TGFbeta stimulated re-epithelialisation is regulated by CTGF and Ras/MEK/ERK signalling

Exp Cell Res. 2008 Jan 1;314(1):131-42. doi: 10.1016/j.yexcr.2007.09.001. Epub 2007 Sep 7.


The complex mechanisms by which transforming growth factor beta (TGFbeta) regulate re-epithelialisation following injury of stratified epithelia are not fully understood. TGFbeta signals via binding to distinct receptors activating downstream effectors, including Smads which initiate transcription of target genes. However, studies have shown that TGFbeta can also signal independently of Smads through MAPK pathways, demonstrating the diversity of TGFbeta signalling. Connective tissue growth factor (CTGF) is strongly induced by and acts downstream of TGFbeta causing pathophysiology in tissues by inducing matrix deposition, conversion of fibroblasts into contractile myofibroblasts (e.g. dermis and corneal stroma) and stimulation of epithelial-to-mesenchymal transition (e.g. kidney and lung) all of which are known to cause fibrosis. However, a role for CTGF in epithelial cell function which does not involve direct contribution to fibrosis has not been demonstrated. We show for the first time that synthesis of CTGF in cultures of human corneal epithelial cells is induced by TGFbeta through the Ras/MEK/ERK MAPK signalling pathway and that this is required for re-epithelialisation to occur through cell migration. These data reveal a novel function for CTGF in the regulation of epithelial tissue repair beyond its established role in fibrosis, and further highlight the complexity of TGFbeta regulation of epithelial cell function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Cells, Cultured
  • Connective Tissue Growth Factor
  • Cornea / cytology
  • Cornea / metabolism*
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Humans
  • Immediate-Early Proteins / drug effects
  • Immediate-Early Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Kinase 1 / drug effects
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 3 / drug effects
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Regeneration / drug effects
  • Regeneration / physiology
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology
  • Wound Healing / drug effects
  • Wound Healing / physiology*
  • ras Proteins / drug effects
  • ras Proteins / metabolism


  • CCN2 protein, human
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Transforming Growth Factor beta
  • Connective Tissue Growth Factor
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase 1
  • ras Proteins