Activin receptor type-2A (ActRIIA) and Activin receptor type-2B (ActRIIB) (ActRIIA / ActRIIB)

Activin receptor type-2A (ActRIIA) and type-2B (ActRIIB) are transmembrane serine/threonine kinases belonging to the transforming growth factor-beta (TGF-beta) receptor superfamily [22, 25]. They play a critical role in mediating signals from various ligands, including activins, myostatin (GDF8), and growth differentiation factor 11 (GDF11), primarily through the activation of the SMAD 2/3 signaling pathway [1, 20, 24]. These receptors are essential regulators of diverse physiological processes such as skeletal muscle growth, erythropoiesis, bone remodeling, and vascular homeostasis [3, 10, 14]. Dysregulation of ActRII signaling is implicated in several pathological conditions; for instance, overactive signaling contributes to muscle wasting in cachexia and sarcopenia, ineffective red blood cell maturation in anemia, and pathological vascular remodeling in pulmonary arterial hypertension (PAH) [2, 3, 5, 27]. Therapeutic strategies targeting these receptors include ligand traps, such as sotatercept and luspatercept, which sequester circulating ligands to prevent receptor activation, and monoclonal antibodies like bimagrumab that directly block the receptors [1, 2, 4, 11]. By modulating these pathways, these drugs aim to restore the balance between pro-proliferative and anti-proliferative signals, offering clinical benefits in treating PAH, hematological disorders, and metabolic diseases [6, 8, 12, 15].

Other names

ACVR2AACVR2BActivin receptor type IIAActivin receptor type IIBACTRIIAACTRIIBActivin receptor type-2AActivin receptor type-2B

Drugs targeting ActRIIA and ActRIIB primarily function as ligand traps or receptor antagonists. Ligand traps, such as sotatercept and luspatercept, consist of the extracellular domain of the receptor fused to an IgG Fc domain; they sequester circulating ligands (e.g., activins, GDF11, myostatin) to prevent them from binding to cell-surface receptors [2, 4, 8]. Receptor antagonists, such as the monoclonal antibody bimagrumab, bind directly to the receptors to competitively inhibit ligand binding and subsequent SMAD 2/3 phosphorylation [1, 11, 27]. These actions serve to rebalance TGF-beta superfamily signaling, particularly by reducing pro-proliferative or anti-differentiation signals [15, 16].