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:

Epithelial cell polarity, stem cells and cancer

Nature Reviews Cancer volume 12, pages 23–38 (2012)Cite this article

Subjects

Key Points

  • The proteins that finely control epithelial cell polarity are known as tumour suppressors or proto-oncoproteins. Loss of epithelial cell polarity — through deregulation of these proteins — is crucial for cancer cell invasion and advanced tumour progression. Accumulating evidence indicates that epithelial cell polarity cues and polarized cell divisions causally contribute to restrict carcinoma formation.

  • Cell polarity proteins crosstalk with signalling pathways that regulate cell growth and proliferation, including the WNT and Hippo pathways, and liver kinase B1 (LKB1)–mTOR-dependent energy metabolism.

  • The components of the evolutionarily conserved Hippo pathway function as important tumour suppressors. Recent studies have provided evidence that the cell polarity regulators lethal (2) giant larvae homologue (LGL; also known as LLGL), atypical protein kinase C (aPKC) and crumbs homologue (CRB), and the adherens junctions components E-cadherin–α-catenin or E-cadherin–β-catenin regulate the Hippo pathway in mammalian and Drosophila melanogaster epithelial cells.

  • The LKB1–AMPK–mTOR pathway, which is a molecular link between polarity and the metabolic status of a cell, is essential in the process of tumorigenesis.

  • The maintenance of most adult epithelial tissues relies on the presence of polarized stem cells, which self-renew through symmetric cell divisions. During differentiation stem cells reorient their mitotic spindles and divide asymmetrically in order to generate the specialized cells that drive epithelial function and homeostasis. The genes that control epithelial cell polarity also regulate spindle orientation and the symmetry of cell divisions in stem cells.

  • Epithelial tumours are highly heterogeneous, and the cell-of-origin that can initiate tumorigenesis is an area of extensive study. Two theories of tumour initiation have been postulated; one proposes that some tumours arise from normal adult stem or progenitor cells that have gone awry, and the other postulates that they arise from differentiated cells that acquire self-renewal capabilities. Evidence for the stem or progenitor cell-of-origin model has been provided for some carcinomas or specific subtypes of carcinomas; however, this seems to be unlikely or has not been well defined for several others.

Abstract

After years of extensive scientific discovery much has been learned about the networks that regulate epithelial homeostasis. Loss of expression or functional activity of cell adhesion and cell polarity proteins (including the PAR, crumbs (CRB) and scribble (SCRIB) complexes) is intricately related to advanced stages of tumour progression and invasiveness. But the key roles of these proteins in crosstalk with the Hippo and liver kinase B1 (LKB1)–AMPK pathways and in epithelial function and proliferation indicate that they may also be associated with the early stages of tumorigenesis. For example, deregulation of adhesion and polarity proteins can cause misoriented cell divisions and increased self-renewal of adult epithelial stem cells. In this Review, we highlight some advances in the understanding of how loss of epithelial cell polarity contributes to tumorigenesis.

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 epithelial cell polarity.
Figure 2: Polarity complex proteins and the Hippo pathway in Drosophila melanogaster.
Figure 3: LKB1 regulates epithelial cell polarity, cell growth and energy metabolism.
Figure 4: Stem cells and polarized cell divisions and cancer.
Figure 5: Tumour suppressors and spindle orientation.

Similar content being viewed by others

References

  1. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. St. Johnston, D. & Ahringer, J. Cell polarity in eggs and epithelia: parallels and diversity. Cell 141, 757–774 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Simons, M. & Mlodzik, M. Planar cell polarity signaling: from fly development to human disease. Annu. Rev. Genet. 42, 517–540 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bornens, M. Organelle positioning and cell polarity. Nature Rev. Mol. Cell Biol. 9, 874–886 (2008).

