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.

Comparison of bioactivities, binding properties and intrafollicular levels of bovine follistatins

“…For the most part, the mass ratio of 'total' activins (i.e. activin ACAB) to FST levels was maintained around 1:1 at all of the follicle stages examined, which is consistent with FST-activin complex formation and at least the partial neutralisation of activin signalling in accordance with the 2:1 binding stochiometry , Welt et al 2002, Chang 2008. This apparent lack of saturation of activin's FST binding capacity implies that the bioavailability of other locally expressed TGFb ligands that are capable of binding FST, such as BMP2, BMP4, BMP7 and GDF9, may by modulated by intrafollicular FST.…”

“…BMP2, BMP4, BMP7, BMP15, GDF9 and myostatin/GDF8) by forming a stable inactive complex with the ligand in the extracellular compartment, which thereby blocks binding to signalling receptors (Sugino et al 1993, Phillips & de Kretser 1998, Chang 2008). However, the existence of multiple isoforms of FST in biological fluids such as ovarian FF and serum (Robertson 1992, Sugino et al 1993, Schneyer et al 1997, Glister et al 2006) is indicative of a more complex scenario, the potential significance of which has yet to be fully resolved.…”

“…This reflects the ability of the carboxy-terminal domain of FST-315 to mask the HSP binding region found within the FS1 domain (Keutmann et al 2004, Hedger & de Kretser 2013. Activin binding activity involves the amino terminal domains FS1 and FS2 (Keutmann et al 2004, Chang 2008. Differences in the propensity of FST isoforms to bind to cell surface proteoglycans is indicative of differential roles in controlling activin distribution and bioavailability at local and/or distant target tissue levels.…”

β-Lapachone Regulates the Transforming Growth Factor-β–Smad Signaling Pathway Associated with Collagen Biosynthesis in Human Dermal Fibroblasts

“…Some of these factors enhance TGF-β signals through regulation of ligand-receptor interaction, other factors control storage, maturation, stabilization, transport, and release of TGF-β ligands. 40) Thus, β-lapachone may have affected extracellular factors which regulate availability and activities of TGF-β ligand as indicated by the increased Smad 2/3 phosphorylation without elevation in TGF-β1 secretion. Further studies are required for detailed characterization of the underlying mechanisms.…”

TGF-β Signaling in Bone Remodeling and Osteosarcoma Progression

“…This protein complex is translocated into the nucleus and regulates target gene expression (Figure 2). At the regulatory DNA binding sequence of genes, the R-Smad/co-Smad complex activates transcription through physical interaction and functional cooperation of DNA-binding Smads with sequence-specific transcription factors [19,20]. The minimal Smad-binding element (SBE) contains four base pairs (5′-AGAC-3′), but binding to other G/C-rich sequences has also been reported [21,22].…”