Figure 1.

Regulation of transforming growth factor β (TGF-β) family signals by extracellular agonists and antagonists. Most extracellular agonists and antagonists act to facilitate or prevent binding of mature TGF-β family ligands to their receptor complexes, respectively. The secreted proteins CHRDL1, BMPER/CV-2, KCP/CRIM2, and connective tissue growth factor (CTGF) act both as agonists and antagonists depending on the particular ligands they regulate and the presence or absence of other factors in cell-type-specific microenvironments they encounter. Certain soluble modulators, including follistatin (FST), FSTL1, BMPER/CV-2, Lefty, and bone morphogenetic protein 3 (BMP-3), can also bind to type I and/or type II receptors to form a nonsignaling complex. Regulation of ligand processing, secretion, activation, and/or stability by CRIM1, SOST, GREM1, and the propeptides in the ligand-producing cells can control ligand availability. Extracellular regulation of ligand processing by Emilin1 and ligand release by Tolloid/BMP-1 family proteinases also control ligand bioactivity. Furthermore, TGF-β family ligands can form heterodimers or interact with each other, which leads to either blocking or enhancing TGF-β family signaling depending on the particular ligands involved. TGN, trans-Golgi network.