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Random versus directionally persistent cell migration

Key Points

  • Directional cell migration is an important feature of cell motility that arises from intrinsic cell directionality or external regulation. The mechanisms that drive this process are being deciphered by identifying the specific factors that promote random versus directionally persistent cell migration.

  • Cells achieve and maintain directionally persistent migration by forming and stabilizing protrusions or lamellipodia at their leading edge. Many processes can affect leading edge formation, and they often depend on local regulation of the Rho family of GTPases.

  • The topography of the extracellular matrix provides an important physical cue that can promote directionally persistent migration, possibly by promoting front–rear polarity with geometrically constrained adhesion formation.

  • The Par (partitioning defective) complex is an important contributor to the formation of the front–rear axis of a migrating cell. The Par complex serves as a nexus at the leading edge, connecting Rho GTPase signalling, centrosome reorientation, microtubule stabilization and membrane trafficking to the regulation of directional persistence during cell migration.

  • At each step of the basic cell motility cycle, localized intracellular signalling and/or membrane trafficking can regulate directionally persistent cell migration by controlling the formation of lateral membrane protrusions.

  • New models are needed to recapitulate the physically and biochemically complex environments through which cells navigate in vivo while confronted with competing guidance cues, to further understand how directed cell migration is achieved.

Abstract

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 the topography of the extracellular matrix, the cellular polarity machinery, receptor signalling, integrin trafficking, integrin co-receptors and actomyosin contraction converge on regulation of the Rho family of GTPases and the control of lamellipodial protrusions to promote directional migration.

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Figure 1: Control of lamellipodial protrusions promotes directional migration.
Figure 2: Topographical control of directional migration.
Figure 3: The Par polarity complex and directional migration.
Figure 4: Integrin trafficking and directional migration.

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References

  1. Lauffenburger, D. A. & Horwitz, A. F. Cell migration: a physically integrated molecular process. Cell 84, 359–369 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Ridley, A. J. et al. Cell migration: integrating signals from front to back. Science 302, 1704–1709 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Stoker, M. & Gherardi, E. Regulation of cell movement: the motogenic cytokines. Biochim. Biophys. Acta 1072, 81–102 (1991).

    CAS  PubMed  Google Scholar 

  4. Seppa, H., Grotendorst, G., Seppa, S., Schiffmann, E. & Martin, G. R. Platelet-derived growth factor is chemotactic for fibroblasts. J. Cell Biol. 92, 584–588 (1982). Identifies PDGF as a chemotactic factor for fibroblasts. This paper is also an excellent resource for understanding how to distinguish between haptotactic, chemotactic, chemokinetic and mitogenic responses when studying cell motility, as well as understanding why it is important to do so.

    Article  CAS  PubMed  Google Scholar 

  5. Arrieumerlou, C. & Meyer, T. A local coupling model and compass parameter for eukaryotic chemotaxis. Dev. Cell 8, 215–227 (2005). Challenges fundamental assumptions that underlie directed cell migration by showing that local signalling in lamellipodia generates small protrusions towards the source of the guidance cue as the basis of chemotaxis in vitro , rather than protrusions being directed by global integration of competing signals.

    Article  CAS  PubMed  Google Scholar 

  6. Bourne, H. R. & Weiner, O. A chemical compass. Nature 419, 21 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Carter, S. B. Principles of cell motility: the direction of cell movement and cancer invasion. Nature 208, 1183–1187 (1965).

    Article  CAS  PubMed  Google Scholar 

  8. Zhao, M. Electrical fields in wound healing — an overriding signal that directs cell migration. Semin. Cell Dev. Biol. 25 Dec 2008 (doi: 10.1016/j.semcdb.2008.12.009).

