GSK3- and PRMT-1-dependent modifications of desmoplakin control desmoplakin-cytoskeleton dynamics

Lauren V. Albrecht, Lichao Zhang, Jeffrey Shabanowitz, Enkhsaikhan Purevjav, Jeffrey Towbin, Donald F. Hunt, Kathleen J. Green

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)597-612
Number of pages16
JournalJournal of Cell Biology
Volume208
Issue number5
DOIs
StatePublished - Jan 1 2015

Fingerprint

Protein-Arginine N-Methyltransferases
Desmoplakins
Glycogen Synthase Kinase 3
Cytoskeleton
Intermediate Filaments
Cardiomyopathies
Phosphorylation
Intermediate Filament Proteins
Intercellular Junctions
Post Translational Protein Processing
Keratinocytes
Skin Diseases
Serine
Methylation
Arginine
Heart Diseases
Mass Spectrometry
Electrons
Skin
Mutation

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

GSK3- and PRMT-1-dependent modifications of desmoplakin control desmoplakin-cytoskeleton dynamics. / Albrecht, Lauren V.; Zhang, Lichao; Shabanowitz, Jeffrey; Purevjav, Enkhsaikhan; Towbin, Jeffrey; Hunt, Donald F.; Green, Kathleen J.

In: Journal of Cell Biology, Vol. 208, No. 5, 01.01.2015, p. 597-612.

Research output: Contribution to journalArticle

Albrecht, Lauren V. ; Zhang, Lichao ; Shabanowitz, Jeffrey ; Purevjav, Enkhsaikhan ; Towbin, Jeffrey ; Hunt, Donald F. ; Green, Kathleen J. / GSK3- and PRMT-1-dependent modifications of desmoplakin control desmoplakin-cytoskeleton dynamics. In: Journal of Cell Biology. 2015 ; Vol. 208, No. 5. pp. 597-612.
@article{b0497098f9964397bb5ac6f423559fa5,
title = "GSK3- and PRMT-1-dependent modifications of desmoplakin control desmoplakin-cytoskeleton dynamics",
abstract = "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.",
author = "Albrecht, {Lauren V.} and Lichao Zhang and Jeffrey Shabanowitz and Enkhsaikhan Purevjav and Jeffrey Towbin and Hunt, {Donald F.} and Green, {Kathleen J.}",
year = "2015",
month = "1",
day = "1",
doi = "10.1083/jcb.201406020",
language = "English (US)",
volume = "208",
pages = "597--612",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "5",

}

TY - JOUR

T1 - GSK3- and PRMT-1-dependent modifications of desmoplakin control desmoplakin-cytoskeleton dynamics

AU - Albrecht, Lauren V.

AU - Zhang, Lichao

AU - Shabanowitz, Jeffrey

AU - Purevjav, Enkhsaikhan

AU - Towbin, Jeffrey

AU - Hunt, Donald F.

AU - Green, Kathleen J.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84924891327&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924891327&partnerID=8YFLogxK

U2 - 10.1083/jcb.201406020

DO - 10.1083/jcb.201406020

M3 - Article

VL - 208

SP - 597

EP - 612

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 5

ER -