Tyrosine phosphorylation-dependent PI 3 kinase/Akt signal transduction regulates TGFbeta-induced fibronectin expression in mesangial cells

Cell Signal. 2004 Jan;16(1):31-41. doi: 10.1016/s0898-6568(03)00094-9.

Abstract

TGFbeta stimulates expression of fibronectin in various cells, including mesangial cells. The mechanism by which TGFbeta exerts this effect is not fully understood. We investigated the involvement of tyrosine phosphorylation and the phosphatidylinositol (PI) 3 kinase/Akt signalling pathway in this process. TGFbeta increased tyrosine phosphorylation, resulting in activation of PI 3 kinase in mesangial cells. Inhibition of tyrosine phosphorylation blocked TGFbeta-induced fibronectin expression. Inhibition of PI 3 kinase activity also prevented fibronectin expression induced by TGFbeta. Furthermore, expression of constitutively active PI 3 kinase by adenovirus-mediated gene transfer increased fibronectin expression similar to TGFbeta. TGFbeta stimulated Akt serine threonine kinase in a tyrosine kinase- and PI 3 kinase-dependent manner. Inhibition of TGFbeta-induced Akt activity by adenovirus-mediated expression of a dominant-negative mutant of Akt abolished expression of fibronectin. Dominant-negative PI 3 kinase or dominant-negative Akt inhibited TGFbeta-induced fibronectin transcription. In contrast, and similarly to TGFbeta, expression of constitutively active PI 3 kinase or constitutively active Akt increased transcription of fibronectin, confirming a prominent role of these kinases in expression of fibronectin. These data provide the evidence that activation of TGFbeta receptor serine threonine kinase stimulates the PI 3 kinase/Akt pathway in a tyrosine phosphorylation-dependent manner and define a role for the same signal transduction pathway in TGFbeta-induced fibronectin expression.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Fibronectins / genetics
  • Fibronectins / metabolism*
  • Gene Expression Regulation / genetics
  • Genetic Vectors / genetics
  • Glomerular Mesangium / cytology
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / enzymology*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Transfection
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Tyrosine / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Enzyme Inhibitors
  • Fibronectins
  • Proto-Oncogene Proteins
  • Transforming Growth Factor beta
  • Tyrosine
  • Phosphatidylinositol 3-Kinases
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt