ACVR2A (activin A receptor type 2A; HGNC:173, NCBI Gene ID 92) is a human locus mapped to chromosome band 2q22.3-q23.1 that encodes transmembrane serine/threonine kinase receptor Activin Receptor Type-2A (513 aa; EC 2.7.11.30). ACVR2A acts in activin A, Myostatin & BMP signaling in skeletal muscle, erythropoiesis, and pulmonary vasculature, together with ACVR2B (Activin Receptor Type-2B Gene), MSTN (Myostatin Gene), and INHBA (Activin A Subunit Gene). Encodes activin receptor type-2A, whose ligand-trap ectodomain forms the basis of FDA-approved biologics sotatercept and luspatercept.
Activin A, Myostatin & BMP signaling in skeletal muscle, erythropoiesis, and pulmonary vasculature
Clinical / Therapeutic Role
Ectodomain powers FDA-approved sotatercept (Winrevair) for PAH & luspatercept (Reblozyl) for MDS/beta-thalassemia; co-blocked by bimagrumab
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 11-exon gene on chromosome 2q22.3-q23.1 structurally paralogous to ACVR2B, containing an 8-adenine mononucleotide repeat tract in exon 10 frequently mutated in microsatellite-unstable (MSI-H) colorectal and endometrial carcinomas.
Cellular & Tissue Expression Profile: Widely expressed across skeletal muscle fibers, bone marrow erythroid precursors, pulmonary arterial endothelial and smooth muscle cells, anterior pituitary gonadotropes, and placental trophoblasts.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Partners with ACVR2B to transduce catabolic Activin A (INHBA) and Myostatin (MSTN) signals in skeletal muscle and adipose tissue, while in pulmonary arteries excess Activin A-ACVR2A-SMAD2/3 signaling drives proliferative vascular remodeling at the expense of anti-proliferative BMPR2-SMAD1/5/8 signaling.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: In skeletal muscle, genetic ablation of ACVR2B alone triggers compensatory signaling through ACVR2A, whereas combined blockade of both ACVR2A and ACVR2B unleashes maximal myofiber hypertrophy; somatic frameshift mutations in the exon 10 polyadenine tract occur in >80% of mismatch-repair-deficient colorectal cancers.
Therapeutic & Clinical Pharmacology: Recombinant soluble ACVR2A-IgG1 Fc fusion proteins (ligand traps) are major FDA-approved medicines: sotatercept (Winrevair, native ACVR2A-Fc) sequesters excess Activin A and GDF11 to reverse pulmonary arterial hypertension (PAH), luspatercept (Reblozyl, modified ACVR2B/2A trap) restores late-stage erythropoiesis in beta-thalassemia and MDS, and bimagrumab blocks both ACVR2A and ACVR2B to build muscle and reduce adiposity.