Table 1 |.

The four pillars of directed cell migration

Migration mode	Cue	Signal generation	Signal sensing	Signal transmission	Signal execution
Chemotaxis	Diffusible chemical released from cells or deposited extracellular vesicles	Simple diffusion Regulated removal by degradation of the chemoattractant or decoy receptors Release of extracellular vesicles	GPCRs RTKs Other receptors, such as axon guidance receptors	Classical signalling pathways involving small and large G proteins PI3K TORC2 PLA2 MAPK/ERK	Leading-edge protrusions (all types) Localized regulation of non-muscle myosin II and contractility
Haptotaxis	Substrate-bound chemical cues such as an immobilized chemokine or ECM	ECM secretion and deposition Binding of soluble factors to a substrate (mostly ECM) Exposing new sites on the substrate through enzymatic action	For ECM, integrins, but different adhesion structure impacts signalling outcome For substrate-bound chemokines, regular receptors, but signalling kinetics may be different for different receptor–ligand pairs	Classical integrin signalling pathways: Rho-family GTPases, FAK–Src, etc. Bound chemokine: probably same as diffusible cue	Biased protrusion generation through a positive-feedback loop. Requires the Arp2/3 complex
Durotaxis	Differential substrate compliance	Passive: creating a stiff substrate by crosslinking of ECM components or ECM deposition Active: cells or tissues exerting a force on the substrate that is sensed by other cells	Integrins Membrane tension and/or invagination Focal adhesion components Actomyosin filaments LINC complex	Unclear, but two mechanisms have been proposed: role of pure mechanics using actomyosin system or the involvement of mechanically triggered signalling events	Similar to other forms of migration but biased relative to stiffness gradient
Topotaxis	Geometric properties of the migration substrate irrespective of mechanical or chemical properties	Preformed tunnels created by other cells Trails created by proteolytic ECM remodelling Topological features created by non-lytic ECM deformation 1D fibrils such as bundles of collagen Topology of natural tissue elements	Cells adhere and conform to the topology and/or the geometry of the migration substrate with the help of focal adhesion components Membrane curvature-sensing proteins Nucleus deformation	Cell and nuclear shape change may affect both signalling and the cytoskeleton but the mechanisms remain unclear	Topology/geometry biases force-generating mechanisms of actin polymerization and actomyosin contractility
Galvanotaxis	Electric fields	Ionic differences generated by transepithelial barriers such as in the skin, disrupted by wounding	Electrophoretic movement of charged surface proteins and lipids within the plane of the membrane	Clustering of membrane proteins/lipids must activate signalling, but the mechanisms remain unclear	Similar to chemotaxis but biased relative to charge

Arp2/3 complex, actin-related protein 2/3 complex; ECM, extracellular matrix; FAK, focal adhesion kinase; GPCR, G protein-coupled receptor; LINC complex, linker of nucleoskeleton and cytoskeleton complex; PI3K, phosphoinositide 3-kinase; PLA₂, phospholipase A₂; RTK, receptor tyrosine kinase; TORC2, target of rapamycin complex 2.