Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Beyond polymer polarity: how the cytoskeleton builds a polarized cell

Nature Reviews Molecular Cell Biology volume 9, pages 860–873 (2008)Cite this article

Key Points

  • Actin and microtubules are dynamic polar polymers that are well suited for providing the structural basis for cell polarity.

  • Nucleation and plus-end regulation are key mechanisms for the assembly of orientated actin and microtubule arrays, respectively.

  • Actin and actin-based motor proteins drive symmetry breaking in several well-studied, polarized cell types.

  • Microtubules promote symmetry breaking in the establishment of neuronal polarity.

  • Microtubules have key roles in the maintenance of cell polarity in many mammalian cell types.

  • Crosstalk coordinates the function of actin and microtubules in cell polarity.

Abstract

Cell polarity relies on the asymmetric organization of cellular components and structures. Actin and microtubules are well suited to provide the structural basis for cell polarization because of their inherent structural polarity along the polymer lattices and intrinsic dynamics that allow them to respond rapidly to polarity cues. In general, the actin cytoskeleton drives the symmetry-breaking process that enables the establishment of a polarized distribution of regulatory molecules, whereas microtubules build on this asymmetry and maintain the stability of the polarized organization. Crosstalk coordinates the functions of the two cytoskeletal systems.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Establishment of orientated cytoskeletal arrays.
Figure 2: Mechanisms of actin-based symmetry breaking in the establishment of cell polarity.
Figure 3: Microtubule-based symmetry breaking in neurons.
Figure 4: Polarization of microtubule arrays in migrating fibroblasts, T cells and differentiating neurons.

Similar content being viewed by others

References

  1. Pollard, T. D. & Cooper, J. A. Actin and actin binding proteins. A critical evaluation of mechanisms and functions. Ann. Rev. Biochem. 55, 987–1035 (1986).

    CAS  PubMed  Google Scholar 

  2. Nogales, E. Structural insights into microtubule function. Annu. Rev. Biochem. 69, 277–302 (2000).

    CAS  PubMed  Google Scholar 

  3. Goldman, R. D., Grin, B., Mendez, M. G. & Kuczmarski, E. R. Intermediate filaments: versatile building blocks of cell structure. Curr. Opin. Cell Biol. 20, 28–34 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Longtine, M. S. & Bi, E. Regulation of septin organization and function in yeast. Trends Cell Biol. 13, 403–409 (2003).

    CAS  PubMed  Google Scholar 

  5. Spiliotis, E. T., Hunt, S. J., Hu, Q., Kinoshita, M. & Nelson, W. J. Epithelial polarity requires septin coupling of vesicle transport to polyglutamylated microtubules. J. Cell Biol. 180, 295–303 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kremer, B. E., Adang, L. A. & Macara, I. G. Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7. Cell 130, 837–850 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Ikebe, M. Regulation of the function of mammalian myosin and its conformational change. Biochem. Biophys. Res. Commun. 369, 157–164 (2008).

    CAS  PubMed  Google Scholar 

  8. Kikkawa, M. The role of microtubules in processive kinesin movement. Trends Cell Biol. 18, 128–135 (2008).

    CAS  PubMed  Google Scholar 

  9. Block, S. M. Kinesin motor mechanics: binding, stepping, tracking, gating, and limping. Biophys. J. 92, 2986–2995 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Numata, N. et al. Molecular mechanism of force generation by dynein, a molecular motor belonging to the AAA+ family. Biochem. Soc. Trans. 36, 131–135 (2008).

    CAS  PubMed  Google Scholar 

  11. Kincaid, M. M. & King, S. J. Motors and their tethers: the role of secondary binding sites in processive motility. Cell Cycle 5, 2733–2737 (2006).

    CAS  PubMed  Google Scholar 

  12. Manahan, C. L., Iglesias, P. A., Long, Y. & Devreotes, P. N. Chemoattractant signaling in Dictyostelium discoideum. Annu. Rev. Cell Dev. Biol. 20, 223–253 (2004).

    CAS  PubMed  Google Scholar 

  13. Irazoqui, J. E., Gladfelter, A. S. & Lew, D. J. Scaffold-mediated symmetry breaking by Cdc42p. Nature Cell Biol. 5, 1062–1070 (2003). Highlights a pathway of symmetry breaking in yeast through the assembly of a signalling complex that contains Cdc42, which contrasts with mechanisms that involve cytoskeletal elements.

    CAS  PubMed  Google Scholar 

  14. Wegner, A. & Engel, J. Kinetics of the cooperative association of actin to actin filaments. Biophys. Chem. 3, 215–225 (1975).

    CAS  PubMed  Google Scholar 

  15. Barton, J. S. & Riazi, G. H. Evidence for two growth steps in microtubule polymerization. Biochim. Biophys. Acta 630, 392–401 (1980).

    CAS  PubMed  Google Scholar 

  16. Pollard, T. D. Regulation of actin filament assembly by Arp2/3 complex and formins. Annu. Rev. Biophys. Biomol. Struct. 36, 451–477 (2007).

    CAS  PubMed  Google Scholar 

  17. Svitkina, T. M. & Borisy, G. G. Arp2/3 complex and actin depolymerizing factor/cofilin in dendritic organization and treadmilling of actin filament array in lamellipodia. J. Cell Biol. 145, 1009–1026 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Chhabra, E. S. & Higgs, H. N. The many faces of actin: matching assembly factors with cellular structures. Nature Cell Biol. 9, 1110–1121 (2007).

