Cells have the ability to respond to various types of environmental cues, and in many cases these cues induce directed cell migration towards or away from these signals. How cells sense these cues and how they transmit that information to the cytoskeletal machinery governing cell translocation is one of the oldest and most challenging problems in biology. Chemotaxis, or migration towards diffusible chemical cues, has been studied for more than a century, but information is just now beginning to emerge about how cells respond to other cues, such as substrate-associated cues during haptotaxis (chemical cues on the surface), durotaxis (mechanical substrate compliance) and topotaxis (geometric features of substrate). Here we propose four common principles, or pillars, that underlie all forms of directed migration. First, a signal must be generated, a process that in physiological environments is much more nuanced than early studies suggested. Second, the signal must be sensed, sometimes by cell surface receptors, but also in ways that are not entirely clear, such as in the case of mechanical cues. Third, the signal has to be transmitted from the sensing modules to the machinery that executes the actual movement, a step that often requires amplification. Fourth, the signal has to be converted into the application of asymmetric force relative to the substrate, which involves mostly the cytoskeleton, but perhaps other players as well. Use of these four pillars has allowed us to compare some of the similarities between different types of directed migration, but also to highlight the remarkable diversity in the mechanisms that cells use to respond to different cues provided by their environment.
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The authors apologize to their colleagues whose work on this vast topic they were unable to cite due to length constraints. They thank M. Butler for designing some of the artwork in Fig. 3c, and J. Haugh for thoughtful discussions. J.E.B. acknowledges support from the NIH (R35GM130312 and U01EB018816). C.A.P. acknowledges support from the NIH (R01AI152517).
The authors declare no competing interests.
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Broad, sheet-like protrusions that contain branched and linear actin filaments. A variety of cell types, including fibroblasts, neural crest cells and macrophages, use lamellipodia to explore longer distances through the extracellular matrix.
Finger-like protrusions that contain bundles of linear F-actin. Filopodia serve to probe local environmental cues, provide directionality and maintain persistence of migrating cells.
- Stress fibres
Contractile arrays of actin and non-muscle myosin II that are mechanically coupled to the substrate through integrin-based focal adhesions.
- Substrate compliance
The mechanical resistance provided by non-rigid substrates (for example, collagen gels) to the contractile forces exerted by cells as they engage the substrate.
Complement proteins are products of the complement pathway generally activated as part of the innate immune response to infection. Some complement proteins, such as C5a, act as chemoattractants that guide leukocytes to sites of infection.
- Posterior lateral line primordium
A group of cells that migrate together from the ear to the tip of the tail of zebrafish as they periodically deposit primary neuromasts.
Signal molecules that originate from a tissue and diffuse to generate a concentration gradient. Morphogens exert long-range signalling effects important for growth and tissue patterning during development.
- Advection fields
Fluid flows such as interstitial flow in tissues that can create an advection field or directional transfer of molecules in the liquid phase around cells, which in turn can create asymmetries in secreted autocrine chemoattractants, leading to autologous chemotaxis. Advection fields can also form in the cytoplasm.
- Extracellular vesicles
A group of heterogeneous vesicles (several nanometres to micrometres in size) that carry a variety of cargos, including proteins, lipids and nucleic acids, and are secreted by cells to the extracellular space to facilitate cell–cell communication.
The smallest subtype of extracellular vesicles, with a size ranging from 50 to 150 nm. Exosomes are generated as intraluminal vesicles which are secreted to the extracellular space when intraluminal vesicle-carrying multivesicular bodies fuse with the plasma membrane.
Integral membrane protein family required for flask-shaped (caveola) membrane structure formation. Caveolins are also involved in membrane trafficking, exocytosis, endocytosis, extracellular vesicle formation and extracellular vesicle cargo selection.
- Rho-family GTPases
A family of small proteins that bind GDP or GTP and regulate a wide array of downstream signalling events. CDC42, Rac, and RhoA are widely studied members of this family of proteins.
- G protein-coupled receptors
(GPCRs). A family of plasma membrane receptors composed of seven transmembrane domains that couple to heterotrimeric G proteins to regulate responses mediated by a variety of external signals.
