Cytoskeletal cross-talk with integrin adhesion complexes in cell morphogenesis

Cytoskeleton and cell-matrix adhesions are key elements determining cell morphogenesis. Here, two aspects of this topic will be discussed. (1) Microtubule-mediated crosstalk between adhesions and actomyosin. Transmembrane integrin adhesion receptors assemble into various types of actin cytoskeleton-associated structures, such as focal adhesions, fibrillar adhesions, and podosomes. These structures are controlled by microtubules via regulation of myosin-IIA-filaments assembly. Microtubules are coupled with integrin adhesions via KANK family proteins. This coupling controls release of guanine nucleotide exchange factor GEF-H1 from microtubules and its activation. GEF-H1 then activates Rho/Rho kinase, and thereby the assembly of myosin IIA filaments, which in turn remodel the adhesions. This mechanism appears to be universal for many cell types. (2) Emerging left-right asymmetry. Human fibroblasts confined to circular adhesive islands exhibit a chiral actin cytoskeleton swirling emerging due to unidirectional tilting of the focal adhesion-nucleated radial actin fibers. Analysis of molecular players by knocking down major actin-associated proteins and automated AI-based measurements of radial fiber tilting revealed a group of actin polymerization regulators required for the development of chirality. Depletion of other regulators reversed chirality direction. The confluent micro-cultures (of ~100 cells) confined to rectangular micropattern demonstrate a chiral cell alignment, an asymmetric tilt of average cell orientation relatively to the rectangle long axis. Analysis of more than 30 different knockdowns and pharmacological treatments revealed remarkable correlation between their effects on the chirality of individual cells and cell groups. Thus, actin-driven cell chirality could trigger the asymmetry in tissues and organs.