    CAS  PubMed  Google Scholar 

  19. Ridley, A. J. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol. 16, 522–529 (2006).

    CAS  PubMed  Google Scholar 

  20. Gundersen, G. G., Gomes, E. R. & Wen, Y. Cortical control of microtubule stability and polarization. Curr. Opin. Cell Biol. 16, 106–112 (2004).

    CAS  PubMed  Google Scholar 

  21. Lansbergen, G. & Akhmanova, A. Microtubule plus end: a hub of cellular activities. Traffic 7, 499–507 (2006).

    CAS  PubMed  Google Scholar 

  22. Martin, S. G., McDonald, W. H., Yates, J. R. & Chang, F. Tea4p links microtubule plus ends with the formin for3p in the establishment of cell polarity. Dev. Cell 8, 479–491 (2005). Uses elegant live-cell imaging in S. pombe to identify a direct mechanism for how microtubules deposit factors at cortical sites that affect actin polymerization and cell polarity.

    CAS  PubMed  Google Scholar 

  23. Segal, M. & Bloom, K. Control of spindle polarity and orientation in Saccharomyces cerevisiae. Trends Cell Biol. 11, 160–166 (2001).

    CAS  PubMed  Google Scholar 

  24. Cowan, C. R. & Hyman, A. A. Asymmetric cell division in C. elegans: cortical polarity and spindle positioning. Annu. Rev. Cell Dev. Biol. 20, 427–453 (2004).

    CAS  PubMed  Google Scholar 

  25. Schuyler, S. C. & Pellman, D. Search, capture and signal: games microtubules and centrosomes play. J. Cell Sci. 114, 247–255 (2001).

    CAS  PubMed  Google Scholar 

  26. Kozlowski, C., Srayko, M. & Nedelec, F. Cortical microtubule contacts position the spindle in C. elegans embryos. Cell 129, 499–510 (2007).

    CAS  PubMed  Google Scholar 

  27. Pruyne, D., Legesse-Miller, A., Gao, L., Dong, Y. & Bretscher, A. Mechanisms of polarized growth and organelle segregation in yeast. Annu. Rev. Cell Dev. Biol. 20, 559–591 (2004).

    CAS  PubMed  Google Scholar 

  28. Evangelista, M., Pruyne, D., Amberg, D. C., Boone, C. & Bretscher, A. Formins direct Arp2/3-independent actin filament assembly to polarize cell growth in yeast. Nature Cell Biol. 4, 32–41 (2002).

    CAS  PubMed  Google Scholar 

  29. Sagot, I., Klee, S. K. & Pellman, D. Yeast formins regulate cell polarity by controlling the assembly of actin cables. Nature Cell Biol. 4, 42–50 (2002). References 28 and 29 established a direct role for formin-family proteins in the assembly of actin cables that mediate polarized transport in yeast.

    CAS  PubMed  Google Scholar 

  30. Liu, H. P. & Bretscher, A. Disruption of the single tropomyosin gene in yeast results in the disappearance of actin cables from the cytoskeleton. Cell 57, 233–242 (1989).

    CAS  PubMed  Google Scholar 

  31. Adams, A. E., Botstein, D. & Drubin, D. G. Requirement of yeast fimbrin for actin organization and morphogenesis in vivo. Nature 354, 404–408 (1991).

    CAS  PubMed  Google Scholar 

  32. Park, H. O. & Bi, E. Central roles of small GTPases in the development of cell polarity in yeast and beyond. Microbiol. Mol. Biol. Rev. 71, 48–96 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Johnson, D. I. Cdc42: An essential Rho-type GTPase controlling eukaryotic cell polarity. Microbiol. Mol. Biol. Rev. 63, 54–105 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Evangelista, M. et al. Bni1p, a yeast formin linking cdc42p and the actin cytoskeleton during polarized morphogenesis. Science 276, 118–122 (1997).

    CAS  PubMed  Google Scholar 

  35. Imamura, H. et al. Bni1p and Bnr1p: downstream targets of the Rho family small G-proteins which interact with profilin and regulate actin cytoskeleton in Saccharomyces cerevisiae. EMBO J. 16, 2745–2755 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Dong, Y., Pruyne, D. & Bretscher, A. Formin-dependent actin assembly is regulated by distinct modes of Rho signaling in yeast. J. Cell Biol. 161, 1081–1092 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Wedlich-Soldner, R., Altschuler, S., Wu, L. & Li, R. Spontaneous cell polarization through actomyosin-based delivery of the Cdc42 GTPase. Science 299, 1231–1235 (2003). Shows a simple mechanism in yeast for symmetry breaking that involves a positive-feedback loop composed of actin- and myosin-mediated transport of the signalling molecule Cdc42, and Cdc42-controlled assembly of orientated actin arrays.

    CAS  PubMed  Google Scholar 

  38. Pruyne, D., Gao, L., Bi, E. & Bretscher, A. Stable and dynamic axes of polarity use distinct formin isoforms in budding yeast. Mol. Biol. Cell 15, 4971–4989 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Wedlich-Soldner, R., Wai, S. C., Schmidt, T. & Li, R. Robust cell polarity is a dynamic state established by coupling transport and GTPase signaling. J. Cell Biol. 166, 889–900 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Severson, A. F. & Bowerman, B. Myosin and the PAR proteins polarize microfilament-dependent forces that shape and position mitotic spindles in Caenorhabditis elegans. J. Cell Biol. 161, 21–26 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Cuenca, A. A., Schetter, A., Aceto, D., Kemphues, K. & Seydoux, G. Polarization of the C. elegans zygote proceeds via distinct establishment and maintenance phases. Development 130, 1255–1265 (2003).