    Article  CAS  Google Scholar 

  5. Ray, S. & Lechler, T. Regulation of asymmetric cell division in the epidermis. Cell Div. 6, 12 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Tamura, A. et al. Megaintestine in claudin-15-deficient mice. Gastroenterology 134, 523–534 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. Weber, G. F., Bjerke, M. A. & DeSimone, D. W. Integrins and cadherins join forces to form adhesive networks. J. Cell Sci. 124, 1183–1193 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ooshio, T. et al. Cooperative roles of Par-3 and afadin in the formation of adherens and tight junctions. J. Cell Sci. 120, 2352–2365 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Sakisaka, T., Ikeda, W., Ogita, H., Fujita, N. & Takai, Y. The roles of nectins in cell adhesions: cooperation with other cell adhesion molecules and growth factor receptors. Curr. Opin. Cell Biol. 19, 593–602 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Adams, C. L., Chen, Y. T., Smith, S. J. & Nelson, W. J. Mechanisms of epithelial cell-cell adhesion and cell compaction revealed by high-resolution tracking of E-cadherin-green fluorescent protein. J. Cell Biol. 142, 1105–1119 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vasioukhin, V., Bauer, C., Yin, M. & Fuchs, E. Directed actin polymerization is the driving force for epithelial cell-cell adhesion. Cell 100, 209–219 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Tsukita, S., Katsuno, T., Yamazaki, Y., Umeda, K. & Tamura, A. Roles of ZO-1 and ZO-2 in establishment of the belt-like adherens and tight junctions with paracellular permselective barrier function. Ann. NY Acad. Sci. 1165, 44–52 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Mege, R. M., Gavard, J. & Lambert, M. Regulation of cell-cell junctions by the cytoskeleton. Curr. Opin. Cell Biol. 18, 541–548 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Kovacs, E. M. & Yap, A. S. Cell-cell contact: cooperating clusters of actin and cadherin. Curr. Biol. 18, R667–R669 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. McCaffrey, L. M. & Macara, I. G. Widely conserved signaling pathways in the establishment of cell polarity. Cold Spring Harb. Perspect. Biol. 1, a001370 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Horikoshi, Y. et al. Interaction between PAR-3 and the aPKC-PAR-6 complex is indispensable for apical domain development of epithelial cells. J. Cell Sci. 122, 1595–1606 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Morais-de-Sa, E., Mirouse, V. & St. Johnston, D. aPKC phosphorylation of Bazooka defines the apical/lateral border in Drosophila epithelial cells. Cell 141, 509–523 (2010). This paper describes how the apical-lateral border and the positioning of apical junctional complexes is regulated in epithelial cells in D. melanogaster.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Walther, R. F. & Pichaud, F. Crumbs/DaPKC-dependent apical exclusion of Bazooka promotes photoreceptor polarity remodeling. Curr. Biol. 20, 1065–1074 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Sotillos, S., Diaz-Meco, M. T., Caminero, E., Moscat, J. & Campuzano, S. DaPKC-dependent phosphorylation of Crumbs is required for epithelial cell polarity in Drosophila. J. Cell Biol. 166, 549–557 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Krahn, M. P., Buckers, J., Kastrup, L. & Wodarz, A. Formation of a Bazooka-Stardust complex is essential for plasma membrane polarity in epithelia. J. Cell Biol. 190, 751–760 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Laprise, P., Viel, A. & Rivard, N. Human homolog of disc-large is required for adherens junction assembly and differentiation of human intestinal epithelial cells. J. Biol. Chem. 279, 10157–10166 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Navarro, C. et al. Junctional recruitment of mammalian Scribble relies on E-cadherin engagement. Oncogene 24, 4330–4339 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Yamanaka, T. et al. Mammalian Lgl forms a protein complex with PAR-6 and aPKC independently of PAR-3 to regulate epithelial cell polarity. Curr. Bio. 13, 734–743 (2003).

    Article  CAS  Google Scholar 

  30. Benton, R. & St. Johnston, D. Drosophila PAR-1 and 14-3-3 inhibit Bazooka/PAR-3 to establish complementary cortical domains in polarized cells. Cell 115, 691–704 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Fehon, R. G., McClatchey, A. I. & Bretscher, A. Organizing the cell cortex: the role of ERM proteins. Nature Rev. Mol. Cell Biol. 11, 276–287 (2010).

    Article  CAS  Google Scholar 

  33. Gladden, A. B., Hebert, A. M., Schneeberger, E. E. & McClatchey, A. I. The NF2 tumor suppressor, Merlin, regulates epidermal development through the establishment of a junctional polarity complex. Dev. Cell 19, 727–739 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yi, C. et al. A tight junction-associated Merlin-angiomotin complex mediates Merlin's regulation of mitogenic signaling and tumor suppressive functions. Cancer Cell 19, 527–540 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Birchmeier, W. & Behrens, J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim. Biophys. Acta 1198, 11–26 (1994).

    CAS  PubMed  Google Scholar 

  36. Jeanes, A., Gottardi, C. J. & Yap, A. S. Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene 27, 6920–6929 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gonzalez-Mariscal, L., Lechuga, S. & Garay, E. Role of tight junctions in cell proliferation and cancer. Prog. Histochem. Cytochem. 42, 1–57 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Escudero-Esparza, A., Jiang, W. G. & Martin, T. A. The Claudin family and its role in cancer and metastasis. Front. Biosci. 16, 1069–1083 (2011).

    Article  CAS  Google Scholar 

  39. Benhamouche, S. et al. Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev. 24, 1718–1730 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tanos, B. & Rodriguez-Boulan, E. The epithelial polarity program: machineries involved and their hijacking by cancer. Oncogene 27, 6939–6957 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Coradini, D., Casarsa, C. & Oriana, S. Epithelial cell polarity and tumorigenesis: new perspectives for cancer detection and treatment. Acta Pharmacol. Sin 32, 552–564 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Huang, L. & Muthuswamy, S. K. Polarity protein alterations in carcinoma: a focus on emerging roles for polarity regulators. Curr. Opin. Genet. Dev. 20, 41–50 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Moreno-Bueno, G., Portillo, F. & Cano, A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 27, 6958–6969 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Brumby, A. M. & Richardson, H. E. scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769–5779 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pagliarini, R. A. & Xu, T. A genetic screen in Drosophila for metastatic behavior. Science 302, 1227–1231 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Wu, M., Pastor-Pareja, J. C. & Xu, T. Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature 463, 545–548 (2010). The authors found that the RAS-G12V and inactivating SCRIB− mutations can cause tumours even when the mutations affect different adjacent epithelial cells. The interaction between RASG12V and SCRIB− clones involves activation of JNK signalling and JNK-induced upregulation of cytokines that activate JAK–signal transducer and activator of transcription (STAT) signalling, a compensatory growth mechanism for tissue homeostasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhan, L. et al. Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell 135, 865–878 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. Dow, L. E. et al. Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling. Oncogene 27, 5988–6001 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Nagasaka, K. et al. The cell polarity regulator hScrib controls ERK activation through a KIM site-dependent interaction. Oncogene 29, 5311–5321 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Aigner, K. et al. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 26, 6979–6988 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Spaderna, S. et al. The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res. 68, 537–544 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Kuphal, S. et al. Expression of Hugl-1 is strongly reduced in malignant melanoma. Oncogene 25, 103–110 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Reischauer, S., Levesque, M. P., Nusslein-Volhard, C. & Sonawane, M. Lgl2 executes its function as a tumor suppressor by regulating ErbB signaling in the zebrafish epidermis. PLoS Genet. 5, e1000720 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Lu, X. et al. Aberrant splicing of Hugl-1 is associated with hepatocellular carcinoma progression. Clin. Cancer Res. 15, 3287–3296 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Karp, C. M. et al. Role of the polarity determinant crumbs in suppressing mammalian epithelial tumor progression. Cancer Res. 68, 4105–4115 (2008). This study identified a mammalian orthologue of the D. melanogaster polarity regulator CRB, CRB3 , the loss of expression of which promoted tumour progression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  59. Hynes, N. E. & MacDonald, G. ErbB receptors and signaling pathways in cancer. Curr. Opin. Cell Biol. 21, 177–184 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Aranda, V. et al. Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nature Cell Biol. 8, 1235–1245 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Nolan, M. E. et al. The polarity protein Par6 induces cell proliferation and is overexpressed in breast cancer. Cancer Res. 68, 8201–8209 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ozdamar, B. et al. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307, 1603–1609 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Townsend, T. A., Wrana, J. L., Davis, G. E. & Barnett, J. V. Transforming growth factor-beta-stimulated endocardial cell transformation is dependent on Par6c regulation of RhoA. J. Biol. Chem. 283, 13834–13841 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Singh, A. & Settleman, J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29, 4741–4751 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Murray, N. R., Kalari, K. R. & Fields, A. P. Protein kinase Ciota expression and oncogenic signaling mechanisms in cancer. J. Cell Physiol. 226, 879–887 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Murray, N. R. et al. Protein kinase Ciota is required for Ras transformation and colon carcinogenesis in vivo. J. Cell Biol. 164, 797–802 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Regala, R. P. et al. Atypical protein kinase C iota is an oncogene in human non-small cell lung cancer. Cancer Res. 65, 8905–8911 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Brumby, A. M. et al. Identification of novel Ras-cooperating oncogenes in Drosophila melanogaster: a RhoGEF/Rho-family/JNK pathway is a central driver of tumorigenesis. Genetics 188, 105–125 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Genevet, A. & Tapon, N. The Hippo pathway and apico-basal cell polarity. Biochem. J. 436, 213–224 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Pan, D. The hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Harvey, K. & Tapon, N. The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network. Nature Rev. Cancer 7, 182–191 (2007).

    Article  CAS  Google Scholar 

  72. Parsons, L. M., Grzeschik, N. A., Allott, M. L. & Richardson, H. E. Lgl/aPKC and Crb regulate the Salvador/Warts/Hippo pathway. Fly (Austin) 4, 288–293 (2010).

    Article  CAS  Google Scholar 

  73. Zhao, M., Szafranski, P., Hall, C. A. & Goode, S. Basolateral junctions utilize warts signaling to control epithelial-mesenchymal transition and proliferation crucial for migration and invasion of Drosophila ovarian epithelial cells. Genetics 178, 1947–1971 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Grzeschik, N. A., Parsons, L. M., Allott, M. L., Harvey, K. F. & Richardson, H. E. Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr. Biol. 20, 573–581 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Robinson, B. S., Huang, J., Hong, Y. & Moberg, K. H. Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr. Biol. 20, 582–590 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Varelas, X. et al. The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. Dev. Cell 19, 831–844 (2010). The authors demonstrate that the CRB polarity complex interacts with the Hippo pathway transcriptional regulators TAZ–YAP1, which relays cell density information by promoting TAZ–YAP1 phosphorylation and its cytoplasmic retention and thereby suppresses TGFβ signalling. Disruption of the CRB complex enhanced TGFβ signalling and predisposed cells to TGFβ-mediated EMT.