  9. Lo, C. M., Wang, H. B., Dembo, M. & Wang, Y. L. Cell movement is guided by the rigidity of the substrate. Biophys. J. 79, 144–152 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gail, M. H. & Boone, C. W. The locomotion of mouse fibroblasts in tissue culture. Biophys. J. 10, 980–993 (1970). One of the first studies to examine fibroblast migration in culture by combining time-lapse imaging and quantitative analysis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bear, J. E. et al. Antagonism between Ena/VASP proteins and actin filament capping regulates fibroblast motility. Cell 109, 509–521 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Chen, L. et al. PLA2 and PI3K/PTEN pathways act in parallel to mediate chemotaxis. Dev. Cell 12, 603–614 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bosgraaf, L. et al. RasGEF-containing proteins GbpC and GbpD have differential effects on cell polarity and chemotaxis in Dictyostelium. J. Cell Sci. 118, 1899–1910 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Pankov, R. et al. A Rac switch regulates random versus directionally persistent cell migration. J. Cell Biol. 170, 793–802 (2005). Shows that Rac activity can control the pattern of cell migration during both intrinsic and directed motility by regulating the formation of lateral protrusions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Andrew, N. & Insall, R. H. Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions. Nature Cell Biol. 9, 193–200 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Fackler, O. T. & Grosse, R. Cell motility through plasma membrane blebbing. J. Cell Biol. 181, 879–884 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Charest, P. G. & Firtel, R. A. Feedback signalling controls leading-edge formation during chemotaxis. Curr. Opin. Genet. Dev. 16, 339–347 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Kay, R. R., Langridge, P., Traynor, D. & Hoeller, O. Changing directions in the study of chemotaxis. Nature Rev. Mol. Cell Biol. 9, 455–463 (2008).

    Article  CAS  Google Scholar 

  19. Petri, B., Phillipson, M. & Kubes, P. The physiology of leukocyte recruitment: an in vivo perspective. J. Immunol. 180, 6439–6446 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Martini, F. J. et al. Biased selection of leading process branches mediates chemotaxis during tangential neuronal migration. Development 136, 41–50 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Fischer, R. S., Gardel, M., Ma, X., Adelstein, R. S. & Waterman, C. M. Local cortical tension by myosin II guides 3D endothelial cell branching. Curr. Biol. 19, 260–265 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bailly, M., Yan, L., Whitesides, G. M., Condeelis, J. S. & Segall, J. E. Regulation of protrusion shape and adhesion to the substratum during chemotactic responses of mammalian carcinoma cells. Exp. Cell Res. 241, 285–299 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Harms, B. D., Bassi, G. M., Horwitz, A. R. & Lauffenburger, D. A. Directional persistence of EGF-induced cell migration is associated with stabilization of lamellipodial protrusions. Biophys. J. 88, 1479–1488 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Garber, B. Quantitative studies on the dependence of cell morphology and motility upon the fine structure of the medium in tissue culture. Exp. Cell Res. 5, 132–146 (1953).

    Article  CAS  PubMed  Google Scholar 

  25. Weiss, P. & Garber, B. Shape and movement of mesenchyme cells as functions of the physical structure of the medium: contributions to a quantitative morphology. Proc. Natl Acad. Sci. USA 38, 264–280 (1952).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dunn, G. A. & Heath, J. P. A new hypothesis of contact guidance in tissue cells. Exp. Cell Res. 101, 1–14 (1976).

    Article  CAS  PubMed  Google Scholar 

  27. Nakatsuji, N. & Johnson, K. E. Cell locomotion in vitro by Xenopus laevis gastrula mesodermal cells. Cell. Motil. 2, 149–161 (1982).

    Article  CAS  PubMed  Google Scholar 

  28. Nakatsuji, N. & Johnson, K. E. Ectodermal fragments from normal frog gastrulae condition substrata to support normal and hybrid mesodermal cell migration in vitro. J. Cell Sci. 68, 49–67 (1984).

    CAS  PubMed  Google Scholar 

  29. Nakatsuji, N. & Johnson, K. E. Experimental manipulation of a contact guidance system in amphibian gastrulation by mechanical tension. Nature 307, 453–455 (1984).

    Article  CAS  PubMed  Google Scholar 

  30. Wood, A. Contact guidance on microfabricated substrata: the response of teleost fin mesenchyme cells to repeating topographical patterns. J. Cell Sci. 90, 667–681 (1988).

    PubMed  Google Scholar 

  31. Webb, A., Clark, P., Skepper, J., Compston, A. & Wood, A. Guidance of oligodendrocytes and their progenitors by substratum topography. J. Cell Sci. 108, 2747–2760 (1995).

