ACVR2B (activin A receptor type 2B; HGNC:174, NCBI Gene ID 93) is a human locus mapped to chromosome band 3p22.2 that encodes transmembrane serine/threonine kinase receptor Activin Receptor Type-2B (512 aa; EC 2.7.11.30). ACVR2B acts in primary high-affinity type II receptor for Myostatin (MSTN), Activin A (INHBA) & GDF11, together with MSTN (Myostatin Gene), ACVR2A (Activin Receptor Type-2A Gene), and FST (Follistatin Gene). Encodes the high-affinity type II serine/threonine kinase receptor for myostatin, activin A, and GDF11 on skeletal muscle fibers.
Primary high-affinity type II receptor for Myostatin (MSTN), Activin A (INHBA) & GDF11
Clinical / Therapeutic Role
Germline mutations cause congenital visceral heterotaxy (HTX4); co-targeted with ACVR2A by bimagrumab & decoy receptor sotatercept
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 11-exon gene at chromosome 3p22.2 encoding a 512-amino-acid single-pass transmembrane receptor featuring an extracellular three-finger toxin-fold cysteine-rich ligand-binding ectodomain, a single transmembrane helix, and a constitutively active cytoplasmic serine/threonine protein kinase domain.
Cellular & Tissue Expression Profile: Abundantly expressed on the sarcolemma of skeletal muscle fibers and satellite cells, cardiac myocytes, white and brown adipocytes, vascular smooth muscle, and embryonic node cells.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Serves as the principal high-affinity primary receptor for Myostatin (MSTN), Activin A (INHBA), and GDF11; ligand binding assembles a heterotetrameric complex of two ACVR2B type II receptors and two ALK4/ALK5/ALK7 type I receptors, enabling ACVR2B to phosphorylate the glycine-serine (GS) box of the type I receptor and initiate SMAD2/3-SMAD4 nuclear translocation.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Heterozygous loss-of-function mutations in ACVR2B disrupt embryonic Nodal signaling across the left-right organizer and cause autosomal dominant visceral heterotaxy type 4 (HTX4) with complex congenital heart defects (dextrocardia, transposition of the great arteries), while dominant-negative or soluble ACVR2B-Fc decoy traps induce rapid ~40–60% increases in adult skeletal muscle mass.
Therapeutic & Clinical Pharmacology: Dual blockade of ACVR2B and ACVR2A with the human monoclonal antibody bimagrumab simultaneously increases lean skeletal muscle mass and drives profound loss of visceral and subcutaneous fat mass in clinical trials for obesity and sarcopenia.