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Induction and Analysis of Epithelial to Mesenchymal Transition
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Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation
Robert M Harmon1, Cory L Simpson, Jodi L Johnson
1Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
The Journal of Clinical Investigation
|March 26, 2013
Summary
Desmoglein-1 (DSG1) and Erbin cooperate to inhibit MAPK/ERK signaling, promoting skin cell differentiation. This mechanism explains skin defects in RASopathies and striate palmoplantar keratoderma (SPPK).
Area of Science:
- Dermatology
- Molecular Biology
- Genetics
Background:
- RASopathies are genetic disorders causing abnormalities, including skin conditions like keratoderma.
- Desmoglein-1 (DSG1) is crucial for keratinocyte differentiation and attenuates MAPK/ERK signaling, linking it to striate palmoplantar keratoderma (SPPK).
Purpose of the Study:
- To identify molecular intermediates through which DSG1 inhibits ERK signaling.
- To elucidate the shared molecular mechanisms underlying cutaneous defects in SPPK and RASopathies.
Main Methods:
- Yeast 2-hybrid screening to identify DSG1-binding proteins.
- Erbin silencing in cultured keratinocytes.
- Analysis of epidermal tissue from DSG1-deficient SPPK patients.
Main Results:
- Erbin was identified as a DSG1-binding protein that regulates ERK signaling.
- Erbin silencing impaired keratinocyte differentiation, mimicking DSG1 deficiency.
- DSG1 and Erbin were shown to cooperate in repressing MAPK signaling and promoting differentiation, with disruptions observed in SPPK patient epidermis.
Conclusions:
- DSG1 and Erbin form a complex that inhibits MAPK signaling by disrupting Ras-Raf scaffolds, thereby promoting keratinocyte differentiation.
- This pathway provides a molecular explanation for skin abnormalities in RASopathies and SPPK.
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