How do focal adhesions mature?2017-12-26T14:19:53+00:00

How do focal adhesions mature?

Adhesions that manage to grow beyond the transient phase further undergo qualitative changes in a phase described as maturation. This transformation of adhesion sites into stress-fiber bound focal adhesions (FAs) is believed to result from the collective effects of Rho GTPase activity [1][2][3], increased tyrosine kinase activity [4][5] (reviewed in [6]), change in composition [7][8] and dynamics [9], actin crosslinking by α-actinin [10]and tension-dependent actomyosin contractility ([11][12][13], reviewed in [14][15]) – all of which take place during local contraction of the lamellipodium [8] (reviewed in [16]).

Rho kinase (ROCK)-mediated phosphorylation of myosinII regulatory light chain (RLC), RhoA-mediated its sustenance of RLC phosphorylation and activation of formin mDia are critical triggering events [17][18]. For more details, see Functional module: Integrin β1/syndecan-4 synergy in membrane protrusion and adhesion dynamics. Myosin IIA and Myosin IIB cooperatively aid actomyosin bundling in a localized manner thus stabilizing the large adhesions [19]. As a result, actin bundles assemble between stable adhesions on the ventral cell surface, forming structures known as stress fibers ([11], reviewed in [20]). Assembly of these stress fibers in the lamellum acts as a structural template for the compositional maturation of FAs and seems to be quintessential despite an intact actomyosin contractile mechanism [21]. At this stage, the adhesion components contain modifications that inhibit Rac-GEF recruitment leading to a local  and hence define the cell rear [19]. Stress fibers participate in mechanotransduction by FAs [22] and can generate high level of forces on rigid and dense matrices [23][24], through actomyosin contractions.

Accumulation of tensional forces (internal or external) that results in FA reinforcement has been shown to ultimately activate and recruit Rho-GEFs to adhesion sites [25]. The two GEFs studied seem to be under the control of distinct pathways- Fyn (a SFK) and FAK-Ras-ERK signaling. Subsequent force-dependent Rho activation leads to events aiding the maturation process.

Thus, bidirectional force transmission between the internal cytoskeletal network and the exterior gets directed through the adhesions [26] (reviewed in [14][15]). Force differences across adhesions influence actin dynamics and signal transduction cascades, leading to the reinforcement and maturation of adhesions (reviewed in [22]).

During growth and early maturation, the FA size correlates with traction stress but can exert variable force depending on its position in the cell [27]. However, upon maturation, the changes in morphology, protein composition and/or phosphorylation of FAs decrease propulsive forces [7]. They do not grow further under tension [27] probably due to altered chemical state of FA signaling components [28].

Thus mature FAs effectively become passive anchorage devices for the maintenance of a spread cell morphology [7] and can sustain up to a six-fold increase in external force load without elongating [27]. Stability of receptor-stress fiber interactions enables mature adhesions to probe their environment over large spatial and temporal scales and to reorient, a feature essential for direction-dependent rigidity sensing [29][30].

FAs typically disassemble within 10 to 20 minutes or mature further into fibrillar adhesions [31][32] that can remodel the extracellular matrix. Alternately, high Src activity suppresses integrin function and contractility, thus fail to assemble the matrix and mediate transformation into podosomes [33].

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References

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