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Crosstalk between small GTPases and polarity proteins in cell polarization

Nature Reviews Molecular Cell Biology volume 9, pages 846–859 (2008)Cite this article

Key Points

  • Three sets of conserved polarity proteins — the partitioning defective (PAR), Scribble and Crumbs complexes — regulate polarization processes in many different cell types and organisms, including worms, flies, fish, frogs and mammals.

  • Small GTPases of the Rho family are potent modulators of the actin and microtubule cytoskeleton.

  • Recent data indicate that the Ras-like RAP1 protein and various Rho proteins crosstalk to polarity proteins to induce spatially restricted cytoskeletal remodelling. This is required for cell polarization in different cellular contexts.

  • The processes that regulate polarization of neuronal cells, T cells and epithelial cells show striking similarities but also cell-type-specific differences. In these various cell types, polarity signalling involves the concerted action of different polarity proteins and different small GTPases, including their regulatory and effector proteins.

  • RhoA activity promotes cell contractility, whereas RAC1 and CDC42 signalling induces the formation of cellular protrusions. RAC1 can suppress RhoA activity and vice versa, a phenomenon that is known as Rho–Rac antagonism and that is crucial during polarization and migration of cells.

  • RhoA can modulate the activity of the PAR polarity complex, and recent studies implicate components of the PAR3 complex in balancing Rho–Rac antagonism by controlling regulatory proteins of RhoA.

  • Recently identified molecular links between signalling by polarity proteins and Rho GTPases have provided intriguing insights into the cell polarization processes that are essential for the normal behaviour of cells or the aberrant behaviour of cancer cells.

Abstract

Cell polarization is crucial for the development of multicellular organisms, and aberrant cell polarization contributes to various diseases, including cancer. How cell polarity is established and how it is maintained remain fascinating questions. Conserved proteins of the partitioning defective (PAR), Scribble and Crumbs complexes guide the establishment of cell polarity in various organisms. Moreover, GTPases that regulate actin cytoskeletal dynamics have been implicated in cell polarization. Recent findings provide insights into polarization mechanisms and show intriguing crosstalk between small GTPases and members of polarity complexes in regulating cell polarization in different cellular contexts and cell types.

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Figure 1: Effectors of Rho GTPases.
Figure 2: Crosstalk between small GTPases and the PAR complex mediates different aspects of neuronal polarity.
Figure 3: Crosstalk between small GTPases and polarity proteins controls front–rear polarization of T cells.
Figure 4: Crosstalk between Rho GTPases and polarity proteins during the formation and loss of epithelial apico–basal cell polarity.
Figure 5: Crosstalk between small GTPases and polarity proteins controls front–rear polarization of epithelial cells, astrocytes and fibroblasts.
Figure 6: The PAR complex has a central role in balancing GTPase function during cellular polarization.

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References

  1. Goldstein, B. & Macara, I. G. The PAR proteins: fundamental players in animal cell polarization. Dev. Cell 13, 609–622 (2007). Excellent review on the discovery of the PAR genes and the various functions of PAR proteins in different species and cell types.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Assemat, E., Bazellieres, E., Pallesi-Pocachard, E., Le Bivic, A. & Massey-Harroche, D. Polarity complex proteins. Biochim. Biophys. Acta 1778, 614–630 (2008).

    CAS  PubMed  Google Scholar 

  3. Humbert, P. O., Dow, L. E. & Russell, S. M. The Scribble and Par complexes in polarity and migration: friends or foes? Trends Cell Biol. 16, 622–630 (2006).

    CAS  PubMed  Google Scholar 

  4. Bos, J. L. Linking Rap to cell adhesion. Curr. Opin. Cell Biol. 17, 123–128 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. 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).

    CAS  PubMed  Google Scholar 

  7. 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 

  8. 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 

  9. Knoblich, J. A. Mechanisms of asymmetric stem cell division. Cell 132, 583–597 (2008).

    CAS  PubMed  Google Scholar 

  10. Gonczy, P. Mechanisms of asymmetric cell division: flies and worms pave the way. Nature Rev. Mol. Cell Biol. 9, 355–366 (2008).

    Google Scholar 

  11. Kemphues, K. J., Priess, J. R., Morton, D. G. & Cheng, N. S. Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell 52, 311–320 (1988).

    CAS  PubMed  Google Scholar 

  12. 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 

  13. Cowan, C. R. & Hyman, A. A. Acto-myosin reorganization and PAR polarity in C. elegans. Development 134, 1035–1043 (2007).

    CAS  PubMed  Google Scholar 

  14. Schonegg, S., Constantinescu, A. T., Hoege, C. & Hyman, A. A. The Rho GTPase-activating proteins RGA-3 and RGA-4 are required to set the initial size of PAR domains in Caenorhabditis elegans one-cell embryos. Proc. Natl Acad. Sci. USA 104, 14976–14981 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Albertson, R. & Doe, C. Q. Dlg, Scrib and Lgl regulate neuroblast cell size and mitotic spindle asymmetry. Nature Cell Biol. 5, 166–170 (2003).

    CAS  PubMed  Google Scholar 

  16. Betschinger, J. & Knoblich, J. A. Dare to be different: asymmetric cell division in Drosophila, C. elegans and vertebrates. Curr. Biol. 14, R674–R685 (2004).

    CAS  PubMed  Google Scholar 

  17. Peng, C. Y., Manning, L., Albertson, R. & Doe, C. Q. The tumour-suppressor genes lgl and dlg regulate basal protein targeting in Drosophila neuroblasts. Nature 408, 596–600 (2000).

    CAS  PubMed  Google Scholar 

  18. Ohshiro, T., Yagami, T., Zhang, C. & Matsuzaki, F. Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature 408, 593–596 (2000).

    CAS  PubMed  Google Scholar 

  19. Betschinger, J., Mechtler, K. & Knoblich, J. A. The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl. Nature 422, 326–330 (2003).

    CAS  PubMed  Google Scholar 

  20. Duncan, F. E., Moss, S. B., Schultz, R. M. & Williams, C. J. PAR-3 defines a central subdomain of the cortical actin cap in mouse eggs. Dev. Biol. 280, 38–47 (2005).

    CAS  PubMed  Google Scholar 

  21. Vinot, S. et al. Asymmetric distribution of PAR proteins in the mouse embryo begins at the 8-cell stage during compaction. Dev. Biol. 282, 307–319 (2005).

    CAS  PubMed  Google Scholar 

  22. Costa, M. R., Wen, G., Lepier, A., Schroeder, T. & Gotz, M. Par-complex proteins promote proliferative progenitor divisions in the developing mouse cerebral cortex. Development 135, 11–22 (2008).

    CAS  PubMed  Google Scholar 

  23. Lechler, T. & Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Chang, J. T. et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315, 1687–1691 (2007).

    CAS  PubMed  Google Scholar 

  25. Watabe-Uchida, M., Govek, E. E. & Van Aelst, L. Regulators of Rho GTPases in neuronal development. J. Neurosci. 26, 10633–10635 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  27. Kozma, R., Sarner, S., Ahmed, S. & Lim, L. Rho family GTPases and neuronal growth cone remodelling: relationship between increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Mol. Cell. Biol. 17, 1201–1211 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. van Leeuwen, F. N., van Delft, S., Kain, H. E., van der Kammen, R. A. & Collard, J. G. Rac regulates phosphorylation of the myosin-II heavy chain, actinomyosin disassembly and cell spreading. Nature Cell. Biol. 1, 242–248 (1999).

    CAS  PubMed  Google Scholar 

  29. 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 

  30. Kunda, P., Paglini, G., Quiroga, S., Kosik, K. & Caceres, A. Evidence for the involvement of Tiam1 in axon formation. J. Neurosci. 21, 2361–2372 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Curmi, P. A. et al. Stathmin and its phosphoprotein family: general properties, biochemical and functional interaction with tubulin. Cell Struct. Funct. 24, 345–357 (1999).

