c-Ski, Smurf2, and Arkadia as regulators of TGF-beta signaling: new targets for managing myofibroblast function and cardiac fibrosis.
Recent studies demonstrate the critical role of the extracellular matrix in the organization of parenchymal cells in the heart. Thus, an understanding of the modes of regulation of matrix production by cardiac myofibroblasts is essential. Transforming growth factor beta (TGF-beta) signaling is transduced through the canonical Smad pathway, and the involvement of this pathway in matrix synthesis and other processes requires precise control. Inhibition of Smad signaling may be achieved at the receptor level through the targeting of the TGF-beta type I receptors with an inhibitory Smad7/Smurf2 complex, or at the transcriptional level through c-Ski/receptor-Smad/co-mediator Smad4 interactions. Conversely, Arkadia protein intensifies TGF-beta-induced effects by marking c-Ski and inhibitory Smad7 for destruction. The study of these TGF-beta mediators is essential for future treatment of fibrotic disease, and this review highlights recent relevant findings that may impact our understanding of cardiac fibrosis.
Cunnington
Ryan H
RH
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Department of Physiology, University of Manitoba, 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada.
Nazari
Mansoreh
M
Dixon
Ian M C
IM
D000818:Animals; D005347:Fibroblasts / Q000187:drug effects*; D005355:Fibrosis / Q000139:chemically induced* / Q000473:pathology; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C060615:SKIL protein, human; D016212:Transforming Growth Factor beta; C471641:SMURF2 protein, human; C486067:RNF111 protein, human; D044767:Ubiquitin-Protein Ligases