Focal adhesions are integrin-containing, multi-protein structures that form mechanical links between intracellular actin bundles and the extracellular matrix or substrate in many cell types . The formation and function of focal adhesions can be described over defined steps that include initiation, clustering, growth, maturation and disassembly. They are commonly found at the ventral surface of cells in 2-dimensional tissue culture and can be envisioned as the feet of the cell , which function as interactive information interfaces between cells and their environment.
Studies show that new adhesions are formed at the leading edge of migrating cells, grow in size and mature as the cells move over them . During cell migration and spreading, focal adhesions serve as holding points that suppress membrane contraction and promote protrusion at the leading edge (reviewed in ). In stationary cells, they serve as anchorage devices that maintain the cell morphology.
Focal adhesions (FAs) are highly dynamic structures that grow or shrink due to the turnover of their component proteins (commonly known as “plaque proteins”) in response to changing mechanical stresses (e.g. actomyosin-generated forces, external forces exerted by or through the surrounding matrix). While the adhesions originate at the cell periphery, they appear to move inward relative to the cell center as the cell migrates over it . However, the structures as such are largely stationary relative to the underlying substrate but for sliding and slowly changing position during disassembly and turnover respectively. Their growth correlates with relative movement, while the composition and organization depends on changes in their microenvironment, demonstrated both in vitro  and in vivo . Unlike podosomes, FAs are long-lived upon maturation.
The different stages of the focal adhesion lifecycle and corresponding force-dependent morphological changes are discussed in detail. Several components undergo turnover, such that early, nascent adhesions exhibit a high turnover rate and mature adhesions show increased stability.
Focal adhesions are consistently found at the end of stress fibers and are therefore highly integrated with the bulk of the cytoskeleton. Consequently, focal adhesions serve to transmit force, internally generated by the cytoskeletal network, to the ECM and vice versa via adhesion receptors . Adhesion assembly and maturation are highly dependent on the presence of force, which is believed to instigate structural rearrangements that in turn foster the recruitment of additional proteins (growth) and induce signaling cascades leading to actin polymerization (strengthening) (reviewed in ).
Actin polymerization and actomyosin contractility generate forces that affect mechanosensitive proteins in the actin linking module, the receptor module (e.g. integrins), the signaling module, and the actin polymerization module . This leads to the assembly and modification of actomyosin stress fibres  that ultimately result in global responses such as directional movement, cell growth, differentiation and survival . Thus, FAs can be generally described as mechanosensory machines that are able to integrate multiple spatiotemporal cues, transducing and propagating these signals into multiple pathways (reviewed in ) that affect critical decision-making process at the cellular level .
Focal adhesions have also been observed in physiologically relevant scenarios such as in endothelial cells on the rigid basal membrane of blood vessels, whose dynamics is modulated by shear-dependent matrix changes  and in Drosophila embryos,where FAs mediate surface-rigidity dependent development (reviewed in ). However, due to the challenge involved in visualization of FA dynamics in 3-dimensions , these are less well documented even when investigated using in vitro studies. From available data, it is known that FAs in 3-dimensions are generally much smaller and dynamic  while elongated ones are also seen . Future studies in this context will reveal potential adhesion-mediated cellular phenotypes and their role in physiological processes.
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- Abercrombie M, and Dunn GA. Adhesions of fibroblasts to substratum during contact inhibition observed by interference reflection microscopy. Exp. Cell Res. 1975; 92(1):57-62. [PMID: 1169157]
- Lloyd C. Hot foot. Nature 1980; 288(5786):13-4. [PMID: 7191947]
- Partridge MA, and Marcantonio EE. Initiation of attachment and generation of mature focal adhesions by integrin-containing filopodia in cell spreading. Mol. Biol. Cell 2006; 17(10):4237-48. [PMID: 16855018]
- Morgan MR, Humphries MJ, and Bass MD. Synergistic control of cell adhesion by integrins and syndecans. Nat. Rev. Mol. Cell Biol. 2007; 8(12):957-69. [PMID: 17971838]
- Ballestrem C, Hinz B, Imhof BA, and Wehrle-Haller B. Marching at the front and dragging behind: differential alphaVbeta3-integrin turnover regulates focal adhesion behavior. J. Cell Biol. 2001; 155(7):1319-32. [PMID: 11756480]
- Holt MR, Calle Y, Sutton DH, Critchley DR, Jones GE, and Dunn GA. Quantifying cell-matrix adhesion dynamics in living cells using interference reflection microscopy. J Microsc 2008; 232(1):73-81. [PMID: 19017203]
