c-Src/Cav1-dependent activation of the EGFR by Dsg2.

Authors

Andrew M. Overmiller, Thomas Jefferson UniversityFollow
Kathleen P. McGuinn, Thomas Jefferson UniversityFollow
Brett J. Roberts, University of Nebraska Medical CenterFollow
Felicia Cooper, Thomas Jefferson UniversityFollow
Donna M. Brennan-Crispi, Thomas Jefferson UniversityFollow
Takahiro Deguchi, University of Turku
Sirkku Peltonen, University of Turku
James K. Wahl, University of Nebraska Medical CenterFollow
Mỹ G. Mahoney, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

2-24-2016

Comments

This article has been peer reviewed. It is the author’s final published version in Oncotarget

Volume 7, Issue 25, February 2016, Pages 37536-37555.

The published version is available at DOI: 10.18632/oncotarget.7675. Copyright © Impact Journals

Abstract

The desmosomal cadherin, desmoglein 2 (Dsg2), is deregulated in a variety of human cancers including those of the skin. When ectopically expressed in the epidermis of transgenic mice, Dsg2 activates multiple mitogenic signaling pathways and increases susceptibility to tumorigenesis. However, the molecular mechanism responsible for Dsg2-mediated cellular signaling is poorly understood. Here we show overexpression as well as co-localization of Dsg2 and EGFR in cutaneous SCCs in vivo. Using HaCaT keratinocytes, knockdown of Dsg2 decreases EGFR expression and abrogates the activation of EGFR, c-Src and Stat3, but not Erk1/2 or Akt, in response to EGF ligand stimulation. To determine whether Dsg2 mediates signaling through lipid microdomains, sucrose density fractionation illustrated that Dsg2 is recruited to and displaces Cav1, EGFR and c-Src from light density lipid raft fractions. STED imaging confirmed that the presence of Dsg2 disperses Cav1 from the cell-cell borders. Perturbation of lipid rafts with the cholesterol-chelating agent MβCD also shifts Cav1, c-Src and EGFR out of the rafts and activates signaling pathways. Functionally, overexpression of Dsg2 in human SCC A431 cells enhances EGFR activation and increases cell proliferation and migration through a c-Src and EGFR dependent manner. In summary, our data suggest that Dsg2 stimulates cell growth and migration by positively regulating EGFR level and signaling through a c-Src and Cav1-dependent mechanism using lipid rafts as signal modulatory platforms.

Recommended Citation

Overmiller, Andrew M.; McGuinn, Kathleen P.; Roberts, Brett J.; Cooper, Felicia; Brennan-Crispi, Donna M.; Deguchi, Takahiro; Peltonen, Sirkku; Wahl, James K.; and Mahoney, Mỹ G., "c-Src/Cav1-dependent activation of the EGFR by Dsg2." (2016). Department of Dermatology and Cutaneous Biology Faculty Papers. Paper 59.
https://jdc.jefferson.edu/dcbfp/59

Creative Commons License

This work is licensed under a Creative Commons Attribution 3.0 License.

PubMed ID

26918609