    CAS  PubMed  Google Scholar 

  32. Gomez, N., Chen, S. & Schmidt, C. E. Polarization of hippocampal neurons with competitive surface stimuli: contact guidance cues are preferred over chemical ligands. J. R. Soc. Interface 4, 223–233 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Teixeira, A. I., Abrams, G. A., Bertics, P. J., Murphy, C. J. & Nealey, P. F. Epithelial contact guidance on well-defined micro- and nanostructured substrates. J. Cell Sci. 116, 1881–1892 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Loesberg, W. A. et al. The threshold at which substrate nanogroove dimensions may influence fibroblast alignment and adhesion. Biomaterials 28, 3944–3951 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Cukierman, E., Pankov, R., Stevens, D. R. & Yamada, K. M. Taking cell-matrix adhesions to the third dimension. Science 294, 1708–1712 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Beningo, K. A., Dembo, M. & Wang, Y. L. Responses of fibroblasts to anchorage of dorsal extracellular matrix receptors. Proc. Natl Acad. Sci. USA 101, 18024–18029 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lammermann, T. et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453, 51–55 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Amatangelo, M. D., Bassi, D. E., Klein-Szanto, A. J. & Cukierman, E. Stroma-derived three-dimensional matrices are necessary and sufficient to promote desmoplastic differentiation of normal fibroblasts. Am. J. Pathol. 167, 475–488 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Doyle, A. D., Wang, F. W., Matsumoto, K. & Yamada, K. M. One-dimensional topography underlies three-dimensional fibrillar cell migration. J. Cell Biol. 184, 481–490 (2009). Establishes that aligned fibrillar matrices can be functionally mimicked by simple 1D lines, but not 2D surfaces, to promote directional cell migration. Also introduces a novel micropatterning technique for generating matrix patterns.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schnell, E. et al. Guidance of glial cell migration and axonal growth on electrospun nanofibers of poly-ɛ-caprolactone and a collagen/poly-ɛ-caprolactone blend. Biomaterials 28, 3012–3025 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Tysseling-Mattiace, V. M. et al. Self-assembling nanofibers inhibit glial scar formation and promote axon elongation after spinal cord injury. J. Neurosci. 28, 3814–3823 (2008). Demonstrates the in vivo use of self-assembling peptide amphiphile molecules to generate nanofibres that inhibit glial cell differentiation and scar tissue formation while promoting motor and sensory neuron regeneration at the site of a spinal cord injury.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sidani, M., Wyckoff, J., Xue, C., Segall, J. E. & Condeelis, J. Probing the microenvironment of mammary tumours using multiphoton microscopy. J. Mammary Gland Biol. Neoplasia 11, 151–163 (2006).

    Article  PubMed  Google Scholar 

  43. Provenzano, P. P. et al. Collagen density promotes mammary tumour initiation and progression. BMC Med. 6, 11 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Provenzano, P. P., Inman, D. R., Eliceiri, K. W., Trier, S. M. & Keely, P. J. Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization. Biophys. J. 95, 5374–5384 (2008). Uses multiple technical methods to show that cancer cells reorganize the ECM perpendicular to tumour explants, a process that depends on Rho kinase and precedes cell migration and invasion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Etienne-Manneville, S. Polarity proteins in migration and invasion. Oncogene 27, 6970–6980 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Iden, S. & Collard, J. G. Crosstalk between small GTPases and polarity proteins in cell polarization. Nature Rev. Mol. Cell Biol. 9, 846–859 (2008).