    CAS  PubMed  Google Scholar 

  42. Munro, E., Nance, J. & Priess, J. R. Cortical flows powered by asymmetrical contraction transport PAR proteins to establish and maintain anterior–posterior polarity in the early C. elegans embryo. Dev. Cell 7, 413–424 (2004). This seminal work in a C. elegans one-cell embryo shows the crucial role of a cortical contractile network that contains actin and myosin-II in establishing an asymmetric distribution of the PAR polarity complexes. A similar mechanism might also operate during the establishment of epithelial apical–basal polarity.

    CAS  PubMed  Google Scholar 

  43. Watts, J. L. et al. par-6, a gene involved in the establishment of asymmetry in early C. elegans embryos, mediates the asymmetric localization of PAR-3. Development 122, 3133–3140 (1996).

    CAS  PubMed  Google Scholar 

  44. Hao, Y., Boyd, L. & Seydoux, G. Stabilization of cell polarity by the C. elegans RING protein PAR-2. Dev. Cell 10, 199–208 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wedlich-Soldner, R. & Li, R. Spontaneous cell polarization: undermining determinism. Nature Cell Biol. 5, 267–270 (2003).

    CAS  PubMed  Google Scholar 

  46. Cowan, C. R. & Hyman, A. A. Centrosomes direct cell polarity independently of microtubule assembly in C. elegans embryos. Nature 431, 92–96 (2004).

    CAS  PubMed  Google Scholar 

  47. Jenkins, N., Saam, J. R. & Mango, S. E. CYK-4/GAP provides a localized cue to initiate anteroposterior polarity upon fertilization. Science 313, 1298–1301 (2006).

    CAS  PubMed  Google Scholar 

  48. Motegi, F. & Sugimoto, A. Sequential functioning of the ECT-2 RhoGEF, RHO-1 and CDC-42 establishes cell polarity in Caenorhabditis elegans embryos. Nature Cell Biol. 8, 978–985 (2006).

    CAS  PubMed  Google Scholar 

  49. Piekny, A., Werner, M. & Glotzer, M. Cytokinesis: welcome to the Rho zone. Trends Cell Biol. 15, 651–658 (2005).

    CAS  PubMed  Google Scholar 

  50. Perez-Moreno, M., Jamora, C. & Fuchs, E. Sticky business: orchestrating cellular signals at adherens junctions. Cell 112, 535–548 (2003).

    CAS  PubMed  Google Scholar 

  51. Baas, A. F. et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116, 457–466 (2004). Describes the surprising discovery that epithelial cells have the capacity to undergo spontaneous symmetry breaking without resorting to cell–cell or cell–matrix contacts. This highlights the commonality of self-organization as the basic principle that underlies cell polarization.

    CAS  PubMed  Google Scholar 

  52. Williams, T. & Brenman, J. E. LKB1 and AMPK in cell polarity and division. Trends Cell Biol. 18, 193–198 (2008).

    CAS  PubMed  Google Scholar 

  53. Lee, J. H. et al. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447, 1017–1020 (2007).

    CAS  PubMed  Google Scholar 

  54. Mirouse, V., Swick, L. L., Kazgan, N., St Johnston, D. & Brenman, J. E. LKB1 and AMPK maintain epithelial cell polarity under energetic stress. J. Cell Biol. 177, 387–392 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Martin-Belmonte, F. & Mostov, K. Regulation of cell polarity during epithelial morphogenesis. Curr. Opin. Cell Biol. 20, 227–234 (2008).

    CAS  PubMed  Google Scholar 

  56. Di Nardo, A. et al. Arp2/3 complex-deficient mouse fibroblasts are viable and have normal leading-edge actin structure and function. Proc. Natl Acad. Sci. USA 102, 16263–16268 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Zigmond, S. H. Beginning and ending an actin filament: control at the barbed end. Curr. Top. Dev. Biol. 63, 145–188 (2004).

    CAS  PubMed  Google Scholar 

  58. Gunning, P. W., Schevzov, G., Kee, A. J. & Hardeman, E. C. Tropomyosin isoforms: divining rods for actin cytoskeleton function. Trends Cell Biol. 15, 333–341 (2005).

    CAS  PubMed  Google Scholar 

  59. Fanning, A. S., Wolenski, J. S., Mooseker, M. S. & Izant, J. G. Differential regulation of skeletal muscle myosin-II and brush border myosin-I enzymology and mechanochemistry by bacterially produced tropomyosin isoforms. Cell. Motil. Cytoskeleton 29, 29–45 (1994).

    CAS  PubMed  Google Scholar 

  60. Wawro, B. et al. Tropomyosin regulates elongation by formin at the fast-growing end of the actin filament. Biochemistry 46, 8146–8155 (2007).

    CAS  PubMed  Google Scholar 

  61. Blanchoin, L., Pollard, T. D. & Hitchcock-DeGregori, S. E. Inhibition of the Arp2/3 complex-nucleated actin polymerization and branch formation by tropomyosin. Curr. Biol. 11, 1300–1304 (2001).

