Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity


Two prominent characteristics of epithelial cells, apical-basal polarity and a highly ordered cytoskeleton, depend on the existence of precisely localized protein complexes associated with the apical plasma membrane1,2, and on a separate machinery that regulates the spatial order of actin assembly3. ERM (ezrin, radixin, moesin) proteins have been proposed to link transmembrane proteins to the actin cytoskeleton4 in the apical domain, suggesting a structural role in epithelial cells, and they have been implicated in signalling pathways5. Here, we show that the sole Drosophila ERM protein Moesin functions to promote cortical actin assembly and apical-basal polarity. As a result, cells lacking Moesin lose epithelial characteristics and adopt invasive migratory behaviour. Our data demonstrate that Moesin facilitates epithelial morphology not by providing an essential structural function, but rather by antagonizing activity of the small GTPase Rho. Thus, Moesin functions in maintaining epithelial integrity by regulating cell-signalling events that affect actin organization and polarity. Furthermore, our results show that there is negative feedback between ERM activation and activity of the Rho pathway.

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Figure 1: Moesin and Rho1 control filamentous actin.
Figure 2: Loss of Moesin and overexpression of Rho1 cause loss of apical-basal polarity.
Figure 3: Loss of Moesin and overexpression of Rho1 induce invasive migratory cellular behaviour.
Figure 4: ERM proteins negatively regulate Rho pathway activity in epithelial cells.


  1. 1

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

    CAS  Article  Google Scholar 

  2. 2

    Bachmann, A., Schneider, M., Theilenberg, E., Grawe, F. & Knust, E. Drosophila Stardust is a partner of Crumbs in the control of epithelial cell polarity. Nature 414, 638–643 (2001)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Baum, B. & Perrimon, N. Spatial control of the actin cytoskeleton in Drosophila epithelial cells. Nature Cell Biol. 3, 883–890 (2001)

    CAS  Article  Google Scholar 

  4. 4

    Bretscher, A., Reczek, D. & Berryman, M. Ezrin: a protein requiring conformational activation to link microfilaments to the plasma membrane in the assembly of cell surface structures. J. Cell Sci. 110, 3011–3018 (1997)

    CAS  PubMed  Google Scholar 

  5. 5

    Bretscher, A., Edwards, K. & Fehon, R. G. ERM proteins and merlin: integrators at the cell cortex. Nature Rev. Mol. Cell Biol. 3, 586–599 (2002)

    CAS  Article  Google Scholar 

  6. 6

    Adams, M. D. et al. The genome sequence of Drosophila melanogaster. Science 287, 2185–2195 (2000)

    Article  Google Scholar 

  7. 7

    McCartney, B. M. & Fehon, R. G. Distinct cellular and subcellular patterns of expression imply distinct functions for the Drosophila homologues of moesin and the neurofibromatosis 2 tumour suppressor, merlin. J. Cell Biol. 133, 843–852 (1996)

    CAS  Article  Google Scholar 

  8. 8

    Matsui, T. et al. Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J. Cell Biol. 140, 647–657 (1998)

    CAS  Article  Google Scholar 

  9. 9

    Shaw, R. J., Henry, M., Solomon, F. & Jacks, T. RhoA-dependent phosphorylation and relocalization of ERM proteins into apical membrane/actin protrusions in fibroblasts. Mol. Biol. Cell 9, 403–419 (1998)

    CAS  Article  Google Scholar 

  10. 10

    Simons, P. C., Pietromonaco, S. F., Reczek, D., Bretscher, A. & Elias, L. C-terminal threonine phosphorylation activates ERM proteins to link the cell's cortical lipid bilayer to the cytoskeleton. Biochem. Biophys. Res. Commun. 253, 561–565 (1998)

    CAS  Article  Google Scholar 

  11. 11

    Polesello, C., Delon, I., Valenti, P., Ferrer, P. & Payre, F. Dmoesin controls actin-based cell shape and polarity during Drosophila melanogaster oogenesis. Nature Cell Biol. 4, 782–789 (2002)

    CAS  Article  Google Scholar 

  12. 12

    Gautreau, A., Louvard, D. & Arpin, M. Morphogenic effects of ezrin require a phosphorylation-induced transition from oligomers to monomers at the plasma membrane. J. Cell Biol. 150, 193–203 (2000)

    CAS  Article  Google Scholar 

  13. 13

    Schmitz, A. A., Govek, E. E., Bottner, B. & Van Aelst, L. Rho GTPases: signaling, migration, and invasion. Exp. Cell Res. 261, 1–12 (2000)