    Article  CAS  Google Scholar 

  47. Etienne-Manneville, S. Cdc42 — the centre of polarity. J. Cell Sci. 117, 1291–1300 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Etienne-Manneville, S. & Hall, A. Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCζ. Cell 106, 489–498 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Shen, Y. et al. Nudel binds Cdc42GAP to modulate Cdc42 activity at the leading edge of migrating cells. Dev. Cell 14, 342–353 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Gomes, E. R., Jani, S. & Gundersen, G. G. Nuclear movement regulated by Cdc42, MRCK, myosin, and actin flow establishes MTOC polarization in migrating cells. Cell 121, 451–463 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Kupfer, A., Louvard, D. & Singer, S. J. Polarization of the Golgi apparatus and the microtubule-organizing center in cultured fibroblasts at the edge of an experimental wound. Proc. Natl Acad. Sci. USA 79, 2603–2607 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Cau, J. & Hall, A. Cdc42 controls the polarity of the actin and microtubule cytoskeletons through two distinct signal transduction pathways. J. Cell Sci. 118, 2579–2587 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Siegrist, S. E. & Doe, C. Q. Microtubule-induced cortical cell polarity. Genes Dev. 21, 483–496 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Bergmann, J. E., Kupfer, A. & Singer, S. J. Membrane insertion at the leading-edge of motile fibroblasts. Proc. Natl Acad. Sci. USA 80, 1367–1371 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Prigozhina, N. L. & Waterman-Storer, C. M. Protein kinase D-mediated anterograde membrane trafficking is required for fibroblast motility. Curr. Biol. 14, 88–98 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Tan, I., Yong, J., Dong, J. M., Lim, L. & Leung, T. A tripartite complex containing MRCK modulates lamellar actomyosin retrograde flow. Cell 135, 123–136 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Nishita, M. et al. Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. J. Cell Biol. 175, 555–562 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Schlessinger, K., McManus, E. J. & Hall, A. Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity. J. Cell Biol. 178, 355–361 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nomachi, A. et al. Receptor tyrosine kinase Ror2 mediates Wnt5a-induced polarized cell migration by activating c-Jun N-terminal kinase via actin-binding protein filamin A. J. Biol. Chem. 283, 27973–27981 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Pestonjamasp, K. N. et al. Rac1 links leading edge and uropod events through Rho and myosin activation during chemotaxis. Blood 108, 2814–2820 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sander, E. E., ten Klooster, J. P., van Delft, S., van der Kammen, R. A. & Collard, J. G. Rac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behaviour. J. Cell Biol. 147, 1009–1022 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pertz, O., Hodgson, L., Klemke, R. L. & Hahn, K. M. Spatiotemporal dynamics of RhoA activity in migrating cells. Nature 440, 1069–1072 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Nishimura, T. et al. PAR-6–PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nature Cell Biol. 7, 270–277 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Pegtel, D. M. et al. The Par–Tiam1 complex controls persistent migration by stabilizing microtubule-dependent front–rear polarity. Curr. Biol. 17, 1623–1634 (2007). Shows that the Par polarity complex, previously known to establish apical–basal polarity, drives front–rear polarization in migrating keratinocytes; blocking Par complex function increases random migration and inhibits chemotaxis, probably by interfering with microtubule stabilization at the leading edge downstream of Rac signalling.

    Article  CAS  PubMed  Google Scholar 

  65. Nakayama, M. et al. Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation. Dev. Cell 14, 205–215 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Drabek, K. et al. Role of CLASP2 in microtubule stabilization and the regulation of persistent motility. Curr. Biol. 16, 2259–2264 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Beardsley, A. et al. Loss of caveolin-1 polarity impedes endothelial cell polarization and directional movement. J. Biol. Chem. 280, 3541–3547 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Grande-Garcia, A. et al. Caveolin-1 regulates cell polarization and directional migration through Src kinase and Rho GTPases. J. Cell Biol. 177, 683–694 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. del Pozo, M. A. et al. Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization. Nature Cell Biol. 7, 901–908 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Gomez, T. M., Robles, E., Poo, M. & Spitzer, N. C. Filopodial calcium transients promote substrate-dependent growth cone turning. Science 291, 1983–1987 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Gomez, T. M. & Zheng, J. Q. The molecular basis for calcium-dependent axon pathfinding. Nature Rev. Neurosci. 7, 115–125 (2006).

