Integrin-mediated cell-matrix adhesions at the crossroad between microtubules and the actomyosin cytoskeleton

Actomyosin cytoskeleton and cell-matrix adhesions are the key elements determining cell morphogenesis. Peripheral domains of the actin cytoskeleton associated with the clusters of integrin transmembrane receptors, comprise several types of mechanosensing cell-matrix adhesions, such as focal adhesions and podosomes. Myosin-IIA filaments assemble into superstructures (“stacks”) organizing and remodeling actin filament networks, including the cell-matrix adhesions. The myosin-IIA filaments affect the adhesion structures in a differential manner, promoting the integrity and growth of focal adhesions but disrupting the podosomes. A feedback response from the integrin adhesions to the myosin IIA filaments is in part mediated by another essential cytoskeletal system, microtubules. Focal adhesions and podosomes capture microtubules through KANK family proteins, which connect the integrin-binding protein talin with the cortical microtubule-stabilizing complexes (CMSCs). Capturing of microtubules by integrin adhesions suppresses, while detachment - promotes the myosin-IIA filament formation. The mechanism underlying these effects depends on Rho activation by guanine nucleotide exchange factor GEF-H1, which is trapped by microtubules when they are coupled with integrin adhesions via KANK proteins. Microtubule uncoupling from the integrin adhesions triggers a release of GEF-H1 from microtubules, activation of Rho and Rho-associated kinase (ROCK), and consequently the assembly of myosin-IIA filaments. Thus, microtubule capturing by integrin-mediated adhesions modulates the effect of microtubules on the actomyosin cytoskeleton. The myosin-IIA filaments then remodel the focal adhesions and podosomes, closing the regulatory loop.

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