    Article  CAS  PubMed  Google Scholar 

  77. Zhao, B., Tumaneng, K. & Guan, K. L. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nature Cell Biol. 13, 877–883 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Ashton, G. H. et al. Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Dev. Cell 19, 259–269 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Cai, J. et al. The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 24, 2383–2388 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Karpowicz, P., Perez, J. & Perrimon, N. The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137, 4135–4145 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Shao, J. & Sheng, H. Amphiregulin promotes intestinal epithelial regeneration: roles of intestinal subepithelial myofibroblasts. Endocrinology 151, 3728–3737 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Shaw, R. L. et al. The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development 137, 4147–4158 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Staley, B. K. & Irvine, K. D. Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation. Curr. Bio. 20, 1580–1587 (2010).

    Article  CAS  Google Scholar 

  84. Ling, C. et al. The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc. Natl Acad. Sci. USA 107, 10532–10537 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chen, C. L. et al. The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc. Natl Acad. Sci. USA 107, 15810–15815 (2010). References 74, 75, 84 and 85 provide evidence that the cell polarity regulators LGL, aPKC and CRB regulate proliferation and survival in the developing eye and imaginal disc epithelia by controlling activity of the Hippo tumour suppressor pathway in D. melanogaster.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kim, N. G., Koh, E., Chen, X. & Gumbiner, B. M. E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc. Natl Acad. Sci. USA 108, 11930–11935 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Heallen, T. et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Schlegelmilch, K. et al. Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell 144, 782–795 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Richter, A. M., Pfeifer, G. P. & Dammann, R. H. The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Biochim. Biophys. Acta 1796, 114–128 (2009).

    CAS  PubMed  Google Scholar 

  90. Seidel, C. et al. Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma. Mol. Carcinog. 46, 865–871 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Takahashi, Y. et al. Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin. Cancer Res. 11, 1380–1385 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Okada, T., You, L. & Giancotti, F. G. Shedding light on Merlin's wizardry. Trends Cell Biol. 17, 222–229 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Morrison, H. et al. The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev. 15, 968–980 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. McClatchey, A. I. & Giovannini, M. Membrane organization and tumorigenesis-the NF2 tumor suppressor, Merlin. Genes Dev. 19, 2265–2277 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Zhang, N. et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19, 27–38 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lee, K. P. et al. The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc. Natl Acad. Sci. USA 107, 8248–8253 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lu, L. et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc. Natl Acad. Sci. USA 107, 1437–1442 (2010). References 39, 95, 96 and 97 link merlin to mammalian Hippo signalling and implicate YAP1 activation as a mediator of phenotypes that occur in patients with neurofibromatosis type II.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  99. Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391, 184–187 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Sanchez-Cespedes, M. A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome. Oncogene 26, 7825–7832 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Wingo, S. N. et al. Somatic LKB1 mutations promote cervical cancer progression. PLoS One 4, e5137 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Mizrachy-Schwartz, S., Cohen, N., Klein, S., Kravchenko-Balasha, N. & Levitzki, A. Up-regulation of AMP-activated protein kinase in cancer cell lines is mediated through c-Src activation. J. Biol. Chem. 286, 15268–15277 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Morton, J. P. et al. LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. Gastroenterology 139, 586–597 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. Partanen, J. I., Nieminen, A. I., Makela, T. P. & Klefstrom, J. Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization. Proc. Natl Acad. Sci. USA 104, 14694–14699 (2007).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  105. Shackelford, D. B. & Shaw, R. J. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nature Rev. Cancer 9, 563–575 (2009).

    Article  CAS  Google Scholar 

  106. 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).

    Article  CAS  PubMed  Google Scholar 

  107. Martin, S. G. & St. Johnston, D. A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity. Nature 421, 379–384 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Baas, A. F. et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116, 457–466 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Mirouse, V. & Billaud, M. The LKB1/AMPK polarity pathway. FEBS Lett. 585, 981–985 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  111. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhang, L., Li, J., Young, L. H. & Caplan, M. J. AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proc. Natl Acad. Sci. USA 103, 17272–17277 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zheng, B. & Cantley, L. C. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc. Natl Acad. Sci. USA 104, 819–822 (2007). References 110–113 provide substantial evidence that LKB1, through AMPK activation and not PAR1 activation, controls cell polarity in D. melanogaster and tight junction formation in human cells. The role of LKB1 and AMPK in cell polarity is mediated by the reorganization of the actin cytoskeleton through the motor protein myosin II.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hurley, R. L. et al. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J. Biol. Chem. 280, 29060–29066 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Woods, A. et al. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell. Metab. 2, 21–33 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Sebbagh, M., Santoni, M. J., Hall, B., Borg, J. P. & Schwartz, M. A. Regulation of LKB1/STRAD localization and function by E-cadherin. Curr. Biol. 19, 37–42 (2009).

