What processes drive focal adhesion growth?2018-02-05T16:55:55+08:30

How do nascent adhesions grow into mature focal adhesions?

Nascent adhesions undergo a transient phase of rapid assembly and disassembly through which a fraction of adhesions survive to evolve into more stable and larger focal adhesions. Typically adhesions during this time vary in size between 0.5 to 1µm, with an average lifetime of ~80 s [1]. They are largely found at the boundary between the lamellum and lamellipodial ruffles [2][3]. These structures help strengthen the physical linkage between the extracellular matrix (ECM) and the loosely packed actin network. Moreover, they transmit mechanical and chemical signals via mechanosensitive components that can act as both scaffolds and signaling molecules.

In the absence of or under low actomyosin contractile forces, adhesion components start dispersing. In such scenarios, the unidirectional shear force (not shown) from the actin retrograde flow may also aid dissociation. B. Under substantial pulling ‘tension’ from actomyosin contractions, aggregation of adhesion components occurs in the direction of pulling. The protein complexes of adhesions (cell’s feet) can be considered as elastic units that expand under force to accommodate new components towards one end (heel). The other end of the adhesion structure that faces the actin retrograde movement is termed ‘toe’. Adapted from [18].

During this transient phase, whether the adhesions grow or disassemble is thought to be dependent on the mechanical forces they experience as a result of substrate stiffness [4]. The balance between the ‘push’ of actin polymerization and the ‘pull’ of the myosin contraction contribute to traction forces upon the substrate and aid in the generation of propulsive forces in the order of 5 nN/µm2 at the leading edge of motile cells [5]. These propulsive forces are greatest during this transient phase and diminish as the adhesions grow [6]. The mechanical forces (stresses) endured at sites of adhesion are believed to result from the following processes:

  1. The retrograde flow of actin in lamellipodial ruffles [7][8]

  2. The remodeling of the dendritic lamellipodial actin networks into linear filaments array of the stress fibers in the vicinity of adhesions at the lamellipodium-lamellum interface [7][9][10][11]

  3. The bundling of actin by myosin II, which distally interacts with adhesions ([1], reviewed in [12]) and stimulates proximal actin assembly [13].

Actomyosin contractility also plays crucial role at later stages.

Since these forces are funneled through mechanosensitive elements of the adhesions, this is believed to result in conformational changes in the actin linking components that subsequently promote the continued assembly of components at sites of adhesion [14][15] (reviewed in [16], see figure below). Conversely, the reduction of tension leads to adhesion dissociation. Adhesion reinforcement can be therefore be thought of as force-induced, anisotropic protein aggregation along the direction of the force [5][17]. This ultimately leads to increased cellular stiffness. However these later stages of adhesion growth are thought to be independent of substrate stiffness [4].

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Adhesion reinforcement has also been explained as a change in the chemical potential of protein aggregates that favors self assembly [18]. For example; rapid binding or breaking of weak β3 integrin-ECM ligand bonds enable continuous force-sensing, resulting in the recruitment of ]Src to integrin tails [19][20] and the stimulation of FAK-mediated phosphorylation in a tension-dependent manner that ultimately promotes vinculin recruitment [21].

The organization of actin into filaments near adhesion sites (reviewed in [12]) and the inward translocation of α5β1 integrins [22] serves as a physical template for further elongation. These spatial constraints orient growing adhesions in a centripetal fashion[23][24]. α-actinin is one of the key orchestrators of elongation, likely setting up the template along which actin filaments will extend and adhesions will grow [25]. Adhesion elongation is also regulated by continual Rac activation [26].

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  2. Bershadsky AD, Tint IS, Neyfakh AA, and Vasiliev JM. Focal contacts of normal and RSV-transformed quail cells. Hypothesis of the transformation-induced deficient maturation of focal contacts. Exp. Cell Res. 1985; 158(2):433-44. [PMID: 2988988]
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  19. Felsenfeld DP, Schwartzberg PL, Venegas A, Tse R, and Sheetz MP. Selective regulation of integrin--cytoskeleton interactions by the tyrosine kinase Src. Nat. Cell Biol. 1999; 1(4):200-6. [PMID: 10559917]
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