title: The ShcA phosphotyrosine docking protein uses distinct mechanisms to regulate myocyte and global heart function.
abstract: BACKGROUND
  Although tyrosine kinases (TKs) are important for cardiac function, their relevant downstream targets in the adult heart are unknown. The ShcA docking protein binds specific phosphotyrosine (pTyr) sites on activated TKs through its N-terminal pTyr-binding (PTB) and C-terminal SH2 domains and stimulates downstream pathways through motifs such as pTyr sites in its central CH1 region. Therefore, ShcA could be a potential hub for downstream TK signaling in the myocardium.
  
  
  OBJECTIVE
  To define the role of ShcA, a TK scaffold, in the adult heart using a myocardial-specific knockout of murine ShcA (ShcA CKO) and domain knock-in models.
  
  
  RESULTS
  ShcA CKO 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 collagen and extracellular matrix compliance 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, whereas 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.
  
  
  CONCLUSIONS
  These data demonstrate a requirement for TK-ShcA PTB domain signaling to maintain cardiac function. In addition, analysis of the SH2 domain and CH1 pTyr sites reveals that ShcA mediates pTyr signaling in the adult heart through multiple distinct signaling elements that control myocardial functions and response to stresses.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Vanderlaan
authors.forename: W Rod
authors.initials: WR
authors.lastname: Hardy
authors.forename: M Golam
authors.initials: MG
authors.lastname: Kabir
authors.forename: Adrian
authors.initials: A
authors.lastname: Pasculescu
authors.forename: Nina
authors.initials: N
authors.lastname: Jones
authors.forename: Pieter P
authors.initials: PP
authors.lastname: deTombe
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019000:Phosphotyrosine / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D016326:Extracellular Matrix Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019000:Phosphotyrosine; D003094:Collagen