    Article  CAS  PubMed  Google Scholar 

  117. Narbonne, P., Hyenne, V., Li, S., Labbe, J. C. & Roy, R. Differential requirements for STRAD in LKB1-dependent functions in C. elegans. Development 137, 661–670 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Tang, X. X. et al. Lymphocytes accelerate epithelial tight junction assembly: role of AMP-activated protein kinase (AMPK). PLoS ONE 5, e12343 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Fu, D., Wakabayashi, Y., Ido, Y., Lippincott-Schwartz, J. & Arias, I. M. Regulation of bile canalicular network formation and maintenance by AMP-activated protein kinase and LKB1. J. Cell Sci. 123, 3294–3302 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Fu, D., Wakabayashi, Y., Lippincott-Schwartz, J. & Arias, I. M. Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway. Proc. Natl Acad. Sci. USA 108, 1403–1408 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Carretero, J. et al. Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer. Oncogene 26, 1616–1625 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Shackelford, D. B. et al. mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. Proc. Natl Acad. Sci. USA 106, 11137–11142 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bultot, L. et al. Myosin light chains are not a physiological substrate of AMPK in the control of cell structure changes. FEBS Lett. 583, 25–28 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. ten Klooster, J. P. et al. Mst4 and Ezrin induce brush borders downstream of the Lkb1/Strad/Mo25 polarization complex. Dev. Cell 16, 551–562 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Vazquez-Martin, A., Oliveras-Ferraros, C. & Menendez, J. A. The active form of the metabolic sensor: AMP-activated protein kinase (AMPK) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis. Cell Cycle 8, 2385–2398 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Boehlke, C. et al. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nature Cell Biol. 12, 1115–1122 (2010). This paper shows that LKB1 localizes in the cilium and flow results in increased AMPK phosphorylation at the basal body. The authors demonstrate that the cilium regulates mTOR signalling and cell size, and identify the cilium-basal body compartment as a spatially restricted activation site for LKB1–AMPK–mTOR signalling.

    Article  CAS  PubMed  Google Scholar 

  128. Blanpain, C., Horsley, V. & Fuchs, E. Epithelial stem cells: turning over new leaves. Cell 128, 445–458 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Knoblich, J. A. Asymmetric cell division: recent developments and their implications for tumour biology. Nature Rev. Mol. Cell Biol. 11, 849–860 (2010).

    Article  CAS  Google Scholar 

  130. Lechler, T. & Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005). This is the first paper to show that asymmetric cell divisions occur in mammalian epidermal stem cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Poulson, N. D. & Lechler, T. Robust control of mitotic spindle orientation in the developing epidermis. J. Cell Biol. 191, 915–922 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Luxenburg, C., Pasolli, H. A., Williams, S. E. & Fuchs, E. Developmental roles for Srf, cortical cytoskeleton and cell shape in epidermal spindle orientation. Nature Cell Biol. 13, 203–214 (2011).

    Article  CAS  PubMed  Google Scholar 

  133. Williams, S. E., Beronja, S., Pasolli, H. A. & Fuchs, E. Asymmetric cell divisions promote Notch-dependent epidermal differentiation. Nature 470, 353–358 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Quyn, A. J. et al. Spindle orientation bias in gut epithelial stem cell compartments is lost in precancerous tissue. Cell Stem Cell 6, 175–181 (2010).

    Article  CAS  PubMed  Google Scholar 

  135. Cicalese, A. et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138, 1083–1095 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. El-Hashash, A. H. et al. Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium. Development 138, 1395–1407 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Lopez-Garcia, C., Klein, A. M., Simons, B. D. & Winton, D. J. Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825 (2010).

    Article  CAS  PubMed  Google Scholar 

  139. Visvader, J. E. Cells of origin in cancer. Nature 469, 314–322 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. Clevers, H. The cancer stem cell: premises, promises and challenges. Nature Med. 17, 313–319 (2011).

    Article  CAS  PubMed  Google Scholar 

  141. Florian, M. C. & Geiger, H. Concise review: polarity in stem cells, disease, and aging. Stem Cells 28, 1623–1629 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Lukasiewicz, K. B. & Lingle, W. L. Aurora A, centrosome structure, and the centrosome cycle. Environ. Mol. Mutagen. 50, 602–619 (2009).

    Article  CAS  PubMed  Google Scholar 

  143. Januschke, J., Llamazares, S., Reina, J. & Gonzalez, C. Drosophila neuroblasts retain the daughter centrosome. Nature Commun. 2, 243 (2011).

    Article  CAS  Google Scholar 

  144. Rebollo, E. et al. Functionally unequal centrosomes drive spindle orientation in asymmetrically dividing Drosophila neural stem cells. Dev. Cell 12, 467–474 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Yamashita, Y. M., Mahowald, A. P., Perlin, J. R. & Fuller, M. T. Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science 315, 518–521 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Wang, X. et al. Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature 461, 947–955 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wirtz-Peitz, F., Nishimura, T. & Knoblich, J. A. Linking cell cycle to asymmetric division: Aurora-A phosphorylates the Par complex to regulate Numb localization. Cell 135, 161–173 (2008). This paper links the cell cycle machinery and the regulation of asymmetric cell divisions in D. melanogaster neuroblasts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Glover, D. M., Leibowitz, M. H., McLean, D. A. & Parry, H. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 81, 95–105 (1995).

