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Rap2A links intestinal cell polarity to brush border formation

Nature Cell Biology volume 14, pages 793–801 (2012)Cite this article

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Abstract

The microvillus brush border at the apex of the highly polarized enterocyte allows the regulated uptake of nutrients from the intestinal lumen. Here, we identify the small G protein Rap2A as a molecular link that couples the formation of microvilli directly to the preceding cell polarization. Establishment of apicobasal polarity, which can be triggered by the kinase LKB1 in single, isolated colon cells, results in enrichment of PtdIns(4,5)P2 at the apical membrane. The subsequent recruitment of phospholipase D1 allows polarized accumulation of phosphatidic acid, which provides a local cue for successive signalling by the guanine nucleotide exchange factor PDZGEF, the small G protein Rap2A, its effector TNIK, the kinase MST4 and, ultimately, the actin-binding protein Ezrin. Thus, epithelial cell polarization is translated directly into the acquisition of brush borders through a small G protein signalling module whose action is positioned by a cortical lipid cue.

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Figure 1: Rap2A is required for intestinal epithelial brush border formation.
Figure 2: Activation of Rap2A by PDZGEF downstream of LKB1.
Figure 3: PDZGEF is apically targeted by local generation of phosphatidic acid.
Figure 4: Rap2A-mediated brush border formation requires its effector TNIK.
Figure 5: Rap2A controls the apical targeting of MST4.
Figure 6: Rap2A controls brush border formation by regulation of Ezrin phosphorylation.

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Change history

  • 17 July 2012

    In the version of this article initially published online, an arrowhead in Fig 6f was incorrectly placed. This has been corrected.

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Acknowledgements

We are grateful to R. Wedlich-Söldner (Max Planck Institute of Biochemistry, Martinsried, Germany), N. Vitale (Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France), T. Balla (National Institutes of Health, Bethesda, USA), J. Chen (University of Illinois, Urbana, USA) and S. van den Heuvel (Universiteit Utrecht, Utrecht, The Netherlands) for providing reagents. We thank W. Vonk, L. Kleij and K. Lee for technical assistance, C. Garner for assistance with lentiviral infections, K. Jalink for discussions, G. Kops, T. Pawson and J. Nelson for critical reading of the manuscript, and the members of our laboratories for continuous support and stimulating discussions. This study is supported by the Dutch Cancer Society (KWF; J.P.t.K. and M.J.V.), Chemical Sciences (M.G.) and the Netherlands Genomics Initiative (J.L.B. and H.C.) of the Netherlands Organization for Scientific Research (NWO).

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  1. Martijn Gloerich

    Present address: Present address: Department of Biology, The James H. Clark Center, The Bio-X Program, Stanford University, 318 Campus Drive (E200-B), Stanford, California 94305-5430, USA,

Authors and Affiliations

  1. Molecular Cancer Research, Centre for Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands

    Martijn Gloerich, Marjolein J. Vliem, Fried J. Zwartkruis & Johannes L. Bos

  2. Hubrecht Institute, KNAW and University Medical Center Utrecht, Centre for Biomedical Genetics and Cancer Genomics Centre, Utrecht 3584 CT, The Netherlands

    Jean Paul ten Klooster & Hans Clevers

  3. Developmental Biology, Utrecht University, Utrecht 3584 CH, The Netherlands

    Thijs Koorman

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Contributions

M.G., J.P.t.K. and J.L.B. designed the study and experiments; M.G., J.P.t.K., M.J.V., T.K. and F.J.Z. performed experiments; M.G. and J.L.B. wrote the manuscript; H.C. and J.L.B. supervised the study.

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Correspondence to Martijn Gloerich or Johannes L. Bos.

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Gloerich, M., ten Klooster, J., Vliem, M. et al. Rap2A links intestinal cell polarity to brush border formation. Nat Cell Biol 14, 793–801 (2012). https://doi.org/10.1038/ncb2537

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