- Rid R, Schiefermeier N, Grigoriev I, Small JV, and Kaverina I. The last but not the least: the origin and significance of trailing adhesions in fibroblastic cells. Cell Motil. Cytoskeleton 2005; 61(3):161-71. [PMID: 15909298]
- Zamir E, Katz M, Posen Y, Erez N, Yamada KM, Katz BZ, Lin S, Lin DC, Bershadsky A, Kam Z, and Geiger B. Dynamics and segregation of cell-matrix adhesions in cultured fibroblasts. Nat. Cell Biol. 2000; 2(4):191-6. [PMID: 10783236]
- Smilenov LB, Mikhailov A, Pelham RJ, Marcantonio EE, and Gundersen GG. Focal adhesion motility revealed in stationary fibroblasts. Science 1999; 286(5442):1172-4. [PMID: 10550057]
- Pelham RJ, and Wang YL. Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Natl. Acad. Sci. U.S.A. 1997; 94(25):13661-5. [PMID: 9391082]
- Delon I, and Brown NH. The integrin adhesion complex changes its composition and function during morphogenesis of an epithelium. J. Cell. Sci. 2009; 122(Pt 23):4363-74. [PMID: 19903692]
- Wang N, and Suo Z. Long-distance propagation of forces in a cell. Biochem. Biophys. Res. Commun. 2005; 328(4):1133-8. [PMID: 15707995]
- Zaidel-Bar R, Cohen M, Addadi L, and Geiger B. Hierarchical assembly of cell-matrix adhesion complexes. Biochem. Soc. Trans. 2004; 32(Pt3):416-20. [PMID: 15157150]
- Gupton SL, Eisenmann K, Alberts AS, and Waterman-Storer CM. mDia2 regulates actin and focal adhesion dynamics and organization in the lamella for efficient epithelial cell migration. J. Cell. Sci. 2007; 120(Pt 19):3475-87. [PMID: 17855386]
- Hirata H, Tatsumi H, and Sokabe M. Mechanical forces facilitate actin polymerization at focal adhesions in a zyxin-dependent manner. J. Cell. Sci. 2008; 121(Pt 17):2795-804. [PMID: 18682496]
- Endlich N, Otey CA, Kriz W, and Endlich K. Movement of stress fibers away from focal adhesions identifies focal adhesions as sites of stress fiber assembly in stationary cells. Cell Motil. Cytoskeleton 2007; 64(12):966-76. [PMID: 17868136]
- Hotulainen P, and Lappalainen P. Stress fibers are generated by two distinct actin assembly mechanisms in motile cells. J. Cell Biol. 2006; 173(3):383-94. [PMID: 16651381]
- Assoian RK, and Klein EA. Growth control by intracellular tension and extracellular stiffness. Trends Cell Biol. 2008; 18(7):347-52. [PMID: 18514521]
- LaFlamme SE, Nieves B, Colello D, and Reverte CG. Integrins as regulators of the mitotic machinery. Curr. Opin. Cell Biol. 2008; 20(5):576-82. [PMID: 18621126]
- Legate KR, Wickström SA, and Fässler R. Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev. 2009; 23(4):397-418. [PMID: 19240129]
- Reddig PJ, and Juliano RL. Clinging to life: cell to matrix adhesion and cell survival. Cancer Metastasis Rev. 2005; 24(3):425-39. [PMID: 16258730]
- Niediek V, Born S, Hampe N, Kirchgessner N, Merkel R, and Hoffmann B. Cyclic stretch induces reorientation of cells in a Src family kinase- and p130Cas-dependent manner. Eur. J. Cell Biol. 2011; 91(2):118-28. [PMID: 22178114]
- Geiger B, and Yamada KM. Molecular architecture and function of matrix adhesions. Cold Spring Harb Perspect Biol 2011; 3(5). [PMID: 21441590]
- Orr AW, Sanders JM, Bevard M, Coleman E, Sarembock IJ, and Schwartz MA. The subendothelial extracellular matrix modulates NF-kappaB activation by flow: a potential role in atherosclerosis. J. Cell Biol. 2005; 169(1):191-202. [PMID: 15809308]
- Wallace CS, Strike SA, and Truskey GA. Smooth muscle cell rigidity and extracellular matrix organization influence endothelial cell spreading and adhesion formation in coculture. Am. J. Physiol. Heart Circ. Physiol. 2007; 293(3):H1978-86. [PMID: 17644568]
- Ngu H, Feng Y, Lu L, Oswald SJ, Longmore GD, and Yin FC. Effect of focal adhesion proteins on endothelial cell adhesion, motility and orientation response to cyclic strain. Ann Biomed Eng 2009; 38(1):208-22. [PMID: 19856213]
- Brown NH, Gregory SL, and Martin-Bermudo MD. Integrins as mediators of morphogenesis in Drosophila. Dev. Biol. 2000; 223(1):1-16. [PMID: 10864456]
- Delon I, and Brown NH. Integrins and the actin cytoskeleton. Curr. Opin. Cell Biol. 2006; 19(1):43-50. [PMID: 17184985]
- Fraley SI, Feng Y, Krishnamurthy R, Kim D, Celedon A, Longmore GD, and Wirtz D. A distinctive role for focal adhesion proteins in three-dimensional cell motility. Nat. Cell Biol. 2010; 12(6):598-604. [PMID: 20473295]
- Kubow KE, and Horwitz AR. Reducing background fluorescence reveals adhesions in 3D matrices. Nat. Cell Biol. 2011; 13(1):3-5; author reply 5-7. [PMID: 21173800]
- Deakin NO, and Turner CE. Distinct roles for paxillin and Hic-5 in regulating breast cancer cell morphology, invasion, and metastasis. Mol. Biol. Cell 2011; 22(3):327-41. [PMID: 21148292]
- Hakkinen KM, Harunaga JS, Doyle AD, and Yamada KM. Direct comparisons of the morphology, migration, cell adhesions, and actin cytoskeleton of fibroblasts in four different three-dimensional extracellular matrices. Tissue Eng Part A 2010; 17(5-6):713-24. [PMID: 20929283]
- Cukierman E, Pankov R, Stevens DR, and Yamada KM. Taking cell-matrix adhesions to the third dimension. Science 2001; 294(5547):1708-12. [PMID: 11721053]