    Article  CAS  Google Scholar 

  72. Jin, M. et al. Ca2+-dependent regulation of rho GTPases triggers turning of nerve growth cones. J. Neurosci. 25, 2338–2347 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wei, C. et al. Calcium flickers steer cell migration. Nature 457, 901–905 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Zheng, J. Q. & Poo, M. M. Calcium signalling in neuronal motility. Annu. Rev. Cell Dev. Biol. 23, 375–404 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Kolsch, V., Charest, P. G. & Firtel, R. A. The regulation of cell motility and chemotaxis by phospholipid signalling. J. Cell Sci. 121, 551–559 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. van Haastert, P. J., Keizer-Gunnink, I. & Kortholt, A. Essential role of PI3-kinase and phospholipase A2 in Dictyostelium discoideum chemotaxis. J. Cell Biol. 177, 809–816 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Haugh, J. M., Codazzi, F., Teruel, M. & Meyer, T. Spatial sensing in fibroblasts mediated by 3' phosphoinositides. J. Cell Biol. 151, 1269–1280 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Weiger, M. C. et al. Spontaneous phosphoinositide 3-kinase signalling dynamics drive spreading and random migration of fibroblasts. J. Cell Sci. 122, 313–323 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nobes, C. D., Hawkins, P., Stephens, L. & Hall, A. Activation of the small GTP-binding proteins rho and rac by growth factor receptors. J. Cell Sci. 108, 225–233 (1995).

    CAS  PubMed  Google Scholar 

  80. Oude Weernink, P. A., Han, L., Jakobs, K. H. & Schmidt, M. Dynamic phospholipid signalling by G protein-coupled receptors. Biochim. Biophys. Acta 1768, 888–900 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Chae, Y. C. et al. Phospholipase D activity regulates integrin-mediated cell spreading and migration by inducing GTP-Rac translocation to the plasma membrane. Mol. Biol. Cell 19, 3111–3123 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kim, J. H., Kim, H. W., Jeon, H., Suh, P. G. & Ryu, S. H. Phospholipase D1 regulates cell migration in a lipase activity-independent manner. J. Biol. Chem. 281, 15747–15756 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Nishikimi, A. et al. Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis. Science 324, 384–387 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Monypenny, J. et al. Cdc42 and Rac family GTPases regulate mode and speed but not direction of primary fibroblast migration during platelet-derived growth factor-dependent chemotaxis. Mol. Cell Biol. 29, 2730–2747 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kraynov, V. S. et al. Localized Rac activation dynamics visualized in living cells. Science 290, 333–337 (2000). Highlights the importance of considering cell-biological dynamics when studying the signalling mechanisms that drive cell migration; live cell imaging shows that Rac activity is targeted to the leading edge of migrating fibroblasts.

    Article  CAS  PubMed  Google Scholar 

  86. Vidali, L., Chen, F., Cicchetti, G., Ohta, Y. & Kwiatkowski, D. J. Rac1-null mouse embryonic fibroblasts are motile and respond to platelet-derived growth factor. Mol. Biol. Cell 17, 2377–2390 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bard, J. B. & Hay, E. D. The behaviour of fibroblasts from the developing avian cornea. Morphology and movement in situ and in vitro. J. Cell Biol. 67, 400–418 (1975). Comprehensive study of the comparative morphology and behaviour of the same population of fibroblasts migrating on glass, in 3D collagen gels or in situ in the developing avian cornea, providing a clear warning of the dangers of using 2D environments to understand cell migration normally occurring in 3D tissues.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bass, M. D. et al. Syndecan-4-dependent Rac1 regulation determines directional migration in response to the extracellular matrix. J. Cell Biol. 177, 527–538 (2007). Brings together the themes of the extracellular environment, localized intracellular signalling and random versus directionally persistent cell migration by showing that syndecan 4 senses external membrane topography to limit RAC1 activity to the leading edge and promote directionally persistent cell migration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nobes, C. D. & Hall, A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81, 53–62 (1995).

    Article  CAS  PubMed  Google Scholar 

  90. Yip, S. C. et al. The distinct roles of Ras and Rac in PI 3-kinase-dependent protrusion during EGF-stimulated cell migration. J. Cell Sci. 120, 3138–3146 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Miki, H., Suetsugu, S. & Takenawa, T. WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac. EMBO J. 17, 6932–6941 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Sells, M. A. et al. Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Curr. Biol. 7, 202–210 (1997).

