Signaling pathways that control cell migration: models and analysis

Abstract

Dissecting the intracellular signaling mechanisms that govern the movement of eukaryotic cells presents a major challenge, not only because of the large number of molecular players involved, but even more so because of the dynamic nature of their regulation by both biochemical and mechanical interactions. Computational modeling and analysis have emerged as useful tools for understanding how the physical properties of cells and their microenvironment are coupled with certain biochemical pathways to actuate and control cell motility. In this focused review, we highlight some of the more recent applications of quantitative modeling and analysis in the field of cell migration. Both in modeling and experiment, it has been prudent to follow a reductionist approach in order to characterize what are arguably the principal modules: spatial polarization of signaling pathways, regulation of the actin cytoskeleton, and dynamics of focal adhesions. While it is important that we "cut our teeth" on these subsystems, focusing on the details of certain aspects whilst ignoring or coarse-graining others, it is clear that the challenge ahead will be to characterize the couplings between them in an integrated framework. KeywordsCell motility; signal transduction; actin cytoskeleton; focal adhesion; mechanotransduction Cell migration is governed by a complex network of signal transduction pathways that involve lipid second messengers, small GTPases, kinases, cytoskeleton-modifying proteins, and motor proteins. For cells to achieve productive movement, these signaling processes must be differentially and persistently localized to particular regions of the cell [1], yet they must also respond in a dynamic fashion to extracellular cues. This spatial patterning or "symmetry breaking" dilemma is resolved in a variety of ways in different cell/ environmental contexts; however, the underlying, molecular-level mechanisms are only partially understood. In cells of mesenchymal origin, such as fibroblasts, a broad, flat lamellipodium with newly formed adhesive contacts at its leading edge protrudes as a consequence of integrin-mediated signaling and associated actin polymerization. A fraction of these nascent adhesions mature in conjunction with actomyosin-dependent forces to form large, long-lived adhesions, which disengage or disassemble in the rear of such cells. In contrast, amoeboid cells exhibit protrusion of the cell front that is unfettered by stable adhesions and balanced by myosin-dependent squeezing forces at the rear. Intriguingly, some cell lineages and cancer cells exhibit a transition from one form of migration to the other as a characteristic of their differentiation/dedifferentiation program [2].Another aspect of cell migration signaling that makes it difficult to analyze using traditional, reductionist approaches is that all of the functional components required for productive movement must work in unison, and they do not function normally without the feedbacks and couplings between them. This is in stark contrast with...

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