    Article  CAS  PubMed  Google Scholar 

  149. Siegrist, S. E. & Doe, C. Q. Microtubule-induced Pins/Galphai cortical polarity in Drosophila neuroblasts. Cell 123, 1323–1335 (2005).

    Article  CAS  PubMed  Google Scholar 

  150. Januschke, J. & Gonzalez, C. The interphase microtubule aster is a determinant of asymmetric division orientation in Drosophila neuroblasts. J. Cell Biol. 188, 693–706 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Zheng, Z. et al. LGN regulates mitotic spindle orientation during epithelial morphogenesis. J. Cell Biol. 189, 275–288 (2010). This study provides evidence that LGN, together with Gα I and NUMA, regulates the orientation of mitotic spindles in mammalian cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Bryant, D. M. & Mostov, K. E. From cells to organs: building polarized tissue. Nature Rev. Mol. Cell Biol. 9, 887–901 (2008).

    Article  CAS  Google Scholar 

  153. Jaffe, A. B., Kaji, N., Durgan, J. & Hall, A. Cdc42 controls spindle orientation to position the apical surface during epithelial morphogenesis. J. Cell Biol. 183, 625–633 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Durgan, J., Kaji, N., Jin, D. & Hall, A. Par6B and atypical PKC regulate mitotic spindle orientation during epithelial morphogenesis. J. Biol. Chem. 286, 12461–12474 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Rodriguez-Fraticelli, A. E. et al. The Cdc42 GEF Intersectin 2 controls mitotic spindle orientation to form the lumen during epithelial morphogenesis. J. Cell Biol. 189, 725–738 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Hao, Y. et al. Par3 controls epithelial spindle orientation by aPKC-mediated phosphorylation of apical pins. Curr. Biol. 20, 1809–1818 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Qin, Y., Meisen, W. H., Hao, Y. & Macara, I. G. Tuba, a Cdc42 GEF, is required for polarized spindle orientation during epithelial cyst formation. J. Cell Biol. 189, 661–669 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Blanpain, C., Lowry, W. E., Pasolli, H. A. & Fuchs, E. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev. 20, 3022–3035 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Gonzalez, C. Spindle orientation, asymmetric division and tumour suppression in Drosophila stem cells. Nature Rev. Genet. 8, 462–472 (2007).

    Article  CAS  PubMed  Google Scholar 

  160. Hernandez, P. & Tirnauer, J. S. Tumor suppressor interactions with microtubules: keeping cell polarity and cell division on track. Dis. Model Mech. 3, 304–315 (2010).

    Article  CAS  PubMed  Google Scholar 

  161. Szczepanska, K. & Maleszewski, M. LKB1/PAR4 protein is asymmetrically localized in mouse oocytes and associates with meiotic spindle. Gene Expr. Patterns 6, 86–93 (2005).

    Article  CAS  PubMed  Google Scholar 

  162. Bonaccorsi, S. et al. The Drosophila Lkb1 kinase is required for spindle formation and asymmetric neuroblast division. Development 134, 2183–2193 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. Thoma, C. R. et al. VHL loss causes spindle misorientation and chromosome instability. Nature Cell Biol. 11, 994–1001 (2009).

    Article  CAS  PubMed  Google Scholar 

  164. Pease, J. C. & Tirnauer, J. S. Mitotic spindle misorientation in cancer--out of alignment and into the fire. J. Cell Sci. 124, 1007–1016 (2011).

    Article  CAS  PubMed  Google Scholar 

  165. Dupin, I., Camand, E. & Etienne-Manneville, S. Classical cadherins control nucleus and centrosome position and cell polarity. J. Cell Biol. 185, 779–786 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Desai, R. A., Gao, L., Raghavan, S., Liu, W. F. & Chen, C. S. Cell polarity triggered by cell-cell adhesion via E-cadherin. J. Cell Sci. 122, 905–911 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. den Elzen, N., Buttery, C. V., Maddugoda, M. P., Ren, G. & Yap, A. S. Cadherin adhesion receptors orient the mitotic spindle during symmetric cell division in mammalian epithelia. Mol. Biol. Cell 20, 3740–3750 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  169. Wu, M. et al. Epicardial spindle orientation controls cell entry into the myocardium. Dev. Cell 19, 114–125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Bahmanyar, S. et al. beta-Catenin is a Nek2 substrate involved in centrosome separation. Genes Dev. 22, 91–105 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Caldwell, C. M. & Kaplan, K. B. The role of APC in mitosis and in chromosome instability. Adv. Exp. Med. Biol. 656, 51–64 (2009).

    Article  CAS  PubMed  Google Scholar 

  172. Le Borgne, R., Bellaiche, Y. & Schweisguth, F. Drosophila E-cadherin regulates the orientation of asymmetric cell division in the sensory organ lineage. Curr. Biol. 12, 95–104 (2002).

