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Cellular and Molecular Life Sciences

, Volume 75, Issue 22, pp 4251–4268 | Cite as

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

  • Hanna Ungewiß
  • Vera Rötzer
  • Michael Meir
  • Christina Fey
  • Markus Diefenbacher
  • Nicolas Schlegel
  • Jens Waschke
Original Article
  • 438 Downloads

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.

Keywords

Desmosomes Desmosomal cadherins Intestinal barrier Cell adhesion 

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

Notes

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.

Author 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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

18_2018_2869_MOESM1_ESM.pdf (1.2 mb)
Supplementary material 1 (PDF 1236 kb)

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Hanna Ungewiß
    • 1
  • Vera Rötzer
    • 1
  • Michael Meir
    • 2
  • Christina Fey
    • 3
  • Markus Diefenbacher
    • 4
  • Nicolas Schlegel
    • 2
  • Jens Waschke
    • 1
  1. 1.Department I, Institute of Anatomy and Cell BiologyLudwig Maximilians University MunichMunichGermany
  2. 2.Department of General, Visceral, Vascular and Paediatric SurgeryJulius-Maximilians-UniversitätWürzburgGermany
  3. 3.Department for Tissue Engineering and Regenerative MedicineUniversity Hospital WürzburgWürzburgGermany
  4. 4.Department of Biochemistry and Molecular BiochemistryUniversity of WürzburgWürzburgGermany

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