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First published online December 31, 2008
doi: 10.1242/10.1242/jcs.018564

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Integrins in cell migration – the actin connection

¹ Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
² Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, VA 22908, USA

View larger version (29K): [in this window] [in a new window]   Fig. 1. The actin-integrin linkage. The linkage between the extracellular matrix (ECM, red strand on top) and the actin cytoskeleton (represented by yellow beaded coils) is depicted. Integrins (represented by the - and β-transmembrane subunits in light blue and pink) can bind directly to the talin head domain (red sphere). Through its tail domain (red rod), talin can bind directly to actin as well as to other components of the linkage, such as vinculin (shown in purple). Vinculin can also bind to actin directly, as well as to the actin cross-linker -actinin (shown as a dimer, in green). Both vinculin and -actinin are anchored to the membrane, and their activity is modulated by interactions with phosphatidylinositol (4,5)-bisphosphate (PIP2). Finally, vinculin and FAK (shown in blue) can bind to the actin nucleator Arp2/3 (shown as a heptamer in grey).

View larger version (19K): [in this window] [in a new window]   Fig. 2. The adhesion lifetime. Adhesions first form in the lamellipodium, where their rate of assembly correlates with the rate of protrusion. As actin disassembles at the rear of the lamellipodium, adhesions turn over. Some adhesions elongate in the region of convergence between the lamellipodium and the lamellum, and mature centripetally along thin actin filaments that are decorated with -actinin, an actin cross-linker (depicted in red). As the bundles become thicker and more stable owing to enhanced cross-linking, myosin II (depicted in green) enters and the adhesions become larger.

View larger version (40K): [in this window] [in a new window]   Fig. 3. The integrin-actin linkage acts as a molecular clutch. (A,B) The linkage is shown in two positions: integrins not linked to actin (disengaged) (A), and integrins linked to actin (engaged) (B). In A, the actin is not anchored to the substratum, and thus the force produced by actin polymerization (P) is counterbalanced by retrograde flow (R) which is caused by myosin contraction and tension on the membrane in the lamellipodium. In the example, they balance and there is no protrusion. In B, actin is coupled to the substratum by the interaction of actin-binding proteins with integrins. Under these conditions, the force generated by the retrograde flow is partially or fully shunted to the substratum (oblique black arrows). The force produced by actin polymerization then exceeds the force that produces retrograde flow, resulting in a higher protrusion rate. New nascent adhesions assemble as the lamellipodium extends. As the protrusion advances, the boundary between the lamellipodium and the lamellum moves forward. In the lamellum, myosin II activity generates a contractile force that drives retrograde flow. Slippage points that result in differential coupling of adhesion proteins to the actin occur at an as-yet-undetermined level between the -actinin (in green) and the other components of the linkage, and/or at the level of interaction of the integrin with the substrate.

View larger version (47K): [in this window] [in a new window]   Fig. 4. Outline of adhesive signaling in migration. Integrin ligation induces the nucleation of different signaling elements. The major categories (kinases, non-catalytic adaptor proteins and actin-binding proteins) are shown. These categories can influence the recruitment and/or activation of other components of adhesions (represented by red arrows). Most migratory signaling converges on the Rho GTPases, which regulate actin polymerization and stability (via nucleators such as the Arp2/3 complex and formins, or actin-filament-severing proteins such as cofilin), actomyosin contractility (via MLC phosphorylation), and microtubules (not shown).

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