    Article  CAS  PubMed  Google Scholar 

  173. Inaba, M., Yuan, H., Salzmann, V., Fuller, M. T. & Yamashita, Y. M. E-cadherin is required for centrosome and spindle orientation in Drosophila male germline stem cells. PLoS ONE 5, e12473 (2010). This study shows that E-cadherin-mediated adhesion not only maintains the stem cell niche but also controls mitotic spindle orientation in germline stem cells.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Meng, W. & Takeichi, M. Adherens junction: molecular architecture and regulation. Cold Spring Harb. Perspect. Biol. 1, a002899 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Chartier, N. T. et al. Cyclin-dependent kinase 2/cyclin E complex is involved in p120 catenin (p120ctn)-dependent cell growth control: a new role for p120ctn in cancer. Cancer Res. 67, 9781–9790 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Dikovskaya, D. et al. Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis. J. Cell Biol. 176, 183–195 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Lu, B., Roegiers, F., Jan, L. Y. & Jan, Y. N. Adherens junctions inhibit asymmetric division in the Drosophila epithelium. Nature 409, 522–525 (2001).

    Article  CAS  PubMed  Google Scholar 

  178. Kuraguchi, M. et al. Adenomatous polyposis coli (APC) is required for normal development of skin and thymus. PLoS Genet. 2, e146 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

    Article  CAS  PubMed  Google Scholar 

  180. Fleming, E. S., Temchin, M., Wu, Q., Maggio-Price, L. & Tirnauer, J. S. Spindle misorientation in tumors from APC(min/+) mice. Mol. Carcinog. 48, 592–598 (2009).

    Article  CAS  PubMed  Google Scholar 

  181. Tao, L. et al. Repression of mammary stem/progenitor cells by p53 is mediated by Notch and separable from apoptotic activity. Stem Cells 29, 119–127 (2010).

    Article  CAS  Google Scholar 

  182. Marion, R. M. et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460, 1149–1153 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Niessen, C. M. & Gottardi, C. J. Molecular components of the adherens junction. Biochim. Biophys. Acta 1778, 562–571 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Drees, F., Pokutta, S., Yamada, S., Nelson, W. J. & Weis, W. I. Alpha-catenin is a molecular switch that binds E-cadherin-beta-catenin and regulates actin-filament assembly. Cell 123, 903–915 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Cereijido, M., Contreras, R. G., Shoshani, L., Flores-Benitez, D. & Larre, I. Tight junction and polarity interaction in the transporting epithelial phenotype. Biochim. Biophys. Acta 1778, 770–793 (2008).

    Article  CAS  PubMed  Google Scholar 

  186. Tsukita, S., Yamazaki, Y., Katsuno, T., Tamura, A. & Tsukita, S. Tight junction-based epithelial microenvironment and cell proliferation. Oncogene 27, 6930–6938 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  188. Bulgakova, N. A. & Knust, E. The Crumbs complex: from epithelial-cell polarity to retinal degeneration. J. Cell Sci. 122, 2587–2596 (2009).

    Article  CAS  PubMed  Google Scholar 

  189. Suzuki, A. & Ohno, S. The PAR-aPKC system: lessons in polarity. J. Cell Sci. 119, 979–987 (2006).

    Article  CAS  PubMed  Google Scholar 

  190. Goldstein, B. & Macara, I. G. The PAR proteins: fundamental players in animal cell polarization. Dev. Cell 13, 609–622 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Humbert, P. O. et al. Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module. Oncogene 27, 6888–6907 (2008).

    Article  CAS  PubMed  Google Scholar 

  192. Feigin, M. E. & Muthuswamy, S. K. Polarity proteins regulate mammalian cell-cell junctions and cancer pathogenesis. Curr. Opin. Cell Biol. 21, 694–700 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Dong, J. et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130, 1120–1133 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Zhao, B. et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21, 2747–2761 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Goulev, Y. et al. SCALLOPED interacts with YORKIE, the nuclear effector of the hippo tumor-suppressor pathway in Drosophila. Curr. Biol. 18, 435–441 (2008).

    Article  CAS  PubMed  Google Scholar 

  196. Wu, S., Liu, Y., Zheng, Y., Dong, J. & Pan, D. The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev. Cell 14, 388–398 (2008).

    Article  CAS  PubMed  Google Scholar 

  197. Zhang, L. et al. The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Dev. Cell 14, 377–387 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Polesello, C., Huelsmann, S., Brown, N. H. & Tapon, N. The Drosophila RASSF homolog antagonizes the hippo pathway. Curr. Biol. 16, 2459–2465 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Donninger, H., Vos, M. D. & Clark, G. J. The RASSF1A tumor suppressor. J. Cell Sci. 120, 3163–3172 (2007).

