Focal adhesions (FAs)

Contributor: Prof Alexander Bershadsky, MBI, Singapore                                     Updated on: January 2012
Reviewer: Asst Prof Pakorn Tony Kanchanawong, MBI, Singapore

It should be noted that the role of focal adhesions in mechanosensing is a relatively new field, with conclusive, experimental evidence still building. Consequently, consensus on a defined model in this context has yet to be reached. We therefore discuss models and ideas that are currently still under investigation, but in general have been posited by more than one major group in the field. Debates and controversies are highlighted where applicable.

Focal adhesions (FAs): Basic Description

Focal adhesions are integrin-containing, multiprotein structures that form mechanical links between intracellular actin bundles and the extracellular substrate in many cell types [1]. They are commonly found at the ventral surface of cells in 2- dimensional tissue culture and can be envisioned as the cell’s feet [2], 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 [3]. During cell migration and spreading, FAs serve as holding points that suppress membrane contraction and promote protrusion at the leading edge (reviewed in [4], see video below). In stationary cells, they serve as anchorage devices that maintain the cell morphology.


Video: Focal adhesions are essential for cell spreading. Upon neuregulin treatment, cell-surface receptors Erb B3/B4 induce lamellipodia formation, most probably through activation of the Rac-WAVE-Arp2/3 pathway. During lamellipodial protrusion, numerous focal adhesions form along the cell periphery and can be visualized as fluorescent spots (GFP-VASP). [Source: Leticia Carramusa, Weizmann Institute of Science, Israel. Permission: Alexander Bershadsky, Mechanobiology Institute, Singapore.]



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) [5, 6, 7, 8]. While the adhesions originate at the cell periphery, they appear to move inward relative to the cell center as the cell migrates over it [9]. 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 [10] and in vivo [11]. Unlike podosomes FAs are long-lived upon maturation.

The different stages of the FA lifecycle and corresponding force-dependent morphological changes are discussed in detail in Steps in formation. Several components undergo turnover, such that nascent adhesions exhibit a high turnover rate and mature adhesions show increased stability. For details see FA dynamics. 


FAs are consistently found at the end of stress fibres and are therefore highly integrated with the bulk of the cytoskeleton. Consequently, FAs serve to transmit force, internally generated by the cytoskeletal network, to the ECM and vice versa via adhesion receptors [12]. Adhesion assembly and maturation are highly dependent on the presence of force (see video here), 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 [13]). FA architecture, hypothetical models for the mechanism of force-sensing by FAs and the dependency of FAs on different factors are described in linked pages.

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 [14, 15]. This leads to the assembly and modification of actomyosin stress fibres [16, 17] that ultimately result in global responses such as directional movement, cell growth, differentiation and survival [18, 19, 20, 21, 22]. 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 [23]) that affect critical decision-making process at the cellular level [18, 19, 20, 21, 22].

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 [24, 25, 26] and in Drosophila eggs, where FAs mediate surface-rigidity dependent development (reviewed in [27, 28]). However, due to challenges in visualization of FA dynamics in 3-dimension [29, 30], these are less well documented even in in vitro studies. From available data, it is known that FAs in 3-dimensions are generally much smaller and dynamic [30, 31, 32, 33] while elongated ones are also seen [33]. Future studies in this context will reveal potential adhesion-mediated cellular phenotypes and their role in physiological processes.

Key Unanswered Questions
1. How do FAs nucleate polymerization of actin filaments?
2. What determines whether the adhesion strengthens under force or disassembles?
3. Do different adhesions generate similar or distinct signals?
4. How do FAs interact with cell-cell adhesions and the nucleus to bring about global changes?
5. How similar or different are FAs in three-dimensions compared to those widely studied in two-dimensional culture?

References

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