    CAS  PubMed  Google Scholar 

  62. Rouiller, I. et al. The structural basis of actin filament branching by the Arp2/3 complex. J. Cell Biol. 180, 887–895 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Bernstein, B. W. & Bamburg, J. R. Tropomyosin binding to F-actin protects the F-actin from disassembly by brain actin-depolymerizing factor (ADF). Cell. Motil. 2, 1–8 (1982).

    CAS  PubMed  Google Scholar 

  64. Ono, S. & Ono, K. Tropomyosin inhibits ADF/cofilin-dependent actin filament dynamics. J. Cell Biol. 156, 1065–1076 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Weiner, O. D. et al. A PtdInsP3- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity. Nature Cell Biol. 4, 509–513 (2002).

    CAS  PubMed  Google Scholar 

  66. Wong, K., Van Keymeulen, A. & Bourne, H. R. PDZRhoGEF and myosin II localize RhoA activity to the back of polarizing neutrophil-like cells. J. Cell Biol. 179, 1141–1148 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 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 behavior. J. Cell Biol. 147, 1009–1022 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Rosenfeldt, H., Castellone, M. D., Randazzo, P. A. & Gutkind, J. S. Rac inhibits thrombin-induced Rho activation: evidence of a Pak-dependent GTPase crosstalk. J. Mol. Signal 1, 8 (2006).

    PubMed  PubMed Central  Google Scholar 

  69. Salhia, B. et al. Inhibition of Rho-kinase affects astrocytoma morphology, motility, and invasion through activation of Rac1. Cancer Res. 65, 8792–8800 (2005).

    CAS  PubMed  Google Scholar 

  70. Nimnual, A. S., Taylor, L. J. & Bar-Sagi, D. Redox-dependent downregulation of Rho by Rac. Nature Cell Biol. 5, 236–241 (2003).

    CAS  PubMed  Google Scholar 

  71. Xu, J. et al. Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils. Cell 114, 201–214 (2003). Shows a mechanism in neutrophils by which mutually exclusive assembly of two different kinds of dynamic cytoskeletal structures promotes the establishment of the front–back polarity of motile cells.

    CAS  PubMed  Google Scholar 

  72. Wong, K., Pertz, O., Hahn, K. & Bourne, H. Neutrophil polarization: spatiotemporal dynamics of RhoA activity support a self-organizing mechanism. Proc. Natl Acad. Sci. USA 103, 3639–3644 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Narang, A. Spontaneous polarization in eukaryotic gradient sensing: a mathematical model based on mutual inhibition of frontness and backness pathways. J. Theor. Biol. 240, 538–553 (2006).

    CAS  PubMed  Google Scholar 

  74. Verkhovsky, A. B., Svitkina, T. M. & Borisy, G. G. Self-polarization and directional motility of cytoplasm. Curr. Biol. 9, 11–20 (1999).

    CAS  PubMed  Google Scholar 

  75. Arimura, N. & Kaibuchi, K. Neuronal polarity: from extracellular signals to intracellular mechanisms. Nature Rev. Neurosci. 8, 194–205 (2007).

    CAS  Google Scholar 

  76. Wiggin, G. R., Fawcett, J. P. & Pawson, T. Polarity proteins in axon specification and synaptogenesis. Dev. Cell 8, 803–816 (2005).

    CAS  PubMed  Google Scholar 

  77. Baas, P. W. & Black, M. M. Individual microtubules in the axon consist of domains that differ in both composition and stability. J. Cell Biol. 111, 495–509 (1990).

    CAS  PubMed  Google Scholar 

  78. Ferreira, A. & Caceres, A. The expression of acetylated microtubules during axonal and dendritic growth in cerebellar macroneurons which develop in vitro. Brain Res. Dev. Brain Res. 49, 205–213 (1989).

    CAS  PubMed  Google Scholar 

  79. Robson, S. J. & Burgoyne, R. D. Differential localisation of tyrosinated, detyrosinated, and acetylated α-tubulins in neurites and growth cones of dorsal root ganglion neurons. Cell. Motil. Cytoskeleton 12, 273–282 (1989).

    CAS  PubMed  Google Scholar 

  80. Witte, H., Neukirchen, D. & Bradke, F. Microtubule stabilization specifies initial neuronal polarization. J. Cell Biol. 180, 619–632 (2008). Shows that microtubule stabilization in one of the minor neurites of hippocampal neurons is sufficient to break symmetry and specify the formation of an axon.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Dotti, C. G. & Banker, G. Intracellular organization of hippocampal neurons during the development of neuronal polarity. J. Cell Sci. Suppl. 15, 75–84 (1991).

    CAS  PubMed  Google Scholar 

  82. de Anda, F. C. et al. Centrosome localization determines neuronal polarity. Nature 436, 704–708 (2005).

    PubMed  Google Scholar 

  83. Bradke, F. & Dotti, C. G. The role of local actin instability in axon formation. Science 283, 1931–1934 (1999).

    CAS  PubMed  Google Scholar 

  84. Garvalov, B. K. et al. Cdc42 regulates cofilin during the establishment of neuronal polarity. J. Neurosci. 27, 13117–13129 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Da Silva, J. S., Hasegawa, T., Miyagi, T., Dotti, C. G. & Abad-Rodriguez, J. Asymmetric membrane ganglioside sialidase activity specifies axonal fate. Nature Neurosci. 8, 606–615 (2005).

    CAS  PubMed  Google Scholar 

  86. Nakata, T. & Hirokawa, N. Neuronal polarity and the kinesin superfamily proteins. Sci. STKE 2007, pe6 (2007).

  87. Nishimura, T. et al. Role of the PAR-3–KIF3 complex in the establishment of neuronal polarity. Nature Cell Biol. 6, 328–334 (2004).

    CAS  PubMed  Google Scholar 

  88. Schwamborn, J. C. & Puschel, A. W. The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity. Nature Neurosci. 7, 923–929 (2004).

    CAS  PubMed  Google Scholar 

  89. Shi, S. H., Jan, L. Y. & Jan, Y. N. Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3-kinase activity. Cell 112, 63–75 (2003).

    CAS  PubMed  Google Scholar 

  90. Rolls, M. M. & Doe, C. Q. Baz, Par-6 and aPKC are not required for axon or dendrite specification in Drosophila. Nature Neurosci. 7, 1293–1295 (2004).

    CAS  PubMed  Google Scholar 

  91. Chen, Y. M. et al. Microtubule affinity-regulating kinase 2 functions downstream of the PAR-3/PAR-6/atypical PKC complex in regulating hippocampal neuronal polarity. Proc. Natl Acad. Sci. USA 103, 8534–8539 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Drewes, G., Ebneth, A., Preuss, U., Mandelkow, E. M. & Mandelkow, E. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89, 297–308 (1997).

    CAS  PubMed  Google Scholar 

  93. Larcher, J. C., Boucher, D., Lazereg, S., Gros, F. & Denoulet, P. Interaction of kinesin motor domains with α- and β-tubulin subunits at a tau-independent binding site. Regulation by polyglutamylation. J. Biol. Chem. 271, 22117–22124 (1996).

    CAS  PubMed  Google Scholar 

  94. Liao, G. & Gundersen, G. G. Kinesin is a candidate for cross-bridging microtubules and intermediate filaments. Selective binding of kinesin to detyrosinated tubulin and vimentin. J. Biol. Chem. 273, 9797–9803 (1998).

    CAS  PubMed  Google Scholar 

  95. Lin, S. X., Gundersen, G. G. & Maxfield, F. R. Export from pericentriolar endocytic recycling compartment to cell surface depends on stable, detyrosinated (Glu) microtubules and kinesin. Mol. Biol. Cell 13, 96–109 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Reed, N. A. et al. Microtubule acetylation promotes kinesin-1 binding and transport. Curr. Biol. 16, 2166–2172 (2006).

    CAS  PubMed  Google Scholar 

  97. Jacobson, C., Schnapp, B. & Banker, G. A. A change in the selective translocation of the Kinesin-1 motor domain marks the initial specification of the axon. Neuron 49, 797–804 (2006).

    CAS  PubMed  Google Scholar 

  98. Nakata, T. & Hirokawa, N. Microtubules provide directional cues for polarized axonal transport through interaction with kinesin motor head. J. Cell Biol. 162, 1045–1055 (2003). References 97 and 98 provide evidence that the kinesin motor domain alone is capable of interpreting cues from microtubules to direct their translocation into specific neuronal processes.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. van Drogen, F., Stucke, V. M., Jorritsma, G. & Peter, M. MAP kinase dynamics in response to pheromones in budding yeast. Nature Cell Biol. 3, 1051–1059 (2001).

    CAS  PubMed  Google Scholar 

  100. Valdez-Taubas, J. & Pelham, H. R. Slow diffusion of proteins in the yeast plasma membrane allows polarity to be maintained by endocytic cycling. Curr. Biol. 13, 1636–1640 (2003). Elegantly shows the crucial role for endocytic recycling in yeast in the polarized localization of membrane proteins.

    CAS  PubMed  Google Scholar 

  101. Boyd, C., Hughes, T., Pypaert, M. & Novick, P. Vesicles carry most exocyst subunits to exocytic sites marked by the remaining two subunits, Sec3p and Exo70p. J. Cell Biol. 167, 889–901 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Kaksonen, M., Toret, C. P. & Drubin, D. G. Harnessing actin dynamics for clathrin-mediated endocytosis. Nature Rev. Mol. Cell Biol. 7, 404–414 (2006).

    CAS  Google Scholar 

  103. Irazoqui, J. E., Howell, A. S., Theesfeld, C. L. & Lew, D. J. Opposing roles for actin in Cdc42p polarization. Mol. Biol. Cell 16, 1296–1304 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Marco, E., Wedlich-Soldner, R., Li, R., Altschuler, S. J. & Wu, L. F. Endocytosis optimizes the dynamic localization of membrane proteins that regulate cortical polarity. Cell 129, 411–422 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Castagnetti, S., Behrens, R. & Nurse, P. End4/Sla2 is involved in establishment of a new growth zone in Schizosaccharomyces pombe. J. Cell Sci. 118, 1843–1850 (2005).

    CAS  PubMed  Google Scholar 

  106. Bretscher, M. S. Endocytosis: relation to capping and cell locomotion. Science 224, 681–686 (1984).

    CAS  PubMed  Google Scholar 

  107. Coumailleau, F. & Gonzalez-Gaitan, M. From endocytosis to tumors through asymmetric cell division of stem cells. Curr. Opin. Cell Biol. 20, 462–469 (2008).

    CAS  PubMed  Google Scholar 

  108. Thompson, A. et al. Recycling endosomes of polarized epithelial cells actively sort apical and basolateral cargos into separate subdomains. Mol. Biol. Cell 18, 2687–2697 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Prigozhina, N. L. & Waterman-Storer, C. M. Decreased polarity and increased random motility in PtK1 epithelial cells correlate with inhibition of endosomal recycling. J. Cell Sci. 119, 3571–3582 (2006).