    Article  CAS  PubMed  Google Scholar 

  93. Suetsugu, S., Yamazaki, D., Kurisu, S. & Takenawa, T. Differential roles of WAVE1 and WAVE2 in dorsal and peripheral ruffle formation for fibroblast cell migration. Dev. Cell 5, 595–609 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Sells, M. A., Boyd, J. T. & Chernoff, J. p21-activated kinase 1 (Pak1) regulates cell motility in mammalian fibroblasts. J. Cell Biol. 145, 837–849 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Higuchi, M., Onishi, K., Kikuchi, C. & Gotoh, Y. Scaffolding function of PAK in the PDK1-Akt pathway. Nature Cell Biol. 10, 1356–1364 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Primo, L. et al. Essential role of PDK1 in regulating endothelial cell migration. J. Cell Biol. 176, 1035–1047 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Carlier, M. F. et al. Actin depolymerizing factor (ADF/cofilin) enhances the rate of filament turnover: implication in actin-based motility. J. Cell Biol. 136, 1307–1322 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hotulainen, P., Paunola, E., Vartiainen, M. K. & Lappalainen, P. Actin-depolymerizing factor and cofilin-1 play overlapping roles in promoting rapid F-actin depolymerization in mammalian nonmuscle cells. Mol. Biol. Cell 16, 649–664 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Danen, E. H. et al. Integrins control motile strategy through a Rho-cofilin pathway. J. Cell Biol. 169, 515–526 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. White, D. P., Caswell, P. T. & Norman, J. C. αvβ3 and α5β1 integrin recycling pathways dictate downstream Rho kinase signalling to regulate persistent cell migration. J. Cell Biol. 177, 515–525 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Sidani, M. et al. Cofilin determines the migration behaviour and turning frequency of metastatic cancer cells. J. Cell Biol. 179, 777–791 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Denker, S. P. & Barber, D. L. Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. J. Cell Biol. 159, 1087–1096 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. van Rheenen, J. et al. EGF-induced PIP2 hydrolysis releases and activates cofilin locally in carcinoma cells. J. Cell Biol. 179, 1247–1259 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Frantz, C. et al. Cofilin is a pH sensor for actin free barbed end formation: role of phosphoinositide binding. J. Cell Biol. 183, 865–879 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Caswell, P. T. & Norman, J. C. Integrin trafficking and the control of cell migration. Traffic 7, 14–21 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Nishimura, T. & Kaibuchi, K. Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3. Dev. Cell 13, 15–28 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Santolini, E. et al. Numb is an endocytic protein. J. Cell Biol. 151, 1345–1352 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Woods, A. J., White, D. P., Caswell, P. T. & Norman, J. C. PKD1/PKCμ promotes αvβ3 integrin recycling and delivery to nascent focal adhesions. EMBO J. 23, 2531–2543 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Roberts, M., Barry, S., Woods, A., van der Sluijs, P. & Norman, J. PDGF-regulated rab4-dependent recycling of αvβ3 integrin from early endosomes is necessary for cell adhesion and spreading. Curr. Biol. 11, 1392–1402 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Caswell, P. T. et al. Rab-coupling protein coordinates recycling of α5β1 integrin and EGFR1 to promote cell migration in 3D microenvironments. J. Cell Biol. 183, 143–155 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Caswell, P. T. et al. Rab25 associates with α5β1 integrin to promote invasive migration in 3D microenvironments. Dev. Cell 13, 496–510 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Strachan, L. R. & Condic, M. L. Cranial neural crest recycle surface integrins in a substratum-dependent manner to promote rapid motility. J. Cell Biol. 167, 545–554 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Mostafavi-Pour, Z. et al. Integrin-specific signalling pathways controlling focal adhesion formation and cell migration. J. Cell Biol. 161, 155–167 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Saoncella, S. et al. Syndecan-4 signals cooperatively with integrins in a Rho-dependent manner in the assembly of focal adhesions and actin stress fibers. Proc. Natl Acad. Sci. USA 96, 2805–2810 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Nishiya, N., Kiosses, W. B., Han, J. & Ginsberg, M. H. An α4 integrin–paxillin–Arf-GAP complex restricts Rac activation to the leading edge of migrating cells. Nature Cell Biol. 7, 343–352 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. De Calisto, J., Araya, C., Marchant, L., Riaz, C. F. & Mayor, R. Essential role of non-canonical Wnt signalling in neural crest migration. Development 132, 2587–2597 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Matthews, H. K. et al. Directional migration of neural crest cells in vivo is regulated by syndecan-4/Rac1 and non-canonical Wnt signalling/RhoA. Development 135, 1771–1780 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Trainor, P. A. Specification of neural crest cell formation and migration in mouse embryos. Semin. Cell Dev. Biol. 16, 683–693 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Abercrombie, M. & Heaysman, J. E. Observations on the social behaviour of cells in tissue culture: II. “Monolayering” of fibroblasts. Exp. Cell Res. 6, 293–306 (1954).

