Figure 2

TGF- β1-initiated signal pathways that converge to WWOX, TIAF1, p53, Hyal-2, and Smad4. TGF-β1 initiates several signal pathways: i) In the canonical signaling, extracellular TGF-β1 binds TβRII, followed by recruiting TβRI for subsequent activation and complex formation of Smad2, 3 and 4. The Smad2/3/4 complex mediates gene transcription in the nucleus [39]. ii) Alternatively, TGF-β1 utilizes membrane hyaluronidase Hyal-2 as a receptor for signaling the complex formation of Hyal-2 with WWOX and Smad4 to control SMAD-responsive promoter activation [41]. iii) Additionally, TGF-β1 induces the complex formation of TIAF1 with Smad4 to regulate the SMAD-responsive promoter activation [35]. iv) WWOX binds and prevents p53 degradation and both proteins exert apoptosis synergistically [2, 3]. p53-WWOX-TIAF1 is an axis of tumor suppression [34, 36]. TGF-β1 is likely to converge the TGF-β1-initiated signal pathways to the complex formation of WWOX, TIAF1, p53, Hyal-2, and Smad4. TIAF1 undergoes aggregation during aberrant TGF-β signaling [35]. WWOX: blue; Hyal-2: light blue; TIAF1: pink; p53: light green; Smad4: orange. Red circle: phosphorylation.