    CAS  PubMed  Google Scholar 

  110. Lu, H. & Bilder, D. Endocytic control of epithelial polarity and proliferation in Drosophila. Nature Cell Biol. 7, 1232–1239 (2005).

    PubMed  Google Scholar 

  111. Tanaka, T. & Nakamura, A. The endocytic pathway acts downstream of Oskar in Drosophila germ plasm assembly. Development 135, 1107–1117 (2008).

    CAS  PubMed  Google Scholar 

  112. Vanzo, N., Oprins, A., Xanthakis, D., Ephrussi, A. & Rabouille, C. Stimulation of endocytosis and actin dynamics by Oskar polarizes the Drosophila oocyte. Dev. Cell 12, 543–555 (2007).

    CAS  PubMed  Google Scholar 

  113. Balklava, Z., Pant, S., Fares, H. & Grant, B. D. Genome-wide analysis identifies a general requirement for polarity proteins in endocytic traffic. Nature Cell Biol. 9, 1066–1073 (2007).

    CAS  PubMed  Google Scholar 

  114. Meinhardt, H. Orientation of chemotactic cells and growth cones: models and mechanisms. J. Cell Sci. 112, 2867–2874 (1999).

    CAS  PubMed  Google Scholar 

  115. Iijima, M. & Devreotes, P. Tumor suppressor PTEN mediates sensing of chemoattractant gradients. Cell 109, 599–610 (2002).

    CAS  PubMed  Google Scholar 

  116. Funamoto, S., Meili, R., Lee, S., Parry, L. & Firtel, R. A. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 109, 611–623 (2002).

    CAS  PubMed  Google Scholar 

  117. Sancho, D. et al. Regulation of microtubule-organizing center orientation and actomyosin cytoskeleton rearrangement during immune interactions. Immunol. Rev. 189, 84–97 (2002).

    CAS  PubMed  Google Scholar 

  118. Stowers, L., Yelon, D., Berg, L. J. & Chant, J. Regulation of the polarization of T cells toward antigen-presenting cells by Ras-related GTPase CDC42. Proc. Natl Acad. Sci. USA 92, 5027–5031 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Kuhn, J. R. & Poenie, M. Dynamic polarization of the microtubule cytoskeleton during CTL-mediated killing. Immunity 16, 111–121 (2002).

    CAS  PubMed  Google Scholar 

  120. Combs, J. et al. Recruitment of dynein to the Jurkat immunological synapse. Proc. Natl Acad. Sci. USA 103, 14883–14888 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Stinchcombe, J. C., Majorovits, E., Bossi, G., Fuller, S. & Griffiths, G. M. Centrosome polarization delivers secretory granules to the immunological synapse. Nature 443, 462–465 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  123. Palazzo, A. F. et al. Cdc42, dynein, and dynactin regulate MTOC reorientation independent of Rho-regulated microtubule stabilization. Curr. Biol. 11, 1536–1541 (2001).

    CAS  PubMed  Google Scholar 

  124. Solecki, D. J., Model, L., Gaetz, J., Kapoor, T. M. & Hatten, M. E. Par6α signaling controls glial-guided neuronal migration. Nature Neurosci. 7, 1195–1203 (2004).

    CAS  PubMed  Google Scholar 

  125. Watanabe, T. et al. Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration. Dev. Cell 7, 871–883 (2004).

    CAS  PubMed  Google Scholar 

  126. 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). Shows that MTOC orientation or centrosome orientation in migrating fibroblasts results from movement of the nucleus, rather than movement of the centrosome.

    CAS  PubMed  Google Scholar 

  127. Yamana, N. et al. The Rho–mDia1 pathway regulates cell polarity and focal adhesion turnover in migrating cells through mobilizing Apc and c-Src. Mol. Cell. Biol. 26, 6844–6858 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Gundersen, G. G. & Bulinski, J. C. Selective stabilization of microtubules oriented toward the direction of cell migration. Proc. Natl Acad. Sci. USA 85, 5946–5950 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Cook, T. A., Nagasaki, T. & Gundersen, G. G. Rho guanosine triphosphatase mediates the selective stabilization of microtubules induced by lysophosphatidic acid. J. Cell Biol. 141, 175–185 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Kodama, A., Karakesisoglou, I., Wong, E., Vaezi, A. & Fuchs, E. ACF7: an essential integrator of microtubule dynamics. Cell 115, 343–354 (2003).

    CAS  PubMed  Google Scholar 

  131. Palazzo, A. F., Cook, T. A., Alberts, A. S. & Gundersen, G. G. mDia mediates Rho-regulated formation and orientation of stable microtubules. Nature Cell Biol. 3, 723–729 (2001).

    CAS  PubMed  Google Scholar 

  132. Infante, A. S., Stein, M. S., Zhai, Y., Borisy, G. G. & Gundersen, G. G. Detyrosinated (Glu) microtubules are stabilized by an ATP-sensitive plus-end cap. J. Cell Sci. 113, 3907–3919 (2000).

    CAS  PubMed  Google Scholar 

  133. Bartolini, F. et al. The formin mDia2 stabilizes microtubules independently of its actin nucleation activity. J. Cell Biol. 181, 523–536 (2008). Shows that a formin, mDia2, with known actin-nucleation activity, independently and directly stabilizes microtubules.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Palazzo, A. F., Eng, C. H., Schlaepfer, D. D., Marcantonio, E. E. & Gundersen, G. G. Localized stabilization of microtubules by integrin- and FAK-facilitated Rho signaling. Science 303, 836–839 (2004).

    CAS  PubMed  Google Scholar 

  135. Wen, Y. et al. EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration. Nature Cell Biol. 6, 820–830 (2004).

    CAS  PubMed  Google Scholar 

  136. Akhmanova, A. et al. Clasps are CLIP-115 and -170 associating proteins involved in the regional regulation of microtubule dynamics in motile fibroblasts. Cell 104, 923–935 (2001).

    CAS  PubMed  Google Scholar 

  137. Lansbergen, G. et al. CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5β. Dev. Cell 11, 21–32 (2006).

    CAS  PubMed  Google Scholar 

  138. Wittmann, T. & Waterman-Storer, C. M. Spatial regulation of CLASP affinity for microtubules by Rac1 and GSK3β in migrating epithelial cells. J. Cell Biol. 169, 929–939 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Schmoranzer, J., Kreitzer, G. & Simon, S. M. Migrating fibroblasts perform polarized, microtubule-dependent exocytosis towards the leading edge. J. Cell Sci. 116, 4513–4519 (2003).

    CAS  PubMed  Google Scholar 

  141. Musch, A. Microtubule organization and function in epithelial cells. Traffic 5, 1–9 (2004).

    PubMed  Google Scholar 

  142. Chausovsky, A., Bershadsky, A. D. & Borisy, G. G. Cadherin-mediated regulation of microtubule dynamics. Nature Cell Biol. 2, 797–804 (2000).

    CAS  PubMed  Google Scholar 

  143. Harris, T. J. & Peifer, M. aPKC controls microtubule organization to balance adherens junction symmetry and planar polarity during development. Dev. Cell 12, 727–738 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Reilein, A. & Nelson, W. J. APC is a component of an organizing template for cortical microtubule networks. Nature Cell Biol. 7, 463–473 (2005).

    CAS  PubMed  Google Scholar 

  145. Rodriguez-Boulan, E., Kreitzer, G. & Musch, A. Organization of vesicular trafficking in epithelia. Nature Rev. Mol. Cell Biol. 6, 233–247 (2005).

    CAS  Google Scholar 

  146. Kreitzer, G. et al. Three-dimensional analysis of post-Golgi carrier exocytosis in epithelial cells. Nature Cell Biol. 5, 126–136 (2003).

    CAS  PubMed  Google Scholar 

  147. Jaulin, F., Xue, X., Rodriguez-Boulan, E. & Kreitzer, G. Polarization-dependent selective transport to the apical membrane by KIF5B in MDCK cells. Dev. Cell 13, 511–522 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Noda, Y. et al. KIFC3, a microtubule minus end-directed motor for the apical transport of annexin XIIIb-associated Triton-insoluble membranes. J. Cell Biol. 155, 77–88 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Goldman, R. D. The role of three cytoplasmic fibers in BHK-21 cell motility. I. Microtubules and the effects of colchicine. J. Cell Biol. 51, 752–762 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Vasiliev, J. M. et al. Effect of colcemid on the locomotory behaviour of fibroblasts. J. Embryol. Exp. Morphol. 24, 625–640 (1970).

    CAS  PubMed  Google Scholar 

  151. Xu, J., Wang, F., Van Keymeulen, A., Rentel, M. & Bourne, H. R. Neutrophil microtubules suppress polarity and enhance directional migration. Proc. Natl Acad. Sci. USA 102, 6884–6889 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Enomoto, T. Microtubule disruption induces the formation of actin stress fibers and focal adhesions in cultured cells: possible involvement of the rho signal cascade. Cell Struct. Funct. 21, 317–326 (1996).

    CAS  PubMed  Google Scholar 

  153. Ren, X. D., Kiosses, W. B. & Schwartz, M. A. Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton. EMBO J. 18, 578–585 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Krendel, M., Zenke, F. T. & Bokoch, G. M. Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton. Nature Cell Biol. 4, 294–301 (2002).

    CAS  PubMed  Google Scholar 

  155. Kaverina, I., Krylyshkina, O. & Small, J. V. Microtubule targeting of substrate contacts promotes their relaxation and dissociation. J. Cell Biol. 146, 1033–1044 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Kaverina, I., Rottner, K. & Small, J. V. Targeting, capture, and stabilization of microtubules at early focal adhesions. J. Cell Biol. 142, 181–190 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Ezratty, E. J., Partridge, M. A. & Gundersen, G. G. Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase. Nature Cell Biol. 7, 581–590 (2005).

    CAS  PubMed  Google Scholar 

  158. Liao, G., Nagasaki, T. & Gundersen, G. G. Low concentrations of nocodazole interfere with fibroblast locomotion without significantly affecting microtubule level: implications for the role of dynamic microtubules in cell locomotion. J. Cell Sci. 108, 3473–3483 (1995).

    CAS  PubMed  Google Scholar 

  159. Wu, X. S., Tsan, G. L. & Hammer, J. A. Melanophilin and myosin Va track the microtubule plus end on EB1. J. Cell Biol. 171, 201–207 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Pearson, C. G. & Bloom, K. Dynamic microtubules lead the way for spindle positioning. Nature Rev. Mol. Cell Biol. 5, 481–492 (2004).

