PDGF-D Signaling in Portal Myofibroblasts and Hepatic Stellate Cells Proves Identical to PDGF-B via Both PDGF Receptor Type α and β

Cell Signal. 2015 Jul;27(7):1305-14. doi: 10.1016/j.cellsig.2015.03.012. Epub 2015 Mar 27.

Abstract

Platelet-derived growth factor-D (PDGF-D) is one member of PDGF growth factors and known to signal by binding to and activating its cognate receptor type β (PDGFR-β). Beside PDGF-B, PDGF-D is a potent growth factor for stellate cell growth and proliferation and therefore potentiates the extracellular matrix deposition in liver fibrogenesis. We aimed to explore the signaling and molecular mechanisms of PDGF-D in liver fibrogenesis using the primary liver portal myofibroblasts and hepatic stellate cells. Unexpectedly we found PDGF-D to bind to PDGFR-α, thus inducing receptor endocytosis and decreasing the amount of PDGFR-α significantly. PDGF-D activates PDGFR-α specific tyrosine 754 and -1018 phosphorylation and CrkII, the adaptor protein that is specifically recruited by activated PDGFR-α. As a novel finding we could also demonstrate that recombinant PDGFR-α-Fc chimera homodimer is able to bind PDGF-D and thus prevent PDGF-D signaling. PDGF-D does induce individual PDGFR-β specific tyrosine phosphorylation similar to the PDGF-B. Additionally, PDGF-D enhances extracellular matrix accumulation comparable to the PDGF-B isoform.

Conclusion: PDGF-D signaling in pMF and HSC is identical to that of PDGF-B by binding to both PDGFR-α and -β.

Keywords: Hepatic stellate cells; MMP; PDGF-D; Portal myofibroblasts; TIMP-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Becaplermin
  • Cells, Cultured
  • Down-Regulation / drug effects
  • Endocytosis / drug effects
  • Hepatic Stellate Cells / cytology
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Lymphokines / pharmacology*
  • Male
  • Myofibroblasts / cytology
  • Myofibroblasts / drug effects
  • Myofibroblasts / metabolism
  • Platelet-Derived Growth Factor / pharmacology*
  • Protein Binding
  • Proto-Oncogene Proteins c-sis / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Signal Transduction / drug effects*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Up-Regulation / drug effects

Substances

  • Lymphokines
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Recombinant Proteins
  • Scdgfb protein, rat
  • Tissue Inhibitor of Metalloproteinase-1
  • tissue inhibitor of metalloproteinase-1 protein, rat
  • Becaplermin
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptor, Platelet-Derived Growth Factor beta