    CAS  PubMed  Google Scholar 

  32. Witte, H., Neukirchen, D. & Bradke, F. Microtubule stabilization specifies initial neuronal polarization. J. Cell Biol. 180, 619–632 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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). This work, together with that of reference 29, unravelled a signalling pathway that involves RAP1, CDC42, RAC1 and crosstalk of these GTPases to PAR polarity proteins during axonal specification.

    CAS  PubMed  Google Scholar 

  34. Schwamborn, J. C., Muller, M., Becker, A. H. & Puschel, A. W. Ubiquitination of the GTPase Rap1B by the ubiquitin ligase Smurf2 is required for the establishment of neuronal polarity. EMBO J. 26, 1410–1422 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 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 

  36. Schwamborn, J. C., Khazaei, M. R. & Puschel, A. W. The interaction of mPar3 with the ubiquitin ligase Smurf2 is required for the establishment of neuronal polarity. J. Biol. Chem. 282, 35259–35268 (2007).

    CAS  PubMed  Google Scholar 

  37. Wang, H. R. et al. Regulation of cell polarity and protrusion formation by targeting RhoA for degradation. Science 302, 1775–1779 (2003).

    CAS  PubMed  Google Scholar 

  38. Fivaz, M., Bandara, S., Inoue, T. & Meyer, T. Robust neuronal symmetry breaking by Ras-triggered local positive feedback. Curr. Biol. 18, 44–50 (2008).

    CAS  PubMed  Google Scholar 

  39. Oinuma, I., Katoh, H. & Negishi, M. R. Ras controls axon specification upstream of glycogen synthase kinase-3β through integrin-linked kinase. J. Biol. Chem. 282, 303–318 (2007).

    CAS  PubMed  Google Scholar 

  40. 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 

  41. Tashiro, A., Minden, A. & Yuste, R. Regulation of dendritic spine morphology by the Rho family of small GTPases: antagonistic roles of Rac and Rho. Cereb Cortex. 10, 927–938 (2000).

    CAS  PubMed  Google Scholar 

  42. Tashiro, A. & Yuste, R. Role of Rho GTPases in the morphogenesis and motility of dendritic spines. Methods Enzymol. 439, 285–302 (2008).

    CAS  PubMed  Google Scholar 

  43. Zhang, H. & Macara, I. G. The polarity protein PAR-3 and TIAM1 cooperate in dendritic spine morphogenesis. Nature Cell Biol. 8, 227–237 (2006).

    CAS  PubMed  Google Scholar 

  44. Zhang, H. & Macara, I. G. The PAR-6 polarity protein regulates dendritic spine morphogenesis through p190 RhoGAP and the Rho GTPase. Dev. Cell 14, 216–226 (2008). Shows that the PAR6–aPKC-mediated downregulation of RhoA involves p190 RhoGAP in the formation of dendritic spines.

    PubMed  PubMed Central  Google Scholar 

  45. Xie, Z., Huganir, R. L. & Penzes, P. Activity-dependent dendritic spine structural plasticity is regulated by small GTPase Rap1 and its target AF-6. Neuron 48, 605–618 (2005).

    CAS  PubMed  Google Scholar 

  46. Pak, D. T., Yang, S., Rudolph-Correia, S., Kim, E. & Sheng, M. Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP. Neuron 31, 289–303 (2001).

    CAS  PubMed  Google Scholar 

  47. del Pozo, M. A. et al. ICAMs redistributed by chemokines to cellular uropods as a mechanism for recruitment of T lymphocytes. J. Cell Biol. 137, 493–508 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Krummel, M. F. & Macara, I. Maintenance and modulation of T cell polarity. Nature Immunol. 7, 1143–1149 (2006).

    CAS  Google Scholar 

  49. del Pozo, M. A., Vicente-Manzanares, M., Tejedor, R., Serrador, J. M. & Sanchez-Madrid, F. Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes. Eur. J. Immunol. 29, 3609–3620 (1999).

