Joining forces: crosstalk between biochemical signalling and physical forces orchestrates cellular polarity and dynamics

Abstract

Dynamic processes like cell migration and morphogenesis emerge from the self-organized interaction between signalling and cytoskeletal rearrangements. How are these molecular to sub-cellular scale processes integrated to enable cell-wide responses? A growing body of recent studies suggest that forces generated by cytoskeletal dynamics and motor activity at the cellular or tissue scale can organize processes ranging from cell movement, polarity and division to the coordination of responses across fields of cells. To do so, forces not only act mechanically but also engage with biochemical signalling. Here, we review recent advances in our understanding of this dynamic crosstalk between biochemical signalling, self-organized cortical actomyosin dynamics and physical forces with a special focus on the role of membrane tension in integrating cellular motility.This article is part of the theme issue 'Self-organization in cell biology'.

Keywords: actin cytoskeleton; cell migration; cell polarity; mechanotransduction; self-organization; signalling.

Figure 1.

Spatio-temporal scales in dynamic feedback between signalling and cellular dynamics. Fast biochemical signalling at the molecular scale underlies all sub-cellular actomyosin dynamics and rearrangement. These mesoscale dynamics of cortical cytoskeleton give rise to forces and global tension that integrate several cellular scale behaviours. The dimensions of each module (box) qualitatively reflect their associated spatio-temporal scales. Interestingly, several regulatory interactions and feedbacks (arrows) exist within and between each module. Understanding the nature of these complex feedbacks will unravel how these modules work together to self-organize cellular dynamics. (Online version in colour.)

Figure 2.

Self-organized sub-cellular patterns of actomyosin dynamics. (a) Self-organized waves of WAVE regulatory complex (WRC) in neutrophils organize polarity and motility. Neutrophil-like HL-60 cells stimulated with chemoattractant uniformly activate the WRC, which asymmetrically disappears and is polarized to one end of the cell (arrow) and starts generating WRC waves (adapted from [5] with permission). (b) Schematic shows the arrangement of WRC waves and F-actin showing the basis for their self-organization. (c) Kymograph showing several sets of waves with gaps indicating zone of activator (WRC, bright) and inhibitor (F-actin, gap region). (d) Starfish blastomere shows the presence of waves of Rho activity (green) and actin (copper) (adapted from [21] with permission). (e) Fast positive feedback from RhoGEF Ect2 drives Rho-driven F-actin formation possibly via formins that exercise delayed negative feedback via possible recruitment of RhoGAPs. (f) Actomyosin pulses are generated by cycles of actomyosin turnover and contractility leading to advective flows and generating contractile forces. (g) Schematic showing the core signalling network underlying the two proposed mechanisms generating pulses; the Rho-pacemaker model [26] and self-organization model [27].

Figure 3.

Membrane tension as global mechanical integrator in polarity and motility. (a) Feedback between actin polymerization and membrane tension. Cell membrane with low F-actin density and/or excess membrane folds has low in-plane tension (left). Increase in F-actin polymerization at the membrane generates outward protrusive forces (vertical arrows) leading to increase in membrane tension (horizontal double-headed arrow, right) until it becomes limiting to growth of new filaments and effectively stalls the network. (b) Membrane tension coordinate leading edge activity and polarity. Resting neutrophils (left) have low cortical actin density and hence low membrane tension allowing uniform increase in actin density and new protrusions (middle) shortly upon chemoattractant stimulation. Consequent increase in tension can mechanically and/or biochemically inhibit secondary fronts to converge on a single polarized leading edge. (c) Feedback between membrane tension and actin growth can be both mechanical (direct) and biochemical (indirect) [58,67]. mTORC2, mechanistic target of rapamycin Complex 2; PLD2, phospholipase D2. (Online version in colour.)

Figure 4.

Cellular strategies for membrane tension regulation. Conditions leading to in-plane membrane tension perturbation and responses by the cell homeostatic machinery. Membrane tension is affected by changes in actin polymerization at the leading edge (a), in the balance of osmolytes across the membrane (b) and in external compression (c) of the cell (e.g. neutrophil squeezing through an epithelial layer). Cells can restore their ‘target’ membrane tension by using their homeostatic machinery to control actin polymerization at the leading edge (d) and to activate volume regulatory machinery to force water across the membrane (and changing the cell volume) (e). (Online version in colour.)