Back to Search
Start Over
GSK3- and PRMT-1–dependent modifications of desmoplakin control desmoplakin–cytoskeleton dynamics
- Source :
- The Journal of Cell Biology
- Publication Year :
- 2015
- Publisher :
- The Rockefeller University Press, 2015.
-
Abstract
- Phosphorylation and methylation of desmoplakin are required for proper junction assembly and adhesion strengthening, and inhibition of these modifications might contribute to skin and heart diseases.<br />Intermediate filament (IF) attachment to intercellular junctions is required for skin and heart integrity, but how the strength and dynamics of this attachment are modulated during normal and pathological remodeling is poorly understood. We show that glycogen synthase kinase 3 (GSK3) and protein arginine methyltransferase 1 (PRMT-1) cooperate to orchestrate a series of posttranslational modifications on the IF-anchoring protein desmoplakin (DP) that play an essential role in coordinating cytoskeletal dynamics and cellular adhesion. Front-end electron transfer dissociation mass spectrometry analyses of DP revealed six novel serine phosphorylation sites dependent on GSK3 signaling and four novel arginine methylation sites including R2834, the mutation of which has been associated with arrhythmogenic cardiomyopathy (AC). Inhibition of GSK3 or PRMT-1 or overexpression of the AC-associated mutant R2834H enhanced DP–IF associations and delayed junction assembly. R2834H blocked the GSK3 phosphorylation cascade and reduced DP–GSK3 interactions in cultured keratinocytes and in the hearts of transgenic R2834H DP mice. Interference with this regulatory machinery may contribute to skin and heart diseases.
- Subjects :
- Keratinocytes
Protein-Arginine N-Methyltransferases
Mutation, Missense
macromolecular substances
Cell junction
Skin Diseases
Article
Phosphorylation cascade
03 medical and health sciences
Glycogen Synthase Kinase 3
Mice
0302 clinical medicine
GSK-3
Animals
Humans
Phosphorylation
Cell adhesion
Cytoskeleton
Intermediate filament
Research Articles
030304 developmental biology
0303 health sciences
biology
integumentary system
Desmoplakin
Myocardium
Arrhythmias, Cardiac
Cell Biology
Molecular biology
3. Good health
Cell biology
Repressor Proteins
HEK293 Cells
Amino Acid Substitution
Desmoplakins
biology.protein
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 15408140 and 00219525
- Volume :
- 208
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- The Journal of Cell Biology
- Accession number :
- edsair.doi.dedup.....203f85538397488168c63f6c486cfc8b