TGFB RECEPTOR EXPRESSION AND FUNCTION IN CARDIOGENESIS

Summary

Principal Investigator: Joey Barnett
Abstract: Peptide growth factors, such as the Transforming Growth Factor beta (TGFbeta) family, play central roles in morphogenesis and organogenesis. The narrowly defined vertebrate TGFbeta family is composed of at least three 25 kilodalton homodimeric proteins, TGFbeta1, TGFbeta2, and TGFbeta3. TGFbeta1 and TGFbeta 3 share identical ligand binding and biological activities while TGFbeta2 has a unique requirement for the Type III TGFbeta receptor (TBRIII) and distinct biological activities. We have recently demonstrated a requirement for TBRIII in TGFbeta-mediated epithelial-mesenchymal cell transformation that occurs in the atrioventricular (AV) cushion of the developing heart. We are testing the hypothesis that a unique receptor signal transduction complex is responsible for AV cushion transformation. Since current models of TGFbeta signal transduction presuppose a requirement for a Type I receptor (TBRI) in the signal transduction complex, initial experiments will determine if a Type I receptor (TBRI) is a component of the receptor complex in the AV cushion. Specifically, we will determine whether the ALK2 or ALK5 TBRI is required for transformation. This will be determined both by misexpression of constituitively active ALK2 and ALK5 and antisense constructs. A well described pathway for downstream signal transduction from TGFbeta receptors includes the Smads family of transcription factors. We will test the hypothesis that specific Smads are necessary for AV cushion transformation by , determining if dominate negative inhibitors of Smads or constitutively active Smads alter transformation in AV cushion explants and ventricular explants. Preliminary data in our laboratory suggests a role for the ALK2, and not ALK5, in transformation. Therefore we will test the hypothesis that ALK2 associates with TBRIII to mediate transformation by immunoprecipitation of the TGFbeta receptor complex and identification of ALK2 and ALK5. We also will immunolocalize TBRI and TBRIII on both chick embryonic fibroblasts and AV cushion endothelial cells to determine whether they associate after the addition of TGFbeta. These experiments are part of a concerted strategy to determine whether TBRIII requires a TBRI and downstream Smad signaling. Our long-term goal to understand the role of TGFbeta in cushion transformation and the genesis of congenital heart defects due to abnormal cushion transformation.
Funding Period: 1996-03-20 - 2006-11-30
more information: NIH RePORT

Top Publications

  1. ncbi Activin receptor-like kinase 2 and Smad6 regulate epithelial-mesenchymal transformation during cardiac valve formation
    Jay S Desgrosellier
    Department of Pharmacology, Vanderbilt University Medical Center, Room 476 RRB, 2220 Pierce Avenue, Nashville, TN 37232 6600, USA
    Dev Biol 280:201-10. 2005
  2. pmc Transforming growth factor-beta stimulates epithelial-mesenchymal transformation in the proepicardium
    Harold E Olivey
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600, USA
    Dev Dyn 235:50-9. 2006
  3. ncbi Transforming growth factor-beta induces loss of epithelial character and smooth muscle cell differentiation in epicardial cells
    Leigh A Compton
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600, USA
    Dev Dyn 235:82-93. 2006
  4. ncbi Transforming growth factor beta regulates the expression of the M2 muscarinic receptor in atrial myocytes via an effect on RhoA and p190RhoGAP
    Ho Jin Park
    Molecular Cardiology Research Institute, Department of Medicine, Tufts New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
    J Biol Chem 281:19995-20002. 2006
  5. ncbi Bone morphogenetic proteins signal through the transforming growth factor-beta type III receptor
    Kellye C Kirkbride
    Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27708, USA
    J Biol Chem 283:7628-37. 2008
  6. pmc Transforming growth factor-beta-stimulated endocardial cell transformation is dependent on Par6c regulation of RhoA
    Todd A Townsend
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600, USA
    J Biol Chem 283:13834-41. 2008

Scientific Experts

  • Ho Jin Park
  • Joey V Barnett
  • Todd A Townsend
  • Nathan A Mundell
  • Kellye C Kirkbride
  • Harold E Olivey
  • Leigh A Compton
  • Jay S Desgrosellier
  • Jeffrey L Wrana
  • George E Davis
  • Gerard C Blobe
  • Monique W Bruinsma
  • Dru A Potash
  • Anita F Austin
  • Harold L Moses
  • Maureen A McDonnell

Detail Information

Publications6

  1. ncbi Activin receptor-like kinase 2 and Smad6 regulate epithelial-mesenchymal transformation during cardiac valve formation
    Jay S Desgrosellier
    Department of Pharmacology, Vanderbilt University Medical Center, Room 476 RRB, 2220 Pierce Avenue, Nashville, TN 37232 6600, USA
    Dev Biol 280:201-10. 2005
    ..These data suggest that ALK2 activation may stimulate EMT in the AV cushion and that Smad6 may act downstream of ALK2 to negatively regulate EMT...
  2. pmc Transforming growth factor-beta stimulates epithelial-mesenchymal transformation in the proepicardium
    Harold E Olivey
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600, USA
    Dev Dyn 235:50-9. 2006
    ..These data demonstrate that TGFbeta stimulates transformation in the PE and suggest that ALK2 partially mediates this effect...
  3. ncbi Transforming growth factor-beta induces loss of epithelial character and smooth muscle cell differentiation in epicardial cells
    Leigh A Compton
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600, USA
    Dev Dyn 235:82-93. 2006
    ..These data demonstrate that TGFbeta stimulates loss of epithelial character and smooth muscle differentiation in epicardial cells by means of a mechanism that requires ALK5 and p160 rho kinase...
  4. ncbi Transforming growth factor beta regulates the expression of the M2 muscarinic receptor in atrial myocytes via an effect on RhoA and p190RhoGAP
    Ho Jin Park
    Molecular Cardiology Research Institute, Department of Medicine, Tufts New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
    J Biol Chem 281:19995-20002. 2006
    ..Thus TGFbeta regulation of M(2) muscarinic receptor expression is dependent on RhoA, and TGFbeta regulation of p190RhoGAP expression may be a cell type-specific mechanism for TGFbeta signaling through RhoA...
  5. ncbi Bone morphogenetic proteins signal through the transforming growth factor-beta type III receptor
    Kellye C Kirkbride
    Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27708, USA
    J Biol Chem 283:7628-37. 2008
    ..The ability of TbetaRIII to serve as a cell surface receptor and mediate BMP, inhibin, and TGF-beta signaling suggests a broader role for TbetaRIII in orchestrating TGF-beta superfamily signaling...
  6. pmc Transforming growth factor-beta-stimulated endocardial cell transformation is dependent on Par6c regulation of RhoA
    Todd A Townsend
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600, USA
    J Biol Chem 283:13834-41. 2008
    ..Manipulation of Rac1 or Cdc42 activity is without effect. These data demonstrate a functional role for Par6/Smurf1/RhoA in regulating EMT in endocardial cells...