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.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/29899 |
| Date | 31 August 2011 |
| Creators | Vanderlaa, Rachel |
| Contributors | Pawson, Tony, Backx, Peter |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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