):32719-22.
- Wang Y, Botvinick EL, Zhao Y, Berns MW, Usami S, Tsien RY and Chien S., 2005. Visualizing the mechanical activation of Src. Nature, 434(7036):1040-5.
- Wolfenson, H., A. Bershadsky, Y. I. Henis, and B. Geiger. 2011. Actomyosin-generated tension controls the molecular kinetics of focal adhesions. J Cell Sci 124 (Pt 9):1425-32.
- MBInfo - Focal Adhesion
- MBInfo - Focal Adhesion Assembly
- MBInfo - Regulation of Focal Adhesion Assembly
- AdhesomeFAnetwork Database with all known focal adhesion proteins and their biochemical interactions
- Intercellular Connections
- Zaidel-Bar Cell Adhesion Lab