    Article  CAS  PubMed  Google Scholar 

  200. Hamaratoglu, F. et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nature Cell Biol. 8, 27–36 (2006).

    Article  CAS  PubMed  Google Scholar 

  201. Rashbass, P. & Skaer, H. Cell polarity: Nailing Crumbs to the scaffold. Curr. Biol. 10, R234–R236 (2000).

    Article  CAS  PubMed  Google Scholar 

  202. Cohen, D., Tian, Y. & Musch, A. Par1b promotes hepatic-type lumen polarity in Madin Darby canine kidney cells via myosin II- and E-cadherin-dependent signaling. Mol. Biol. Cell 18, 2203–2215 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Ducharme, N. A. et al. MARK2/EMK1/Par-1Balpha phosphorylation of Rab11-family interacting protein 2 is necessary for the timely establishment of polarity in Madin-Darby canine kidney cells. Mol. Biol. Cell 17, 3625–3637 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Ossipova, O., Dhawan, S., Sokol, S. & Green, J. B. Distinct PAR-1 proteins function in different branches of Wnt signaling during vertebrate development. Dev. Cell 8, 829–841 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank C. M. Ruiz-Jarabo for comments on the manuscript and all members of the Martín-Belmonte and Perez-Moreno laboratories for their insightful discussions and support. Research by F.M-B. is supported by grants from the Human Frontiers Science Program (HFSP-CDA 00011/2009), Marie Curie (IRG-209382), MICINN (BFU2008-01916) and CONSOLIDER (CSD2009-00016). An institutional Grant from Fundación Ramón Areces to CBMSO is also acknowledged. M.P-M.'s group is supported by grants from the Spanish Ministry of Science and Innovation (BFU2009-11885), the Association for International Cancer Research AICR-UK (10-0746), and from the CNIO (BC1102).

Author information

Authors and Affiliations

  1. Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Madrid, 28049, Spain

    Fernando Martin-Belmonte

  2. Epithelial Cell Biology Group, Cancer Cell Biology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, 28019, Spain

    Mirna Perez-Moreno

Authors
  1. Fernando Martin-Belmonte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mirna Perez-Moreno
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Fernando Martin-Belmonte or Mirna Perez-Moreno.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Alterations of polarity complex proteins in epithelial transformation and human cancer (PDF 210 kb)

Supplementary information S2 (table)

Role of cell polarity pathways in epithelial transformation and human cancer (PDF 232 kb)

Related links

Related links

FURTHER INFORMATION

Fernando Martin-Belmonte's homepage

Mirna Perez-Moreno's homepage

Glossary

Cell polarity

A fundamental feature of many types of cells that describes the asymmetrical distribution of its components within a cell.

Microvilli

Small plasma membrane protrusions on the surface of cells that increase the surface area and facilitate absorption and secretion.

Primary cilium

In mammalian cells, a specialized protrusion with sensory functions.

Vectorial transport

The transportation of ions or molecules within a polarized cell across an epithelium in a specific direction.

Tight junctions

A type of intercellular junction, which is comprised of several interconnecting integral plasma membrane proteins that are anchored to the cytoskeleton. They link adjacent plasma membranes of neighbouring cells to limit the movement of proteins and lipids between the apical and lateral plasma membrane domains and the intercellular passage of molecules.

Cell cortex

A cytoplasmic region under the inner face of the plasma membrane that forms a contractile, mesh-like structure that is rich in contractile actin-myosin filaments (termed cortical actin filaments) and spectrin filaments.

Adhesive homophilic interactions

Adhesive interactions in which the interacting molecules are of the same type. Also known as homotypic interactions.

Subapical

A plasma membrane domain that is spatially separated between the apical and basolateral domains. It is thought to coordinate molecular pathways, such as endocytic pathways and sorting machinery between these distinct plasma membrane domains.

Septate junctions

Intercellular junctions of invertebrate epithelia that act as a barrier restricting the diffusion of proteins and lipids between the apical and lateral plasma membrane domains and the intercellular passage of molecules.

Lateral domains

Plasma membrane domains that face neighbouring cells.

Spectrin filaments

A meshwork of filaments comprised of the cytoskeletal protein spectrin, which has a role in the maintenance of plasma membrane integrity and cytoskeletal structure.

Epithelial-to-mesenchymal transition

(EMT). A process through which cells transit from a polarized, epithelial phenotype to a highly motile mesenchymal phenotype. EMT causes pronounced morphological and functional changes in cells, such as loss of epithelial adherens junctions, reorganization of the actin cytoskeleton and loss of apical-basal polarity.

Bile canaliculi

The hepatocyte apical lumen.

Centrosome

Small organelle that nucleates microtubules, which are important for cell shape, transport, signalling and cell division.

Neuroblasts

Neuronal precursor cells that generate neurons and glia cells in the brain.

Centrioles

Constituents of the centrosome, which is formed by two pairs of barrel-shaped structures. Involved in the organization of microtubules and mitotic spindles.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martin-Belmonte, F., Perez-Moreno, M. Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer 12, 23–38 (2012). https://doi.org/10.1038/nrc3169

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3169

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer