Dysbindin is a potent inducer of RhoA-SRF-mediated cardiomyocyte hypertrophy

J Cell Biol. 2013 Nov 25;203(4):643-56. doi: 10.1083/jcb.201303052.

Abstract

Dysbindin is an established schizophrenia susceptibility gene thoroughly studied in the context of the brain. We have previously shown through a yeast two-hybrid screen that it is also a cardiac binding partner of the intercalated disc protein Myozap. Because Dysbindin is highly expressed in the heart, we aimed here at deciphering its cardiac function. Using a serum response factor (SRF) response element reporter-driven luciferase assay, we identified a robust activation of SRF signaling by Dysbindin overexpression that was associated with significant up-regulation of SRF gene targets, such as Acta1 and Actc1. Concurrently, we identified RhoA as a novel binding partner of Dysbindin. Further phenotypic and mechanistic characterization revealed that Dysbindin induced cardiac hypertrophy via RhoA-SRF and MEK1-ERK1 signaling pathways. In conclusion, we show a novel cardiac role of Dysbindin in the activation of RhoA-SRF and MEK1-ERK1 signaling pathways and in the induction of cardiac hypertrophy. Future in vivo studies should examine the significance of Dysbindin in cardiomyopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology
  • Carrier Proteins / metabolism*
  • Cell Line
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Models, Biological
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology*
  • Nerve Tissue Proteins / metabolism*
  • Protein Binding
  • Rats
  • Rats, Wistar
  • Serum Response Factor / metabolism*
  • Signal Transduction
  • rhoA GTP-Binding Protein / antagonists & inhibitors
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Carrier Proteins
  • Dtnbp1 protein, mouse
  • Dtnbp1 protein, rat
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Nerve Tissue Proteins
  • Serum Response Factor
  • Extracellular Signal-Regulated MAP Kinases
  • rhoA GTP-Binding Protein