Activin receptor type-2B ligands (ActRIIB ligands)

Activin receptor type-2B (ActRIIB) ligands comprise a subset of the Transforming Growth Factor-beta (TGF-beta) superfamily, including Activin A, Activin B, Myostatin (GDF8), and Growth Differentiation Factor 11 (GDF11) (Attisano & Wrana, 2002). These proteins function as extracellular signaling molecules that bind to the ActRIIB receptor, subsequently recruiting type I receptors to activate the SMAD2/3 intracellular signaling pathway (Sako et al., 2010). This pathway is a critical regulator of diverse physiological processes such as skeletal muscle growth, bone homeostasis, and erythroid maturation. Dysregulation of these ligands is implicated in several pathologies; for instance, overactivation of SMAD2/3 signaling contributes to the vascular remodeling seen in pulmonary arterial hypertension (PAH) and the impaired red blood cell production in myelodysplastic syndromes (Humbert et al., 2021). Pharmacological intervention typically utilizes "ligand traps," such as Luspatercept and Sotatercept, which are fusion proteins designed to bind and sequester these ligands before they can interact with their cell-surface receptors (Hae-Pyo et al., 2018). By neutralizing these ligands, these drugs help restore the balance between pro-proliferative and anti-proliferative signals, offering therapeutic benefits in hematologic and cardiovascular diseases.

Other names

SMAD2/3-activating ligandsTGF-beta superfamily ligandsActRIIB-binding proteinsMyostatinActivin AActivin BGrowth differentiation factor 11 (GDF11)Growth differentiation factor 8 (GDF8)

Ligand sequestration via decoy receptors (ligand traps) to prevent activation of the ActRIIB/SMAD2/3 signaling pathway.