Transforming growth factor-beta superfamily ligands (TGF-β superfamily ligands) (TGF-β superfamily)

The Transforming growth factor-beta (TGF-β) superfamily ligands are a large group of structurally related extracellular signaling proteins, including TGF-β isoforms, activins, and bone morphogenetic proteins (BMPs), that play essential roles in regulating cell growth, differentiation, and tissue homeostasis [1][2]. These ligands signal by assembling a heterotetrameric complex of Type I and Type II serine/threonine kinase receptors, which triggers the phosphorylation of intracellular SMAD proteins to regulate gene expression [3]. Dysregulation of this signaling network is a hallmark of various diseases; for example, an overabundance of certain ligands like activin A and GDF11 can drive pathological vascular remodeling in pulmonary arterial hypertension or inhibit erythroid maturation in chronic anemias [4][5]. Therapeutic strategies targeting these ligands often utilize "ligand traps"—fusion proteins that combine the extracellular binding domain of a receptor with an Fc immunoglobulin fragment—to sequester the ligands before they can activate their cognate receptors [6]. Notable examples include sotatercept for pulmonary arterial hypertension and luspatercept for anemia in myelodysplastic syndromes, both of which aim to restore signaling balance within the TGF-β superfamily [4][5]. However, due to the widespread biological influence of these ligands, therapeutic modulation can lead to off-target effects such as hypertension, erythrocytosis, and vascular telangiectasia [4][6].

Other names

ActivinsTGF-beta familyBone morphogenetic proteinsGrowth and differentiation factorsInhibinsTGF-beta superfamily ligands

Ligand sequestration using decoy receptors (ligand traps) or monoclonal antibodies to prevent binding to type I and type II receptors and subsequent SMAD signaling.