Agonists and Antagonists of TGF-β Family Ligands

Abstract

The discovery of the transforming growth factor β (TGF-β) family ligands and the realization that their bioactivities need to be tightly controlled temporally and spatially led to intensive research that has identified a multitude of extracellular modulators of TGF-β family ligands, uncovered their functions in developmental and pathophysiological processes, defined the mechanisms of their activities, and explored potential modulator-based therapeutic applications in treating human diseases. These studies revealed a diverse repertoire of extracellular and membrane-associated molecules that are capable of modulating TGF-β family signals via control of ligand availability, processing, ligand-receptor interaction, and receptor activation. These molecules include not only soluble ligand-binding proteins that were conventionally considered as agonists and antagonists of TGF-β family of growth factors, but also extracellular matrix (ECM) proteins and proteoglycans that can serve as "sink" and control storage and release of both the TGF-β family ligands and their regulators. This extensive network of soluble and ECM modulators helps to ensure dynamic and cell-specific control of TGF-β family signals. This article reviews our knowledge of extracellular modulation of TGF-β growth factors by diverse proteins and their molecular mechanisms to regulate TGF-β family signaling.

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.

Figure 2.

Regulation of bone morphogenetic protein (BMP) signaling by chordin-dependent extracellular regulatory network. Inhibition of BMP signaling by chordin can be enhanced by formation of a ternary complex with Twsg1/Tsg. At the same time, this complex promotes transport of the BMP ligands to a distant site to allow formation of a sharp high BMP activity center. Inactivation of chordin function is achieved by Tolloid/BMP-1-dependent proteolytic processing to release the associated BMP ligands. Cleavage of chordin is prevented by Sizzled, Crescent, or Sfrp5, which titrate Tolloid/BMP-1 away from chordin. The scaffolding protein ONT1 binds both Tolloid/BMP-1 and chordin to facilitate chordin processing. The proteins containing chordin-like cysteine-rich (CR) domains, including CHRDLs and CV-2, can form a similar ternary complex with BMP and Twsg1 to have stronger BMP-inhibitory activity.

Figure 3.

Regulation of transforming growth factor β (TGF-β) family signals by proteoglycans and extracellular matrix proteins. Small leucine-rich proteoglycans, such as decorin, biglycan, and Tsukushi, interact with both TGF-β family ligands and extracellular matrix (ECM) proteins. Depending on the composition of ECM proteins, they may tether the ligands in the ECM to prevent signaling, or release the ligands to create a local pool of cytokines to enhance signaling. Biglycan and Tsukushi also form a ternary complex with chordin and bone morphogenetic protein (BMP) to block BMP signaling. Cell-surface heparan sulfate proteoglycans (HSPGs), including glypicans and syndecans, interact with both TGF-β family proteins and their secreted modulators. They can serve as ligand coreceptors to enhance TGF-β family signaling, but they can also trap and facilitate internalization of the ligands and their soluble regulators to modulate signal duration and range. They, therefore, have cell-context-dependent positive or negative roles in regulation of TGF-β signals. The Drosophila protein Notum facilitates release of glypicans from the cell surface and can convert glypicans from ligand-presenting factors to ligand-binding antagonists. Several ECM proteins bind TGF-β family ligands directly and influence storage, activation, and diffusion of these proteins to control signaling strength and range. Secreted TGF-β family regulators can also associate with ECM proteins to affect ligand availability. LTBPs (latent TGF-β-binding proteins) interact with ECM proteins to control TGF-β activation from the small latent complex (SLC).