Soluble CD109 binds TGF-β and antagonizes TGF-β signalling and responses

Biochem J. 2016 Mar 1;473(5):537-47. doi: 10.1042/BJ20141488. Epub 2015 Nov 30.


Transforming growth factor-β (TGF-β) is a multifunctional cytokine implicated in many diseases, including tissue fibrosis and cancer. TGF-β mediates diverse biological responses by signalling through type I and II TGF-β receptors (TβRI and TβRII). We have previously identified CD109, a glycosylphosphatidylinositol (GPI)-anchored protein, as a novel TGF-β co-receptor that negatively regulates TGF-β signalling and responses and demonstrated that membrane-anchored CD109 promotes TGF-β receptor degradation via a SMAD7/Smurf2-mediated mechanism. To determine whether CD109 released from the cell surface (soluble CD109 or sCD109) also acts as a TGF-β antagonist, we determined the efficacy of recombinant sCD109 to interact with TGF-β and inhibit TGF-β signalling and responses. Our results demonstrate that sCD109 binds TGF-β with high affinity as determined by surface plasmon resonance (SPR) and cell-based radioligand binding and affinity labelling competition assays. SPR detected slow dissociation kinetics between sCD109 and TGF-β at low concentrations, indicating a stable and effective interaction. In addition, sCD109 antagonizes TGF-β-induced Smad2/3 phosphorylation, transcription and cell migration. Together, our results suggest that sCD109 can bind TGF-β, inhibit TGF-β binding to its receptors and decrease TGF-β signalling and TGF-β-induced cellular responses.

Keywords: CD109; TGF-β isoforms; binding; glycoprotein; inhibitor; trap.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism*
  • Cell Line
  • Cell Movement
  • Fibronectins / metabolism
  • GPI-Linked Proteins / metabolism
  • Humans
  • Keratinocytes / metabolism
  • Neoplasm Proteins / metabolism*
  • Phosphorylation
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Radioligand Assay
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transcription, Genetic
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / metabolism*


  • Antigens, CD
  • CD109 protein, human
  • Fibronectins
  • GPI-Linked Proteins
  • Neoplasm Proteins
  • Plasminogen Activator Inhibitor 1
  • Protein Isoforms
  • Recombinant Proteins
  • SERPINE1 protein, human
  • SMAD3 protein, human
  • Smad3 Protein
  • Transforming Growth Factor beta