Trends in Cell Biology
ReviewProductive tension: force-sensing and homeostasis of cell–cell junctions
Section snippets
Cell–cell junctions and force
By definition, cell adhesion molecules resist force, both forces exerted upon cells by their environment and those exerted by cells upon the environment. For example, hemidesmosomal integrins mediate strong adhesion to the basal lamina and support epidermal integrity in the skin [1]; and by resisting cellular detachment from matrix, integrins allow contractile forces to productively drive cell migration [2]. In these examples, integrin adhesion resists disruptive external force and transmits
Contractile tension and junctional homeostasis
Cells are capable of generating both protrusive and contractile forces upon cell adhesions. Protrusion, driven notably by actin assembly, has been best analyzed during integrin-based cell locomotion, where it is implicated in extension of the leading edge of migrating cells [12]. The role of protrusive force at cell–cell junctions is less well understood, although the actin nucleator Arp2/3 is found at cadherin adhesions and contributes to efficient formation of cell–cell contacts [13].
Mechanosensing by cadherins
The symmetry of cell–cell junctions implies that contractile forces exerted on a junction within one cell will be experienced as external pulling forces by neighboring cells. Importantly, activation of Rho signaling in one cell of a pair caused junctional tensile forces to increase in both cells, strongly implying that its neighbor was able to sense, and actively respond to, the pulling force exerted upon it [22]. This indicates that junctions do not resist force passively, but instead are
Mechanosensitive signal transduction by cadherin adhesion systems
How then might cadherin receptors signal in response to mechanical stimuli? Several modes of signal transduction have been implicated in mechanotransduction [26], including stretch-sensitive ion channels and signal transduction pathways through intracellular second messengers. Many signaling pathways, including small GTPases, PI3-kinase and Src kinases, function at junctions and can be activated in response to cadherin ligation [36]. Whether any or all of these also participate in cadherin
The cytoskeletal response
The potential role of α-catenin emphasizes the importance of the cytoskeleton as an upstream element in cadherin-based mechanosensing. Downstream, cytoskeletal responses also appear to be amongst the earliest consequences of cadherin-dependent mechanotransduction (Figure 3). These include cellular stiffening, which requires both actin integrity and Myosin II [31] and cellular contractility itself [22]. This is consistent with evidence that cadherin adhesion itself can regulate many parameters
Concluding remarks
In summary, recent developments, especially in the past year, establish cadherin-based cell–cell junctions as sites where mechanical forces are sensed and elicit proportional cellular responses. Sensing the mechanical environment through integrins affects many cellular pathways, including regulation of cell growth [55] and cell fate [56]. It is possible that this will also pertain for cadherin-based mechanosensing, although these remain open possibilities. Nonetheless, current data establish
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