test Browse by Author Names Browse by Titles of Works Browse by Subjects of Works Browse by Issue Dates of Works
       

Advanced Search
Home   
 
Browse   
Communities
& Collections
  
Issue Date   
Author   
Title   
Subject   
 
Sign on to:   
Receive email
updates
  
My Account
authorized users
  
Edit Profile   
 
Help   
About T-Space   

T-Space at The University of Toronto Libraries >
School of Graduate Studies - Theses >
Doctoral >

Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/29899

Title: The Role of ShcA Phosphotyrosine Signaling in the Myocardium
Authors: Vanderlaa, Rachel
Advisor: Pawson, Tony
Backx, Peter
Department: Molecular and Medical Genetics
Keywords: adaptor protein
cardiovascular
Issue Date: 31-Aug-2011
Abstract: Tyrosine kinases (TK) are important for cardiac function, but their downstream targets in the adult heart have yet to be established. The ShcA docking protein binds specific phosphotyrosine (pTyr) sites on activated TKs through its N-terminal PTB and C-terminal SH2 domains and stimulates downstream pathways through motifs such as pTyr sites in its central CH1 region. To explore the role of this TK scaffold in the adult heart, we generated a myocardial-specific knockout of murine ShcA (ShcA CKO). Such mice developed a dilated cardiomyopathy phenotype involving impaired systolic function with enhanced cardiomyocyte contractility. This uncoupling of global heart and intrinsic myocyte functions was associated with altered perimysial collagen and extracellular matrix complicance properties, suggesting disruption of mechanical coupling. In vivo dissection of ShcA signaling properties revealed that selective inactivation of the PTB domain in the myocardium had effects resembling those seen in ShcA CKO mice, while disruption of the SH2 domain caused a less severe cardiac phenotype. Downstream signaling through the CH1 pTyr sites was dispensable for baseline cardiac function, but necessary to prevent adverse remodeling after hemodynamic overload. Therefore, ShcA mediates pTyr signaling in the adult heart through multiple distinct signaling elements that control myocardial functions and response to stresses.
URI: http://hdl.handle.net/1807/29899
Appears in Collections:Doctoral

Files in This Item:

File Description SizeFormat
Vanderlaan_Rachel_201106_PhD_thesis.pdf1.94 MBAdobe PDF
View/Open

This item is licensed under a Creative Commons License
Creative Commons

Items in T-Space are protected by copyright, with all rights reserved, unless otherwise indicated.

uoft