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Dsg2 via Src-mediated transactivation shapes EGFR signaling towards cell adhesion

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A Correction to this article was published on 10 July 2019

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Abstract

Rapidly renewing epithelial tissues such as the intestinal epithelium require precise tuning of intercellular adhesion and proliferation to preserve barrier integrity. Here, we provide evidence that desmoglein 2 (Dsg2), an adhesion molecule of desmosomes, controls cell adhesion and proliferation via epidermal growth factor receptor (EGFR) signaling. Dsg2 is required for EGFR localization at intercellular junctions as well as for Src-mediated EGFR activation. Src binds to EGFR and is required for localization of EGFR and Dsg2 to cell–cell contacts. EGFR is critical for cell adhesion and barrier recovery. In line with this, Dsg2-deficient enterocytes display impaired barrier properties and increased cell proliferation. Mechanistically, Dsg2 directly interacts with EGFR and undergoes heterotypic-binding events on the surface of living enterocytes via its extracellular domain as revealed by atomic force microscopy. Thus, our study reveals a new mechanism by which Dsg2 via Src shapes EGFR function towards cell adhesion.

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Change history

  • 10 July 2019

    In the published article, the legend for figure��3 was incorrect. The correct legend is given below.

  • 10 July 2019

    In the published article, the legend for figure��3 was incorrect. The correct legend is given below.

Abbreviations

AFM:

Atomic force microscopy

AJ:

Adherens junction

Cld4:

Claudin 4

Dsc2:

Desmocollin 2

Dsg2:

Desmoglein

DP:

Desmoplakin

Ecad:

E-cadherin

EGFR:

Epidermal growth factor receptor

MAPK:

Mitogen-activated protein kinase

PG:

Plakoglobin

Pkp:

Plakophilin

RTK:

Receptor tyrosine kinase

STED:

Stimulated emission depletion microscopy

TER:

Transepithelial resistance

TJ:

Tight junction

WT:

Wild type

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Acknowledgements

This work was supported by the DFG priority program SPP 1782. DLD1 cells were a gift from S.T. Suzuki (Kwansei Gakuin University, Japan). STED microscopy was performed in the lab of H. Leonhardt (Ludwig-Maximilians-University, Munich). The authors would like to thank Andreas Meiser and Hartmann Harz for their assistance in STED sample preparation and image acquisition.

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Authors and Affiliations

  1. Department I, Institute of Anatomy and Cell Biology, Ludwig Maximilians University Munich, Pettenkoferstr. 11, 80336, Munich, Germany

    Hanna Ungewiß, Vera Rötzer & Jens Waschke

  2. Department of General, Visceral, Vascular and Paediatric Surgery, Julius-Maximilians-Universität, Oberdürrbacher Str. 6, 97080, Würzburg, Germany

    Michael Meir & Nicolas Schlegel

  3. Department for Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Röntgenring 11, 97070, Würzburg, Germany

    Christina Fey

  4. Department of Biochemistry and Molecular Biochemistry, University of Würzburg, Am Hubland, 97074, Würzburg, Germany

    Markus Diefenbacher

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  1. Hanna Ungewiß
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Contributions

HU and JW designed the study. HU performed and analyzed the experiments. VR performed the hanging drop bead aggregation assay. MM obtained and prepared the human tissue samples. CF generated the enteroids. MD generated the Dsg2-deficient Caco2 cell line. All authors interpreted the data. HU wrote the manuscript and prepared the figures. All authors reviewed the manuscript.

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Correspondence to Jens Waschke.

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Ungewiß, H., Rötzer, V., Meir, M. et al. Dsg2 via Src-mediated transactivation shapes EGFR signaling towards cell adhesion. Cell. Mol. Life Sci. 75, 4251–4268 (2018). https://doi.org/10.1007/s00018-018-2869-x

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  • DOI: https://doi.org/10.1007/s00018-018-2869-x

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