Pre- and postreceptor regulation of TGF-β₁ signaling. Latent TGF-β₁ can be activated by proteases (such asMMPs, plasmin) and by binding to TSP-1 or the integrin α_vβ₆, expressed on epithelial cells. Signaling through the TGF-β₁ receptor leads to phosphorylation of SMADs 2 and 3 and their translocation to the nucleus to mediate transcription of target genes. IFN-γ and IL-7 induce counter-regulatory SMAD 7. Cellular responses to TGF-β₁ signaling are modulated by concurrent signaling through growth factor (GF) and adhesion receptors (β1 integrins). Integrated inputs from the pathways shown in the figure link deposition and turnover of ECM elements and GFs to expansion of mesenchymal elements such as fibroblasts and smooth muscle cells and the matrix proteins they secrete. Chemokines acting through G protein–coupled receptors also modulate TFβ1 responses (not shown).