- Axon growth cone
Motile structure at the tip of growing axons that guides directed extension of the axon and is important for patterning of the nervous system.
- Cell–cell junctions
Stable or dynamic sites where borders of two neighbouring cells contact each other. Cell–cell adhesion receptors and recruited adaptor proteins are mechanically coupled to the actin cytoskeleton.
- Focal adhesions
Multiprotein assemblies that physically connect extracellular matrix components to the intracellular actin cytoskeleton through integrin clusters. Integrin-mediated adhesion to extracellular matrix ligands recruits a plethora of signalling (Src and FAK) and structural (talin, paxillin and vinculin) molecules to focal adhesions. Large, mechanically engaged focal adhesions play a crucial role in sensing mechanical cues, while smaller, nascent adhesions are critical for sensing haptotactic cues.
- Traction force
The stress vector at the interface between a migrating cell and its substrate.
- LIM domains
Protein structural domains named after the proteins LIN-11, ISL1 and MEC-3. A subset of these domains, such as those found in the proteins zyxin, paxillin and testin, bind actin filaments in a mechanical stress-dependent manner.
- LINC complex
Linker of nucleoskeleton and cytoskeleton (LINC) complex is a complex of nuclear envelope proteins that connects the cytoskeleton to the nuclear lamina and is thus involved in transferring signals from sensing mechanical cues at the cell surface or in the cytosol into nucleus.
- BAR-family proteins
Bin/amphiphysin/Rvs161 domain (BAR) proteins are membrane-binding proteins that aid in regulating membrane shape.
- Arp2/3 complex
A seven-subunit protein complex that possesses actin nucleation and branching activities leading to the generation of branched actin networks.
Neuronal Wiskott–Aldrich syndrome protein activates the Arp2/3 complex and promotes branched actin filament formation.
A nucleation promoting factor that activates the Arp2/3 complex and promotes branched actin filament formation.
- Pleckstrin homology (PH) domain
Small protein domains of approximately 120 amino acids that are known to have phosphoinositide-binding specificity.
A protein complex consisting of an adaptor protein, ELMO, and a Rac-specific guanine nucleotide exchange factor, DOCK.
Target of rapamycin complex 2 is composed of seven conserved subunits and is involved in regulating proliferation, survival, cell migration and cytoskeletal reorganization.
- Phospholipase A2
An enzyme that cleaves phospholipids to give rise to lipid products (arachidonic acid or lysophosphatidic acid) that either have the ability to regulate signalling events or are substrates in the generation of bioactive lipids.
A group of protein kinases that transduce signals from cell surface receptors to the nucleus.
- Förster resonance energy transfer
A mechanism describing energy transfer between two light-sensitive molecules.
Protrusive structures in amoeboid cells generated by branched and linear actin filament arrays in the leading edge and aligned with the direction of movement.
Enabled/vasodilator-stimulated phosphoproteins are actin polymerases that drive actin filament elongation and antagonize filament capping, leading to the generation of linear actin filaments.
A group of actin polymerases that drives the formation of linear actin filaments.
Suppressor of cAR/WASP family verprolin-homologous protein is a nucleation-promoting factor that activates actin nucleation activity of the Arp2/3 complex.
Calcium-activated cysteine protease that cleaves adhesion complex proteins.
- Border cell
A specialized cell type that migrates as a group through the egg chambers in Drosophila melanogaster.
Spherical membrane protrusions that rely on myosin-based contraction and pressure-driven cytosolic flow. Bleb-like protrusions are commonly used for motility by amoebas and embryonic cells. However, leukocytes and tumour cells can use blebbing motility especially in 3D environments under confined conditions.
- Reynolds number
A dimensionless number important in fluid mechanics. Cellular scales are inherently a low Reynolds number environment where inertia and momentum are negligible and thus movement requires strategies different from those for human-relevant length scales.
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SenGupta, S., Parent, C.A. & Bear, J.E. The principles of directed cell migration. Nat Rev Mol Cell Biol 22, 529–547 (2021). https://doi.org/10.1038/s41580-021-00366-6