Activin receptor type 2A and 2B (ActR2A/B)

Activin receptor type 2A and 2B (ActR2A/B) are transmembrane serine/threonine kinase receptors belonging to the transforming growth factor-beta (TGF-beta) superfamily [1, 3]. They serve as the primary high-affinity receptors for various ligands, including activins, myostatin (GDF8), and GDF11, which are essential for maintaining tissue homeostasis [2, 9]. Upon ligand binding, these type II receptors recruit and phosphorylate type I receptors (such as ALK4 or ALK5), initiating an intracellular signaling cascade through SMAD2 and SMAD3 proteins to regulate gene expression [4, 11]. This pathway is a critical negative regulator of skeletal muscle mass and bone density, and it also plays significant roles in the regulation of erythropoiesis and vascular remodeling [5, 10]. In clinical contexts, dysregulated ActR2A/B signaling is implicated in several conditions, including muscle wasting (cachexia), anemia, obesity, and pulmonary arterial hypertension (PAH) [10, 12]. Therapeutic targeting of these receptors has led to the development of ligand traps like Sotatercept and Luspatercept, which sequester circulating ligands to prevent receptor activation, as well as monoclonal antibodies like Bimagrumab that directly block the receptors [3, 15]. While these therapies have shown significant efficacy in treating PAH and anemia in myelodysplastic syndromes, the broad expression of ActR2A/B and the promiscuity of their ligands necessitate careful monitoring for side effects such as erythrocytosis and vascular complications like telangiectasia [9, 12].

Other names

ActRIIA/BActRIIACVR2A/BActivin A receptor type IIAActivin A receptor type IIBActivin receptor type IIAActivin receptor type IIB

Ligand sequestration (ligand trap) and competitive receptor antagonism to inhibit SMAD2/3 signaling.