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Post-Translational Modifications of ...

Albrecht, Lauren V.

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Post-Translational Modifications of Desmoplakin (DP) Regulate Intermediate Filament Cytoskeletal Dynamics in Skin and Heart Disease.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Post-Translational Modifications of Desmoplakin (DP) Regulate Intermediate Filament Cytoskeletal Dynamics in Skin and Heart Disease./
Author:	Albrecht, Lauren V.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2016,
Description:	226 p.
Notes:	Source: Dissertation Abstracts International, Volume: 78-02(E), Section: B.
Contained By:	Dissertation Abstracts International78-02B(E).
Subject:	Cellular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10160384
ISBN:	9781369152920

Post-Translational Modifications of Desmoplakin (DP) Regulate Intermediate Filament Cytoskeletal Dynamics in Skin and Heart Disease.
Albrecht, Lauren V.

Post-Translational Modifications of Desmoplakin (DP) Regulate Intermediate Filament Cytoskeletal Dynamics in Skin and Heart Disease. - Ann Arbor : ProQuest Dissertations & Theses, 2016 - 226 p.

Source: Dissertation Abstracts International, Volume: 78-02(E), Section: B.

Thesis (Ph.D.)--Northwestern University, 2016.

The desmosome is an intercellular junction that provides structural integrity to tissues that undergo mechanical stress such as the epidermis and the heart. Desmoplakin (DP) is a critical component of the desmosome as it anchors the intermediate filament (IF) cytoskeleton to site of cell-cell contact. My work identifies a series of post translational modifications (PTMs), lying within a short flexible region downstream of the IF-binding domain, in the DP C-terminal tail that cooperate to govern the interconversion of DP-IF complexes between tight binding and dynamic forms. Further, AMPK, GSK3, and PRMT-1 signaling pathways converge on the DP C-tail to regulate DP-IF complexes during the formation of intercellular junctions. The correct functioning of DP-IF dynamics depends on AMPK and GSK3-beta processive phosphorylation of a twelve-residue segment of the DP C-tail. We also identify for the first time that arginine, 2834, is one of four arginines in the C-tail that becomes methylated and that the arginine methyltransferase PRMT-1 is required for DP processive phosphorylation and proper DP dynamics. Together, this work demonstrates that a coordinated role between arginine methylation and processive phosphorylation mediates DP-IF cytoskeletal dynamics.

ISBN: 9781369152920Subjects--Topical Terms:

3172791
Cellular biology.

Post-Translational Modifications of Desmoplakin (DP) Regulate Intermediate Filament Cytoskeletal Dynamics in Skin and Heart Disease.
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245 1 0 $a Post-Translational Modifications of Desmoplakin (DP) Regulate Intermediate Filament Cytoskeletal Dynamics in Skin and Heart Disease.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2016
300 $a 226 p.
500 $a Source: Dissertation Abstracts International, Volume: 78-02(E), Section: B.
500 $a Adviser: Kathleen J. Green.
502 $a Thesis (Ph.D.)--Northwestern University, 2016.
520 $a The desmosome is an intercellular junction that provides structural integrity to tissues that undergo mechanical stress such as the epidermis and the heart. Desmoplakin (DP) is a critical component of the desmosome as it anchors the intermediate filament (IF) cytoskeleton to site of cell-cell contact. My work identifies a series of post translational modifications (PTMs), lying within a short flexible region downstream of the IF-binding domain, in the DP C-terminal tail that cooperate to govern the interconversion of DP-IF complexes between tight binding and dynamic forms. Further, AMPK, GSK3, and PRMT-1 signaling pathways converge on the DP C-tail to regulate DP-IF complexes during the formation of intercellular junctions. The correct functioning of DP-IF dynamics depends on AMPK and GSK3-beta processive phosphorylation of a twelve-residue segment of the DP C-tail. We also identify for the first time that arginine, 2834, is one of four arginines in the C-tail that becomes methylated and that the arginine methyltransferase PRMT-1 is required for DP processive phosphorylation and proper DP dynamics. Together, this work demonstrates that a coordinated role between arginine methylation and processive phosphorylation mediates DP-IF cytoskeletal dynamics.
520 $a Genetic mutations in skin and heart diseases interfere with DP-IF dynamics and alter the kinetics of junction assembly and epithelial sheet integrity by causing DP retention on cytoplasmic filaments. We identify that the presence of a point mutation at DP arginine methylation site, R2834H, found in an inherited form of human cardiomyopathy, dramatically impairs DP-IF dynamics during junction assembly through the disruption of GSK3 phosphorylation cascades on DP. Additionally, DP dynamics are altered in Darier Disease (DD), a genetic skin disorder caused by mutations in the endoplasmic reticulum (ER) calcium pump, SERCA2. We identify a novel link between SERCA2 and AMP-activated kinase (AMPK), a calcium-dependent kinase that serves as the metabolic energy sensor of the cell. DD keratinocytes and normal keratinocytes subjected to pharmacological inhibition or RNAi directed against SERCA2 exhibited significantly decreased AMPK activity. A decrease in AMPK-dependent phosphorylation of DP was associated with impaired DP-IF cytoskeletal dynamics during junction assembly. The resulting misregulation of intercellular adhesion and DP-IF complexes in DD patient cells was reversed with the AMPK activator, metformin, along with restoration of DP phosphorylation. These data connect SERCA2 and AMPK signaling in the regulation of desmosome dynamics and raise the possibility that metformin treatment could ameliorate adhesion defects in DD. By understanding the molecular basis through which the C-tail regulates DP this work contributes to our understanding of the nature of IF-associations at desmosomal junctions and defines new therapeutic targets and drug design strategies for amelioration of a number of cardiac and cutaneous disorders.
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