    Article  CAS  PubMed  Google Scholar 

  120. Carmona-Fontaine, C. et al. Contact inhibition of locomotion in vivo controls neural crest directional migration. Nature 456, 957–961 (2008). Shows how the basic cell biological processes of contact inhibition of movement, non-canonical Wnt signalling and RHOA-mediated actin–myosin contraction combine to trigger directional migration of neural crest cells in vivo .

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Totsukawa, G. et al. Distinct roles of ROCK (Rho-kinase) and MLCK in spatial regulation of MLC phosphorylation for assembly of stress fibers and focal adhesions in 3T3 fibroblasts. J. Cell Biol. 150, 797–806 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Chrzanowska-Wodnicka, M. & Burridge, K. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J. Cell Biol. 133, 1403–1415 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. Van Keymeulen, A. et al. To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front. J. Cell Biol. 174, 437–445 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wessels, D., Lusche, D. F., Kuhl, S., Heid, P. & Soll, D. R. PTEN plays a role in the suppression of lateral pseudopod formation during Dictyostelium motility and chemotaxis. J. Cell Sci. 120, 2517–2531 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Vicente-Manzanares, M., Zareno, J., Whitmore, L., Choi, C. K. & Horwitz, A. F. Regulation of protrusion, adhesion dynamics, and polarity by myosins IIA and IIB in migrating cells. J. Cell Biol. 176, 573–580 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Even-Ram, S. et al. Myosin IIA regulates cell motility and actomyosin-microtubule crosstalk. Nature Cell Biol. 9, 299–309 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Lo, C. M. et al. Nonmuscle myosin IIb is involved in the guidance of fibroblast migration. Mol. Biol. Cell 15, 982–989 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Vicente-Manzanares, M., Koach, M. A., Whitmore, L., Lamers, M. L. & Horwitz, A. F. Segregation and activation of myosin IIB creates a rear in migrating cells. J. Cell Biol. 183, 543–554 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Weeraratna, A. T. et al. Wnt5a signalling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell 1, 279–288 (2002).

    Article  CAS  PubMed  Google Scholar 

  130. Witze, E. S., Litman, E. S., Argast, G. M., Moon, R. T. & Ahn, N. G. Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors. Science 320, 365–369 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Dodd, J. & Jessell, T. M. Axon guidance and the patterning of neuronal projections in vertebrates. Science 242, 692–699 (1988).

    Article  CAS  PubMed  Google Scholar 

  132. Singer, A. J. & Clark, R. A. Cutaneous wound healing. N. Engl. J. Med. 341, 738–746 (1999).

    Article  CAS  PubMed  Google Scholar 

  133. Heit, B. et al. PTEN functions to 'prioritize' chemotactic cues and prevent 'distraction' in migrating neutrophils. Nature Immunol. 9, 743–752 (2008). Combines in vitro and in vivo approaches to model the complex environment found during the inflammatory neutrophil response, in which cells are often forced to choose between competing guidance cues. It exemplifies the innovative experimentation needed to decipher the complex mechanisms underlying directional cell migration.

    Article  CAS  Google Scholar 

  134. Gail, M. in Locomotion of Tissue Cells 287–302 (Elsevier, Amsterdam, 1973).

    Google Scholar 

  135. Jaffe, A. B. & Hall, A. Rho GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. 21, 247–269 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Raftopoulou, M. & Hall, A. Cell migration: Rho GTPases lead the way. Dev. Biol. 265, 23–32 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Bos, J. L., Rehmann, H. & Wittinghofer, A. GEFs and GAPs: critical elements in the control of small G proteins. Cell 129, 865–877 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Kestler, H. A. & Kuhl, M. From individual Wnt pathways towards a Wnt signalling network. Philos. Trans. R. Soc. Lond. B Biol. Sci. 363, 1333–1347 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Croce, J. C. & McClay, D. R. The canonical Wnt pathway in embryonic axis polarity. Semin. Cell Dev. Biol. 17, 168–174 (2006).

