Activin receptor type-2 (ActRII)

Activin receptor type-2 (ActRII) is a class of transmembrane serine/threonine-protein kinases within the transforming growth factor-beta (TGF-beta) receptor family, primarily existing as two isoforms, ACVR2A and ACVR2B [1, 5]. These receptors play a pivotal role in cellular signaling by binding a variety of ligands, including activins, myostatin (GDF8), and growth differentiation factor 11 (GDF11) [1, 17]. Upon ligand binding, ActRII forms a heteromeric complex with type I receptors, leading to the phosphorylation and activation of Smad2 and Smad3 transcription factors, which regulate genes involved in muscle growth, hematopoiesis, and vascular homeostasis [1, 23]. Dysregulation of ActRII signaling is a key driver in several pathological conditions, such as muscle wasting (sarcopenia and cachexia), chronic anemia (including beta-thalassemia), and pulmonary arterial hypertension (PAH) [1, 8, 16]. In the therapeutic landscape, ActRII is targeted through two main strategies: soluble ligand traps and monoclonal antibodies [1, 18]. Ligand traps, such as sotatercept and luspatercept, consist of the extracellular domain of the receptor fused to an Fc fragment, effectively sequestering circulating ligands to prevent receptor activation [1, 14]. Alternatively, monoclonal antibodies like bimagrumab directly bind to the receptor to block ligand interaction [7, 19]. These therapies have shown significant clinical utility, with sotatercept approved for PAH and luspatercept for anemia, while others are being investigated for their potential to increase lean muscle mass and treat metabolic disorders [1, 7].

Other names

ActRIIACVR2Activin receptor type IIActivin A receptor type IIActR2Activin receptor type-2AActivin receptor type-2B

Ligand sequestration via soluble decoy receptors (ligand traps) or direct receptor antagonism using monoclonal antibodies to inhibit Smad2/3 signaling and rebalance TGF-beta superfamily pathways.