Directional migration is an important component of cell motility. Although the basic mechanisms of random cell movement are well characterized, no single model explains the complex regulation of directional migration. Multiple factors operate at each step of cell migration to stabilize lamellipodia and maintain directional migration. Factors such as topography of the extracellular matrix, the cellular polarity machinery, receptor signalling, integrin trafficking and co-receptors, and actin–myosin contraction converge on regulation of the Rho family of GTPases and control of lamellipodial protrusions to promote directional migration.

The elastic behavior of the 3D extracellular matrix determines the relative polarization of intracellular signaling and whether cells migrate using lamellipodia or lobopodia.

Cells use actomyosin contractility to move through three-dimensional (3D) extracellular matrix. Contractility affects the type of protrusions cells use to migrate in 3D, but the mechanisms are unclear. Here we found that contractility generated high-pressure lobopodial protrusions in cells migrating in a 3D matrix. In these cells, the nucleus physically divided the cytoplasm into forward and rear compartments. Actomyosin contractility with the nucleoskeleton-intermediate filament linker protein nesprin 3 pulled the nucleus forward and pressurized the front of the cell. Reducing expression of nesprin 3 reduced and equalized the intracellular pressure. Thus, the nucleus can act as a piston that physically compartmentalizes the cytoplasm and increases the hydrostatic pressure between the nucleus and the leading edge to drive lamellipodia-independent 3D cell migration.

The microscopic environment inside a metazoan organism is highly crowded. Whether individual cells can tailor their behavior to the limited space remains unclear. In this study, we found that cells measure the degree of spatial confinement by using their largest and stiffest organelle, the nucleus. Cell confinement below a resting nucleus size deforms the nucleus, which expands and stretches its envelope. This activates signaling to the actomyosin cortex via nuclear envelope stretch-sensitive proteins, up-regulating cell contractility. We established that the tailored contractile response constitutes a nuclear ruler–based signaling pathway involved in migratory cell behaviors. Cells rely on the nuclear ruler to modulate the motive force that enables their passage through restrictive pores in complex three-dimensional environments, a process relevant to cancer cell invasion, immune responses, and embryonic development.

SummaryCells migrating on flat two-dimensional (2D) surfaces use actin polymerization to extend the leading edge of the plasma membrane during lamellipodia-based migration. This mode of migration is not universal; it represents only one of several mechanisms of cell motility in three-dimensional (3D) environments. The distinct modes of 3D migration are strongly dependent on the physical properties of the extracellular matrix, and they can be distinguished by the structure of the leading edge and the degree of matrix adhesion. How are these distinct modes of cell motility in 3D environments related to each other and regulated? Recent studies show that the same type of cell migrating in 3D extracellular matrix can switch between different leading edge structures. This mode-switching behavior, or plasticity, by a single cell suggests that the apparent diversity of motility mechanisms is integrated by a common intracellular signaling pathway that governs the mode of cell migration. In this Commentary, we propose that the mode of 3D cell migration is governed by a signaling axis involving cell-matrix adhesions, RhoA signaling and actomyosin contractility, and that this might represent a universal mechanism that controls 3D cell migration.

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The importance of cell migration for both normal physiological functions and disease processes has been clear for the past 50 years. Although investigations of two-dimensional (2D) migration in regular tissue culture have elucidated many important molecular mechanisms, recent evidence suggests that cell migration depends profoundly on the dimensionality of the extracellular matrix (ECM). Here we review a number of evolving concepts revealed when cell migration is examined in different dimensions.

Membrane microdomains (lipid rafts) are enriched in selected signaling molecules and may compartmentalize receptor-mediated signals. Here, we report that in primary human B lymphocytes and in Ramos B cells B cell receptor (BCR) stimulation induces rapid and transient redistribution of a subset of engaged BCRs to lipid rafts and phosphorylation of raft-associated tyrosine kinase substrates. Cholesterol sequestration disrupted the lipid rafts, preventing BCR redistribution, but did not inhibit tyrosine kinase activation or phosphorylation of mitogen-activated protein kinase/extracellular regulated kinase. However, raft disruption enhanced the release of calcium from intracellular stores, suggesting that rafts may sequester early signaling events that down-regulate calcium flux. Consistent with this, BCR stimulation induced rapid and transient translocation of the Src homology 2 domain-containing inositol phosphatase, SHIP, into lipid rafts.