    CAS  Google Scholar 

  161. Fukata, M. et al. Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell 109, 873–885 (2002).

    CAS  PubMed  Google Scholar 

  162. Eng, C. H., Huckaba, T. M. & Gundersen, G. G. The formin mDia regulates GSK3β through novel PKCs to promote microtubule stabilization but not MTOC reorientation in migrating fibroblasts. Mol. Biol. Cell 17, 5004–5016 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  164. Mimori-Kiyosue, Y. et al. CLASP1 and CLASP2 bind to EB1 and regulate microtubule plus-end dynamics at the cell cortex. J. Cell Biol. 168, 141–153 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Ligon, L. A. & Holzbaur, E. L. Microtubules tethered at epithelial cell junctions by dynein facilitate efficient junction assembly. Traffic 8, 808–819 (2007).

    CAS  PubMed  Google Scholar 

  166. Ligon, L. A., Karki, S., Tokito, M. & Holzbaur, E. L. Dynein binds to β-catenin and may tether microtubules at adherens junctions. Nature Cell Biol. 3, 913–917 (2001).

    CAS  PubMed  Google Scholar 

  167. Adames, N. R. & Cooper, J. A. Microtubule interactions with the cell cortex causing nuclear movements in Saccharomyces cerevisiae. J. Cell Biol. 149, 863–874 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Korinek, W. S., Copeland, M. J., Chaudhuri, A. & Chant, J. Molecular linkage underlying microtubule orientation toward cortical sites in yeast. Science 287, 2257–2259 (2000).

    CAS  PubMed  Google Scholar 

  169. Lee, L. et al. Positioning of the mitotic spindle by a cortical-microtubule capture mechanism. Science 287, 2260–2262 (2000).

    CAS  PubMed  Google Scholar 

  170. Heil-Chapdelaine, R. A., Oberle, J. R. & Cooper, J. A. The cortical protein Num1p is essential for dynein-dependent interactions of microtubules with the cortex. J. Cell Biol. 151, 1337–1344 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Brunner, D. & Nurse, P. CLIP170-like tip1p spatially organizes microtubular dynamics in fission yeast. Cell 102, 695–704 (2000).

    CAS  PubMed  Google Scholar 

  172. Busch, K. E., Hayles, J., Nurse, P. & Brunner, D. Tea2p kinesin is involved in spatial microtubule organization by transporting tip1p on microtubules. Dev. Cell 6, 831–843 (2004).

    CAS  PubMed  Google Scholar 

  173. Snaith, H. A. & Sawin, K. E. Fission yeast mod5p regulates polarized growth through anchoring of tea1p at cell tips. Nature 423, 647–651 (2003).

    CAS  PubMed  Google Scholar 

  174. des Georges, A. et al. Mal3, the Schizosaccharomyces pombe homolog of EB1, changes the microtubule lattice. Nature Struct. Mol. Biol. 15, 1102–1108 (2008).

    CAS  Google Scholar 

Download references

Acknowledgements

This work is supported by National Institutes of Health grants to R.L. and G.G.G. The authors apologize for not being able to discuss all relevant and important data in this review owing to space limitations.

Author information

Authors and Affiliations

  1. The Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri, 64110, USA

    Rong Li

  2. Department of Pathology & Cell Biology, Columbia University, 1217 Black Building, 630 West 168th Street, New York, 10032, New York, USA

    Gregg G. Gundersen

  3. Gregg G. Gundersen

Authors
  1. Rong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregg G. Gundersen
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

FURTHER INFORMATION

Rong Li's homepage

Gregg Gundersen's homepage

Glossary

Septin family

A conserved family of GTP-binding proteins that were first identified in yeast and later found in a wide range of fungi and animal cells.

Lamellipodium

A broad, flat cellular protrusion that contains extensively branched and crosslinked arrays of actin filaments. These are orientated with their barbed ends towards the plasma membrane.

PAR protein

One of a set of six proteins that were initially identified in Caenorhabditis elegans. Inactivation of the PAR proteins results in a partitioning-defective phenotype in early embryos. PAR proteins are now recognized to be widely involved in cell polarity.

Actomyosin

A complex of myosin and actin filaments that is responsible for a range of cellular movements in eukaryotic cells. Myosins can translocate vesicles or other cargo on actin filaments or slide actin filaments to generate contraction.

Filopodium

A thin cellular process that contains long, unbranched, parallel bundles of actin filaments.

Detyrosination

The post-translational removal of the C-terminal Tyr residue of α-tubulin by an as yet unidentified carboxypeptidase.

Polyglutamylation

The post-translational addition of chains of Glu residues to the γ-carboxyl groups of specific Glu residues of α- and β-tubulin.

Endocytic recycling

A process of internalization of plasma membrane proteins, which are subsequently sorted in endosomes and either directed to lysosomes for destruction or recycled back to specific locations on the plasma membrane.

SNARE

(Soluble N-ethyl-maleimide-sensitive fusion protein-attachment-protein receptor). A family of membrane-tethered, coiled-coil proteins that regulate fusion reactions and target specificity in exocytosis and other membrane trafficking events.

Focal adhesion

A plaque-like cellular structure that links the extracellular matrix on the outside of the cell to the actin cytoskeleton inside the cell through integrin receptors and associated proteins.

Adherens junction

An adhesive structure that connects adjacent cells through cadherins and other membrane proteins and is associated with cortical actin filaments.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, R., Gundersen, G. Beyond polymer polarity: how the cytoskeleton builds a polarized cell. Nat Rev Mol Cell Biol 9, 860–873 (2008). https://doi.org/10.1038/nrm2522

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2522

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing