PDGF receptor-α promotes TGF-β signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-β receptors

Am J Physiol Gastrointest Liver Physiol. 2014 Oct 1;307(7):G749-59. doi: 10.1152/ajpgi.00138.2014. Epub 2014 Aug 28.


Platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) signaling are required for hepatic stellate cell (HSC) activation under pathological conditions such as liver metastatic tumor growth. These two signaling pathways are functionally divergent; PDGF signaling promotes proliferation and migration of HSCs, and TGF-β induces transdifferentiation of quiescent HSCs into myofibroblasts. Although PDGF signaling is implicated in TGF-β-mediated epithelial mesenchymal transition of tumor cells, the role of PDGF receptors in TGF-β activation of HSCs has not been investigated. Here we report that PDGF receptor-α (PDGFR-α) is required for TGF-β signaling of cultured human HSCs although HSCs express both PDGF-α and -β receptors. PDGFR-α knockdown inhibits TGF-β-induced phosphorylation and nuclear accumulation of SMAD2 with no influence on AKT or ERK phosphorylation associated with noncanonical TGF-β signaling. PDGFR-α knockdown suppresses TGF-β receptor I (TβRI) but increases TβRII gene transcription. At the protein level, PDGFR-α is recruited to TβRI/TβRII complexes by TGF-β stimulation. PDGFR-α knockdown blocks TGF-β-mediated internalization of TβRII and induces accumulation of TβRII at the plasma membrane, thereby inhibiting TGF-β phosphorylation of SMAD2. Functionally, knockdown of PDGFR-α reduces paracrine effects of HSCs on colorectal cancer cell proliferation and migration in vitro. In mice and patients, colorectal cancer cell invasion of the liver induces upregulation of PDGFR-α of HSCs. In summary, our finding that PDGFR-α knockdown inhibits SMAD-dependent TGF-β signaling by repressing TβRI transcriptionally and blocking endocytosis of TGF-β receptors highlights a convergence of PDGF and TGF-β signaling for HSC activation and PDGFR-α as a therapeutic target for liver metastasis and other settings of HSC activation.

Keywords: colorectal liver metastasis; gene transcription; myofibroblasts; receptor endocytosis and trafficking; tumor microenvironment.

Publication types

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

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Movement
  • Cell Proliferation
  • Colorectal Neoplasms / pathology
  • Gene Expression Regulation
  • HEK293 Cells
  • HT29 Cells
  • Hepatic Stellate Cells / metabolism*
  • Humans
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / secondary
  • Mice, SCID
  • Paracrine Communication
  • Phosphorylation
  • Protein Processing, Post-Translational*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction
  • Smad2 Protein / metabolism
  • Time Factors
  • Transcription, Genetic*
  • Transfection
  • Transforming Growth Factor beta / metabolism*


  • Receptors, Transforming Growth Factor beta
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta
  • Receptor, Platelet-Derived Growth Factor alpha
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II