    Article  CAS  PubMed  Google Scholar 

  140. van Amerongen, R., Mikels, A. & Nusse, R. Alternative Wnt signalling is initiated by distinct receptors. Sci. Signal 1, re9 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Y. Endo, A. Green, J. Harunaga and E. Joo for helpful comments on the manuscript. Support was provided by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health.

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Correspondence to Ryan J. Petrie or Kenneth M. Yamada.

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Glossary

Motogenic signal

A signal, such as a growth factor, that activates the cell motility machinery without providing directional information and thereby triggers intrinsic cell migration.

Extracellular matrix

A network of proteins and polysaccharides secreted by cells that provides structural support for cells in tissues.

Lamellipodium

A flattened, actin-rich protrusion found at the leading edge of a migrating cell.

Integrin

A member of a large family of transmembrane proteins, which exist in the plasma membrane as heterodimers of α and β subunits and frequently mediate the interaction of cells with the ECM.

Chemokinesis

Non-directional cell migration triggered by an extracellular cue.

Contact guidance

The process by which cells are guided by topographical structures that are often associated with the ECM.

Gastrulation

The process during embryogenesis whereby the embryo is transformed from a hollow sphere of cells into a structure with three germ layers: ectoderm, mesoderm and endoderm.

Lamella

The flattened region immediately behind the lamellipodium.

Glu-tubulin

(Also known as detyrosinated tubulin). A post-translational modification of tubulin that is associated with microtubule stabilization.

Metastasis

The spreading of cancer cells from a site of origin to distant parts of the body, which often involves cell motility.

GTPase-activating protein

(GAP). A protein that accelerates the intrinsic GTPase activity of small G proteins to inactivate them.

Scratch wound healing assay

An in vitro cell motility assay. When an area of cells in a monolayer is cleared (scratched), cells will directionally migrate into the wound and close it.

Guanine nucleotide exchange factor

A protein that activates small G proteins by catalysing the exchange of GDP for GTP.

Anterograde transport

The transport of material from the Golgi to the cell surface through the secretory pathway.

Retrograde actin flow

The net movement of filamentous actin away from the cell edge.

Dishevelled

A family of cytoplasmic proteins that participate in Wnt signalling immediately downstream of the Frizzled receptors.

Cell cortex

An actin-rich layer near the inner surface of the plasma membrane.

Caveola

A flask-shaped invagination of the plasma membrane that contributes to cell polarity and directional cell migration.

Arp2/3

A protein complex that nucleates actin filament growth from the sides of pre-existing actin filaments to form branched actin networks.

Clathrin-coated pit

An invagination in the plasma membrane that is coated by lattices made up of the protein clathrin and is the precursor to an endocytic vesicle.

Rab family

A large family of small GTPases, found on organelles and the plasma membrane, that confer specificity on vesicle docking and membrane trafficking.

Matrigel

A commercially available basement membrane matrix, composed primarily of laminin and collagen, which can be used as a 3D tissue culture model for studying cell migration and differentiation.

Proteoglycan

A protein core that is linked to at least one long, linear and highly charged polysaccharide chain.

Focal adhesion

A large protein complex that mediates the attachment of the ECM to the actin cytoskeleton through an integrin heterodimer.

Neural crest

A group of cells that migrate to various regions of the embryo and form, in part, the bones of the skull and teeth and portions of the peripheral nervous system.

Morpholino

A synthetic molecule that binds to specific mRNAs to block their translation and is thereby used to assay protein function.

Contact inhibition

The response that occurs when a migrating cell contacts another migrating cell and changes direction to move away from the point of contact.

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Petrie, R., Doyle, A. & Yamada, K. Random versus directionally persistent cell migration. Nat Rev Mol Cell Biol 10, 538–549 (2009). https://doi.org/10.1038/nrm2729

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