    CAS  Article  Google Scholar 

  14. 14

    Hirao, M. et al. Regulation mechanism of ERM (ezrin/radixin/moesin) protein/plasma membrane association: possible involvement of phosphatidylinositol turnover and Rho-dependent signaling pathway. J. Cell Biol. 135, 37–51 (1996)

    CAS  Article  Google Scholar 

  15. 15

    Mackay, D. J., Esch, F., Furthmayr, H. & Hall, A. Rho- and rac-dependent assembly of focal adhesion complexes and actin filaments in permeabilized fibroblasts: an essential role for ezrin/radixin/moesin proteins. J. Cell Biol. 138, 927–938 (1997)

    CAS  Article  Google Scholar 

  16. 16

    Strutt, D. I., Weber, U. & Mlodzik, M. The role of RhoA in tissue polarity and Frizzled signalling. Nature 387, 292–295 (1997)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Winter, C. G. et al. Drosophila Rho-associated kinase (Drok) links Frizzled-mediated planar cell polarity signaling to the actin cytoskeleton. Cell 105, 81–91 (2001)

    CAS  Article  Google Scholar 

  18. 18

    Halsell, S. R., Chu, B. I. & Kiehart, D. P. Genetic analysis demonstrates a direct link between rho signaling and nonmuscle myosin function during Drosophila morphogenesis. Genetics 156, 469 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Hayashi, K., Yonemura, S., Matsui, T. & Tsukita, S. Immunofluorescence detection of ezrin/radixin/moesin (ERM) proteins with their carboxyl-terminal threonine phosphorylated in cultured cells and tissues. J. Cell Sci. 112, 1149–1158 (1999)

    CAS  PubMed  Google Scholar 

  20. 20

    Edwards, K. A., Demsky, M., Montague, R. A., Weymouth, N. & Kiehart, D. P. GFP-moesin illuminates actin cytoskeleton dynamics in living tissue and demonstrates cell shape changes during morphogenesis in Drosophila. Dev. Biol. 191, 103–117 (1997)

    CAS  Article  Google Scholar 

  21. 21

    Takahashi, K. et al. Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein. J. Biol. Chem. 272, 23371–23375 (1997)

    CAS  Article  Google Scholar 

  22. 22

    Takahashi, K. et al. Interaction of radixin with Rho small G protein GDP/GTP exchange protein Dbl. Oncogene 16, 3279–3284 (1998)

    Article  Google Scholar 

  23. 23

    Shaw, R. J. et al. The Nf2 tumour suppressor, merlin, functions in Rac-dependent signaling. Dev. Cell 1, 63–72 (2001)

    CAS  Article  Google Scholar 

  24. 24

    LaJeunesse, D. R., McCartney, B. M. & Fehon, R. G. Structural analysis of Drosophila merlin reveals functional domains important for growth control and subcellular localization. J. Cell Biol. 141, 1589–1599 (1998)

    CAS  Article  Google Scholar 

  25. 25

    Brand, A. H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993)

    CAS  PubMed  Google Scholar 

  26. 26

    Rebay, I., Fehon, R. G. & Artavanis-Tsakonas, S. Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor. Cell 74, 319–329 (1993)

    CAS  Article  Google Scholar 

  27. 27

    Fehon, R. G., Dawson, I. A. & Artavanis-Tsakonas, S. A Drosophila homologue of membrane-skeleton protein 4.1 is associated with septate junctions and is encoded by the coracle gene. Development 120, 545–557 (1994)

    CAS  PubMed  Google Scholar 

  28. 28

    Prokop, A., Landgraf, M., Rushton, E., Broadie, K. & Bate, M. Presynaptic development at the Drosophila neuromuscular junction: assembly and localization of presynaptic active zones. Neuron 17, 617–626 (1996)

    CAS  Article  Google Scholar 

  29. 29

    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  Article  Google Scholar 

  30. 30

    Noren, N. K., Liu, B. P., Burridge, K. & Kreft, B. p120 catenin regulates the actin cytoskeleton via Rho family GTPases. J. Cell Biol. 150, 567–580 (2000)

    CAS  Article  Google Scholar 

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We are grateful to K. Burridge for providing resources for the Rho activation assay; K. Johnson for sharing bench space and expertise; T. Jacks, in whose laboratory the work with mouse ERMs was begun during a sabbatical leave; J. Genova for advice on electron microscopy, and D. Kiehart, D. Lew, I. Rebay, J. Genova and S. Maitra for comments on the manuscript. We would also like to thank H. Gavilan for valuable technical assistance. This work was supported by National Institutes of Health grants to R.G.F. and to K. Burridge.

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Correspondence to Richard G. Fehon.

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Speck, O., Hughes, S., Noren, N. et al. Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity. Nature 421, 83–87 (2003).

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