    CAS  PubMed  Google Scholar 

  50. D'Souza-Schorey, C., Boettner, B. & Van Aelst, L. Rac regulates integrin-mediated spreading and increased adhesion of T lymphocytes. Mol. Cell. Biol. 18, 3936–3946 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Nurmi, S. M., Autero, M., Raunio, A. K., Gahmberg, C. G. & Fagerholm, S. C. Phosphorylation of the LFA-1 integrin β2-chain on Thr-758 leads to adhesion, Rac-1/Cdc42 activation, and stimulation of CD69 expression in human T cells. J. Biol. Chem. 282, 968–975 (2007).

    CAS  PubMed  Google Scholar 

  52. Lee, J. H. et al. Roles of p-ERM and Rho–ROCK signaling in lymphocyte polarity and uropod formation. J. Cell Biol. 167, 327–337 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Shimonaka, M. et al. Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow. J. Cell Biol. 161, 417–427 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Gerard, A., Mertens, A. E., van der Kammen, R. A. & Collard, J. G. The Par polarity complex regulates Rap1- and chemokine-induced T cell polarization. J. Cell Biol. 176, 863–875 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Ludford-Menting, M. J. et al. A network of PDZ-containing proteins regulates T cell polarity and morphology during migration and immunological synapse formation. Immunity 22, 737–748 (2005).

    CAS  PubMed  Google Scholar 

  56. Labno, C. M. et al. Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP. Curr. Biol. 13, 1619–1624 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Faure, S. et al. ERM proteins regulate cytoskeleton relaxation promoting T cell–APC conjugation. Nature Immunol. 5, 272–279 (2004).

    CAS  Google Scholar 

  58. Yeh, J. H., Sidhu, S. S. & Chan, A. C. Regulation of a late phase of T cell polarity and effector functions by Crtam. Cell 132, 846–859 (2008).

    CAS  PubMed  Google Scholar 

  59. Yamada, S. & Nelson, W. J. Synapses: sites of cell recognition, adhesion, and functional specification. Annu. Rev. Biochem. 76, 267–294 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Yamanaka, T. & Ohno, S. Role of Lgl/Dlg/Scribble in the regulation of epithelial junction, polarity and growth. Front. Biosci. 13, 6693–6707 (2008).

    CAS  PubMed  Google Scholar 

  61. Gumbiner, B. & Simons, K. The role of uvomorulin in the formation of epithelial occluding junctions. Ciba Found. Symp. 125, 168–186 (1987).

    CAS  PubMed  Google Scholar 

  62. Ebnet, K. Organization of multiprotein complexes at cell–cell junctions. Histochem. Cell Biol. 130, 1–20 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Nakagawa, M., Fukata, M., Yamaga, M., Itoh, N. & Kaibuchi, K. Recruitment and activation of Rac1 by the formation of E-cadherin-mediated cell–cell adhesion sites. J. Cell Sci. 114, 1829–1838 (2001).

    CAS  PubMed  Google Scholar 

  64. Kim, S. H., Li, Z. & Sacks, D. B. E-cadherin-mediated cell–cell attachment activates Cdc42. J. Biol. Chem. 275, 36999–37005 (2000).

    CAS  PubMed  Google Scholar 

  65. Fukuhara, T. et al. Activation of Cdc42 by trans interactions of the cell adhesion molecules nectins through c-Src and Cdc42–GEF FRG. J. Cell Biol. 166, 393–405 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kawakatsu, T. et al. Trans-interactions of nectins induce formation of filopodia and Lamellipodia through the respective activation of Cdc42 and Rac small G proteins. J. Biol. Chem. 277, 50749–50755 (2002).

    CAS  PubMed  Google Scholar 

  67. Yamanaka, T. et al. PAR-6 regulates aPKC activity in a novel way and mediates cell–cell contact-induced formation of the epithelial junctional complex. Genes Cells 6, 721–731 (2001). Proposes a mechanism through which binding of CDC42 to PAR6 might lead to aPKC activation, which is a crucial event in several polarization processes.

