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Updated: Mar 25, 2026
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
c-Src/Cav1-dependent activation of the EGFR by Dsg2
Andrew M Overmiller1, Kathleen P McGuinn1, Brett J Roberts2
1Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
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.
Insights
Desmoglein 2 (Dsg2) promotes skin cancer by enhancing epidermal growth factor receptor (EGFR) signaling. Dsg2 utilizes lipid rafts to regulate EGFR, c-Src, and Cav1, driving cell growth and migration.
Area of Science:
- Cell Biology
- Cancer Research
- Dermatology
Background:
- Desmoglein 2 (Dsg2) is implicated in various cancers, including skin cancer.
- Ectopic Dsg2 expression in mouse epidermis activates mitogenic pathways and promotes tumorigenesis.
- The precise molecular mechanisms of Dsg2-mediated signaling remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying Dsg2-mediated cellular signaling in skin cancer.
- To investigate the role of Dsg2 in regulating epidermal growth factor receptor (EGFR) signaling.
- To determine if Dsg2 utilizes lipid rafts to modulate signaling pathways.
Main Methods:
- Investigated Dsg2 and EGFR co-localization in cutaneous squamous cell carcinomas (SCCs).
- Utilized HaCaT keratinocytes for Dsg2 knockdown and EGF stimulation experiments.
- Employed sucrose density fractionation and STED imaging to analyze lipid raft composition and protein localization.
- Assessed cell proliferation and migration in human SCC A431 cells overexpressing Dsg2.
Main Results:
- Dsg2 knockdown reduced EGFR expression and abrogated EGFR, c-Src, and Stat3 activation upon EGF stimulation.
- Dsg2 localized to lipid rafts, displacing Cav1, EGFR, and c-Src, and dispersed Cav1 from cell-cell borders.
- Perturbation of lipid rafts altered protein localization and activated signaling pathways.
- Dsg2 overexpression enhanced EGFR activation, promoting cell proliferation and migration via c-Src and EGFR.
Conclusions:
- Dsg2 stimulates cell growth and migration in skin cancer.
- Dsg2 positively regulates EGFR levels and signaling through a c-Src and Cav1-dependent mechanism.
- Lipid rafts serve as platforms for Dsg2-mediated signal modulation, impacting cancer progression.
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