Figure 3. Schematic model for the proposed role of CD109 in regulating TGF-ß signaling in human keratinocytes. In the canonical TGF-ß signaling pathway, TGF-ß1 ligand (green) binds the TGF-ß type II receptor (RII; pink), a constitutively active kinase, which recruits the TGF-ß type I receptor (RI; purple) to form a hetero-tetrameric receptor complex. RII then phosphorylates RI and the activated RI propagates the signal downstream. CD109 (red) is a GPI-anchored protein that binds TGF-ß1 and interacts with RI and RII to inhibit TGF-ß1 induced signaling and responses in human keratinocytes. TGF-ß1 induced responses inhibited by CD109 include phosphorylation of Smad2 and Smad3, transcriptional activity, PAI-1 and fibronectin production, cellular growth inhibition, and in vitro wound closure. The inhibition of TGF-ß signaling and responses by CD109 can occur independently of ligand sequestration and may involve direct modulation of receptor activity.