The Src homology and collagen A (ShcA) adaptor protein is required for the spatial organization of the costamere/Z-disk network during heart development

J Biol Chem. 2015 Jan 23;290(4):2419-30. doi: 10.1074/jbc.M114.597377. Epub 2014 Dec 8.


Src homology and collagen A (ShcA) is an adaptor protein that binds to tyrosine kinase receptors. Its germ line deletion is embryonic lethal with abnormal cardiovascular system formation, and its role in cardiovascular development is unknown. To investigate its functional role in cardiovascular development in mice, ShcA was deleted in cardiomyocytes and vascular smooth muscle cells by crossing ShcA flox mice with SM22a-Cre transgenic mice. Conditional mutant mice developed signs of severe dilated cardiomyopathy, myocardial infarctions, and premature death. No evidence of a vascular contribution to the phenotype was observed. Histological analysis of the heart revealed aberrant sarcomeric Z-disk and M-band structures, and misalignments of T-tubules with Z-disks. We find that not only the ErbB3/Neuregulin signaling pathway but also the baroreceptor reflex response, which have been functionally associated, are altered in the mutant mice. We further demonstrate that ShcA interacts with Caveolin-1 and the costameric protein plasma membrane Ca(2+)/calmodulin-dependent ATPase (PMCA), and that its deletion leads to abnormal dystrophin signaling. Collectively, these results demonstrate that ShcA interacts with crucial proteins and pathways that link Z-disk and costamere.

Keywords: Adaptor Protein; Costamere; ErbB; Gene Knockout; Heart Development; Heart Failure; Molecular Biology; ShcA; Z-disks.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Aorta, Thoracic / metabolism
  • Blood Pressure
  • Cell Survival
  • Costameres / metabolism*
  • Dystrophin / metabolism
  • Echocardiography
  • Gene Deletion
  • Gene Expression Regulation, Developmental
  • Heart / embryology*
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Transgenic
  • Microscopy, Confocal
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Smooth Muscle / metabolism*
  • Phenotype
  • Plasma Membrane Calcium-Transporting ATPases / metabolism
  • RNA, Small Interfering / metabolism
  • Rats
  • Receptor, ErbB-3 / metabolism
  • Shc Signaling Adaptor Proteins / genetics
  • Shc Signaling Adaptor Proteins / metabolism*
  • Src Homology 2 Domain-Containing, Transforming Protein 1


  • Dystrophin
  • RNA, Small Interfering
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Receptor, ErbB-3
  • Plasma Membrane Calcium-Transporting ATPases