    CAS  PubMed  Google Scholar 

  68. Takaishi, K., Sasaki, T., Kotani, H., Nishioka, H. & Takai, Y. Regulation of cell–cell adhesion by rac and rho small G proteins in MDCK cells. J. Cell Biol. 139, 1047–1059 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Chen, X. & Macara, I. G. Par-3 controls tight junction assembly through the Rac exchange factor Tiam1. Nature Cell Biol. 7, 262–269 (2005).

    CAS  PubMed  Google Scholar 

  70. Mertens, A. E., Rygiel, T. P., Olivo, C., van der Kammen, R. & Collard, J. G. The Rac activator Tiam1 controls tight junction biogenesis in keratinocytes through binding to and activation of the Par polarity complex. J. Cell Biol. 170, 1029–1037 (2005). References 69 and 70 show that TIAM1, in association with PAR3, controls tight-junction biogenesis in epithelial cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. O'Brien, L. E. et al. Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nature Cell Biol. 3, 831–838 (2001).

    CAS  PubMed  Google Scholar 

  72. Liu, K. D. et al. Rac1 is required for reorientation of polarity and lumen formation through a PI 3-kinase-dependent pathway. Am. J. Physiol. Renal Physiol. 293, F1633–F1640 (2007).

    CAS  PubMed  Google Scholar 

  73. Mertens, A. E., Pegtel, D. M. & Collard, J. G. Tiam1 takes PARt in cell polarity. Trends Cell Biol. 16, 308–316 (2006).

    CAS  PubMed  Google Scholar 

  74. Martin-Belmonte, F. et al. Cell-polarity dynamics controls the mechanism of lumen formation in epithelial morphogenesis. Curr. Biol. 18, 507–513 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Noren, N. K., Niessen, C. M., Gumbiner, B. M. & Burridge, K. Cadherin engagement regulates Rho family GTPases. J. Biol. Chem. 276, 33305–33308 (2001).

    CAS  PubMed  Google Scholar 

  76. Wildenberg, G. A. et al. p120-catenin and p190RhoGAP regulate cell–cell adhesion by coordinating antagonism between Rac and Rho. Cell 127, 1027–1039 (2006).

    CAS  PubMed  Google Scholar 

  77. Yamada, S. & Nelson, W. J. Localized zones of Rho and Rac activities drive initiation and expansion of epithelial cell–cell adhesion. J. Cell Biol. 178, 517–527 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Ivanov, A. I., Hunt, D., Utech, M., Nusrat, A. & Parkos, C. A. Differential roles for actin polymerization and a myosin II motor in assembly of the epithelial apical junctional complex. Mol. Biol. Cell 16, 2636–2650 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Vaezi, A., Bauer, C., Vasioukhin, V. & Fuchs, E. Actin cable dynamics and Rho/Rock orchestrate a polarized cytoskeletal architecture in the early steps of assembling a stratified epithelium. Dev. Cell 3, 367–381 (2002).

    CAS  PubMed  Google Scholar 

  80. Sahai, E. & Marshall, C. J. ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nature Cell Biol. 4, 408–415 (2002).

    CAS  PubMed  Google Scholar 

  81. Martin, P. & Parkhurst, S. M. Parallels between tissue repair and embryo morphogenesis. Development 131, 3021–3034 (2004).

    CAS  PubMed  Google Scholar 

  82. Qin, Y., Capaldo, C., Gumbiner, B. M. & Macara, I. G. The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J. Cell Biol. 171, 1061–1071 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Wells, C. D. et al. A Rich1/Amot complex regulates the Cdc42 GTPase and apical-polarity proteins in epithelial cells. Cell 125, 535–548 (2006).

    CAS  PubMed  Google Scholar 

  84. Yang, J. & Weinberg, R. A. Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14, 818–829 (2008).

    CAS  PubMed  Google Scholar 

  85. Ozdamar, B. et al. Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science 307, 1603–1609 (2005). Implicates PAR6-dependent proteasomal degradation of RhoA in the onset of TGFβ-induced EMT.

    CAS  PubMed  Google Scholar 

  86. Wang, X. et al. Downregulation of Par-3 expression and disruption of Par complex integrity by TGF-β during the process of epithelial to mesenchymal transition in rat proximal epithelial cells. Biochim. Biophys. Acta 1782, 51–59 (2008).

    CAS  PubMed  Google Scholar 

  87. Whiteman, E. L., Liu, C. J., Fearon, E. R. & Margolis, B. The transcription factor snail represses Crumbs3 expression and disrupts apico-basal polarity complexes. Oncogene 27, 3875–3879 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Wodarz, A. & Nathke, I. Cell polarity in development and cancer. Nature Cell Biol. 9, 1016–1024 (2007).

    CAS  PubMed  Google Scholar 

  89. Lee, M. & Vasioukhin, V. Cell polarity and cancer-cell and tissue polarity as a non-canonical tumor suppressor. J. Cell Sci. 121, 1141–1150 (2008).

    CAS  PubMed  Google Scholar 

  90. Hariharan, I. K. & Bilder, D. Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annu. Rev. Genet. 40, 335–361 (2006).

    CAS  PubMed  Google Scholar 

  91. Dow, L. E. & Humbert, P. O. Polarity regulators and the control of epithelial architecture, cell migration, and tumorigenesis. Int. Rev. Cytol. 262, 253–302 (2007).

    CAS  PubMed  Google Scholar 

  92. Malliri, A. et al. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417, 867–871 (2002).

    CAS  PubMed  Google Scholar 

  93. Sahai, E. & Marshall, C. J. RHO–GTPases and cancer. Nature Rev. Cancer 2, 133–142 (2002).

    Google Scholar 

  94. Ellenbroek, S. I. & Collard, J. G. Rho GTPases: functions and association with cancer. Clin. Exp. Metastasis 24, 657–672 (2007).

    CAS  PubMed  Google Scholar 

  95. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  98. Trentin, A. G. Thyroid hormone and astrocyte morphogenesis. J. Endocrinol. 189, 189–197 (2006).

    CAS  PubMed  Google Scholar 

  99. Etienne-Manneville, S. & Hall, A. Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCζ. Cell 106, 489–498 (2001). References 99–102 identified the sequential signalling of CDC42 and of PAR and Scribble-complex components during wound-induced astrocyte migration.

    CAS  PubMed  Google Scholar 

  100. Etienne-Manneville, S. & Hall, A. Cdc42 regulates GSK-3β and adenomatous polyposis coli to control cell polarity. Nature 421, 753–756 (2003).

    CAS  PubMed  Google Scholar 

  101. Etienne-Manneville, S., Manneville, J. B., Nicholls, S., Ferenczi, M. A. & Hall, A. Cdc42 and Par6–PKCζ regulate the spatially localized association of Dlg1 and APC to control cell polarization. J. Cell Biol. 170, 895–901 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Osmani, N., Vitale, N., Borg, J. P. & Etienne-Manneville, S. Scrib controls Cdc42 localization and activity to promote cell polarization during astrocyte migration. Curr. Biol. 16, 2395–2405 (2006).

    CAS  PubMed  Google Scholar 

  103. Dow, L. E. et al. The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge. Oncogene 26, 2272–2282 (2007).

    CAS  PubMed  Google Scholar 

  104. Shin, K., Wang, Q. & Margolis, B. PATJ regulates directional migration of mammalian epithelial cells. EMBO Rep. 8, 158–164 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  107. Nakayama, M. et al. Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation. Dev. Cell 14, 205–215 (2008). Shows that Rho–ROCK induces disassembly of the PAR complex and thereby inhibits CDC42-induced RAC1 activation during cell migration.

    CAS  PubMed  Google Scholar 

  108. Jiang, W. et al. p190A RHOGAP is a glycogen synthase kinase-3β substrate required for polarized cell migration. J. Biol. Chem. 283, 20978–20988 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  111. Soloff, R. S., Katayama, C., Lin, M. Y., Feramisco, J. R. & Hedrick, S. M. Targeted deletion of protein kinase C λ reveals a distribution of functions between the two atypical protein kinase C isoforms. J. Immunol. 173, 3250–3260 (2004).

    CAS  PubMed  Google Scholar 

  112. Hirose, T. et al. PAR3 is essential for cyst-mediated epicardial development by establishing apical cortical domains. Development 133, 1389–1398 (2006).

    CAS  PubMed  Google Scholar 

  113. Sugihara, K. et al. Rac1 is required for the formation of three germ layers during gastrulation. Oncogene 17, 3427–3433 (1998).

    CAS  PubMed  Google Scholar 

  114. Chen, F. et al. Cdc42 is required for PIP2-induced actin polymerization and early development but not for cell viability. Curr. Biol. 10, 758–765 (2000).

    CAS  PubMed  Google Scholar 

  115. Thumkeo, D. et al. Targeted disruption of the mouse rho-associated kinase 2 gene results in intrauterine growth retardation and fetal death. Mol. Cell. Biol. 23, 5043–5055 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Makarova, O., Roh, M. H., Liu, C. J., Laurinec, S. & Margolis, B. Mammalian Crumbs3 is a small transmembrane protein linked to protein associated with Lin-7 (Pals1). Gene 302, 21–29 (2003).

    CAS  PubMed  Google Scholar 

  117. Roh, M. H. & Margolis, B. Composition and function of PDZ protein complexes during cell polarization. Am. J. Physiol. Renal Physiol. 285, F377–F387 (2003).

    PubMed  Google Scholar 

  118. Kowalczyk, A. P. & Moses, K. Photoreceptor cells in flies and mammals: Crumby homology? Dev. Cell 2, 253–254 (2002).

    CAS  PubMed  Google Scholar 

  119. Tepass, U., Tanentzapf, G., Ward, R. & Fehon, R. Epithelial cell polarity and cell junctions in Drosophila. Annu. Rev. Genet. 35, 747–784 (2001).

    CAS  PubMed  Google Scholar 

  120. Fogg, V. C., Liu, C. J. & Margolis, B. Multiple regions of Crumbs3 are required for tight junction formation in MCF10A cells. J. Cell Sci. 118, 2859–2869 (2005).

    CAS  PubMed  Google Scholar 

  121. Michel, D. et al. PATJ connects and stabilizes apical and lateral components of tight junctions in human intestinal cells. J. Cell Sci. 118, 4049–4057 (2005).

    CAS  PubMed  Google Scholar 

  122. Bilder, D., Li, M. & Perrimon, N. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289, 113–116 (2000).

    CAS  PubMed  Google Scholar 

  123. Budnik, V. et al. Regulation of synapse structure and function by the Drosophila tumor suppressor gene dlg. Neuron 17, 627–640 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Mathew, D. et al. Recruitment of scribble to the synaptic scaffolding complex requires GUK-holder, a novel DLG binding protein. Curr. Biol. 12, 531–539 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Mertens, A. E., Roovers, R. C. & Collard, J. G. Regulation of Tiam1–Rac signalling. FEBS Lett. 546, 11–16 (2003).

    CAS  PubMed  Google Scholar 

  126. Bishop, A. L. & Hall, A. Rho GTPases and their effector proteins. Biochem. J. 348, 241–255 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Nombela-Arrieta, C. et al. Differential requirements for DOCK2 and phosphoinositide-3-kinase γ during T and B lymphocyte homing. Immunity 21, 429–441 (2004).

    CAS  PubMed  Google Scholar 

  128. Nakaya, Y., Sukowati, E. W., Wu, Y. & Sheng, G. RhoA and microtubule dynamics control cell–basement membrane interaction in EMT during gastrulation. Nature Cell Biol. 10, 765–775 (2008).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize to all those authors whose papers we could not cite because of space limitations. We thank A. Gerard for helpful comments. Work in our laboratory is supported by the Seventh Framework Program of the European Commission (TuMIC) and by grants from the Dutch Cancer Society to J.G.C.

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  1. Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066, CX, The Netherlands

    Sandra Iden & John G. Collard

  2. Sandra Iden & John G. Collard

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Glossary

GTPase effector

A protein that directly binds to the GTPase in a GTP-dependent manner, and mediates downstream signalling.

Epithelial–mesenchymal transition

(EMT). A developmental programme, during which epithelial cells adopt a mesenchymal phenotype that is marked by the loss of intercellular adhesion and by increased cell migration. During EMT, epithelial marker proteins, such as E-cadherin, are downregulated, whereas mesenchymal markers, including vimentin, are upregulated.

Apico–basal polarity

The polarity axis along the apical (uppermost) plasma membrane domain and the basal plasma membrane. In epithelial cells, the basolateral plasma membrane contains different components than the apical plasma membrane, and vesicular trafficking in part occurs along different apical and basolateral routes.

Actomyosin contractility

Myosin-II multimers that are associated with actin filaments can generate contractility by antiparallel sliding of actin filaments. Actomyosin meshworks provide the cell with mechanical stability and are required during cell division, cell migration and cell polarization processes.

Dendritic spine

A small, actin-rich membrane extrusion that is found along dendrites and forms the postsynaptic terminal, a part of the neuronal synapse. Spines are frequently remodelled in response to neuronal signals.

Stress fibre

A structure at the base of a cell that mediates contractile forces and consists of axial filamentous actin bundles that are associated with myosin-II molecules.

Lamellipodium

A sheet-like cellular protrusion that is enriched in branched filamentous actin and is often observed at the front of migrating cells.

Filopodium

A thin, actin-rich plasma membrane protrusion that is often observed in motile cells and sometimes precedes lamellipodium formation.

Growth cone

The large cone-shaped motile tip of the developing axon or dendrite.

Phosphatidylinositol-3,4,5-trisphosphate

(PtdIns(3,4,5)P3). A phospholipid component of cellular membranes that is involved in signalling processes and that serves as a binding site for pleckstrin homology domain-containing proteins.

Pleckstrin-homology (PH) domain

A protein domain with high affinity for phosphatidylinositol-3,4,5-trisphosphate.

Uropod

A large membrane protrusion at the rear of polarized leukocytes that is implicated in many processes, including T-cell activation, cell–cell adhesion and leukocyte migration.

Antigen-presenting cell

An immune cell, such as a B cell, a dendritic cell or a macrophage, that presents fragments of foreign proteins on the cell surface to initiate an immune response. These fragments are bound to major histocompatibility complex (MHC) class II molecules. T cells can recognize the MHC class II–antigen complex through their T-cell receptor, and might subsequently become activated.

Adherens junction

An adhesive intercellular contact site that mediates mechanical stability. Cadherin molecules of adjacent cells bind to each other, and are coupled to the actin cytoskeleton by their cytoplasmic domains.

Classical cadherin

A Ca2+-dependent transmembrane adhesion protein that mediates intercellular adhesion in many different cell types. The extracellular domains of classical cadherins form homotypic dimers with cadherins on opposing cells, and the intracellular protein domain interacts with many cytoplasmic proteins, including members of the catenin family.

Tight junction

A selective barrier in epithelial cells that prevents the free diffusion of soluble molecules and membrane components through the intercellular space and within different membrane domains, respectively.

Nectin

A member of a family of Ca2+-independent, immunoglobulin-like, transmembrane molecules that mediate adhesion between cells.

Glial cell

A non-neuronal cell of the brain (such as an astrocyte, an oligodendrocyte or a Schwann cell) that provides nutrients to neurons, forms myelin and contributes to axon guidance and neuronal signalling.

Dynein

A minus-end-directed microtubule motor protein that consists of several subunits. Dynein is required for various cellular processes, including organelle positioning and vesicle transport along microtubules.

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Iden, S., Collard, J. Crosstalk between small GTPases and polarity proteins in cell polarization. Nat Rev Mol Cell Biol 9, 846–859 (2008). https://doi.org/10.1038/nrm2521

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