ACVR2B

Detailed Information

The ACVR2B gene, located on human chromosome 3p22.2, encodes a highly conserved protein known as activin receptor type IIB, a transmembrane serine/threonine kinase receptor and a member of the transforming growth factor-β (TGF-β) superfamily. It has orthologs in at least 216 species ranging from amphibians to primates, underscoring its evolutionary importance.

Structurally, ACVR2B includes three characteristic domains: an extracellular cysteine-rich ligand-binding domain, a single-pass transmembrane segment, and a cytoplasmic kinase domain with constitutive activity. The mature human ACVR2B protein comprises 512 amino acids, with an approximate molecular weight of 57.7 kDa and a theoretical isoelectric point of 5.46. Protein interaction network analyses reveal that ACVR2B forms complexes with multiple type I receptors (such as ACVR1, ACVR1B, and ACVR1C) and ligands (e.g., activins, inhibins, and GDF11), collectively regulating downstream signaling pathways.

Figure 1. Activin receptors transmit signals via canonical SMAD pathways and non-SMAD signaling cascades to regulate gene expression. (Du R, et al., 2024)

Gene expression profiling indicates that ACVR2B is broadly but differentially expressed across tissues. It is relatively highly expressed in the testis (RPKM 1.5) and brain (RPKM 1.3), and is present in over 25 other tissues, including the heart, liver, and skeletal muscle. This widespread distribution suggests its involvement in various physiological processes. Notably, compared to its paralog ACVR2A, ACVR2B shows a 3- to 4-fold higher affinity for ligands like activin A, giving it an advantage in ligand capture and signal initiation. This difference stems from structural variations in key amino acid residues in the extracellular domain that optimize the ligand-binding interface.

Multiple alternatively spliced variants of ACVR2B generate isoforms with distinct functionalities. Post-translational modifications, such as glycosylation and phosphorylation, also modulate its stability and signaling efficacy. Its extracellular domain contains several N-linked glycosylation sites. In contrast, the intracellular domain features serine/threonine residues subject to phosphorylation by itself or other kinases, forming a complex regulatory network that defines its central role in cellular signaling.

Biological Functions and Signaling Mechanisms

As a type II receptor, ACVR2B acts as the initial ligand sensor in TGF-β superfamily signaling. It specifically binds to ligands including activin A (INHBA), activin B (INHBB), and inhibin A (INHA-INHBA). Upon ligand binding, ACVR2B forms a stable heterotetrameric complex with type I receptors such as ACVR1B. In this complex, ACVR2B serves a dual role: it captures ligands via high-affinity binding sites and, through its constitutive kinase activity, phosphorylates and activates the GS domain of the type I receptor—a critical initiation step for signal amplification.

Although it is most commonly associated with classical activins, ACVR2B can also interact with other TGF-β superfamily members, including bone morphogenetic proteins (BMPs) and growth differentiation factors (GDFs). For instance, GDF11 (also known as BMP11) binds to ACVR2B with high affinity and participates in embryonic patterning. This broad ligand spectrum makes ACVR2B a key signaling hub across TGF-β subfamilies.

ACVR2B primarily transduces signals via the canonical SMAD pathway. Following activation of the type I receptor, receptor-regulated SMADs (R-SMADs), particularly SMAD2 and SMAD3, are phosphorylated and form a trimeric complex with the co-SMAD SMAD4. This complex translocates into the nucleus to regulate target gene transcription by binding TGF-β response elements (TREs) in gene promoters, thereby controlling cell cycle, differentiation, and apoptosis.

ACVR2B also activates non-canonical pathways such as ERK/MAPK, PI3K/AKT, and JNK/p38 under certain conditions. These alternative cascades typically follow SMAD activation and play a pivotal role in fine-tuning cell responses. For example, ACVR2B inhibits myogenic differentiation via ERK signaling in muscle cells and promotes neuronal survival through PI3K/AKT signaling in neurons. Under physiological conditions, ACVR2B is involved in:

• Reproductive regulation: modulating FSH secretion and follicular development
• Musculoskeletal balance: controlling muscle fiber formation and bone remodeling
• Metabolic homeostasis: influencing adipose browning and insulin sensitivity
• Immune regulation: mediating tolerance and resolving inflammation

Dysregulation of ACVR2B signaling is implicated in numerous diseases. In muscle-wasting conditions such as cachexia, hyperactivation of activin/ACVR2B signaling upregulates E3 ubiquitin ligases (e.g., MuRF1, Atrogin-1), accelerating muscle protein degradation. Conversely, in metabolic disorders, this pathway contributes to insulin resistance by modulating adipose plasticity and hepatic gluconeogenesis. Recent studies have shown that ACVR2B has dual roles in cancer progression—initially suppressing tumor growth via cell cycle arrest, but later promoting metastasis through epithelial-to-mesenchymal transition (EMT).

Clinical Relevance and Translational Advances

Based on its molecular properties, researchers have developed soluble ACVR2B-Fc fusion proteins (e.g., Sotatercept and Luspatercept). These recombinant proteins combine the extracellular ligand-binding domain of ACVR2B with an immunoglobulin Fc fragment, acting as decoy receptors to sequester circulating ligands like activins, GDF8 (myostatin), and GDF11. In preclinical models, sACVR2B-Fc significantly increased bone density and muscle mass while reducing fat accumulation. Notably, in a cardiometabolic disease model induced by Western diet and L-NAME, sACVR2B-Fc improved metabolic dysfunction-associated steatotic liver disease (MASLD), inhibited hepatic fibrogenesis, lowered total cholesterol, prevented browning-to-whitening of brown adipose tissue, and enhanced diastolic cardiac function.

Polymorphisms in the ACVR2B gene have been linked to growth traits in livestock. A 2023 study in Boer goats identified several SNPs in the 5′ regulatory region, including g.-1725G>A, which was significantly associated with birth weight and body length. Animals with the AG genotype had higher birth weight and length compared to GG genotype. This site showed moderate polymorphism (PIC = 0.29) and complete linkage with nearby SNPs, indicating that ACVR2B variants could serve as genetic markers for early growth traits.

In clinical diagnostics, biomarker assays based on ACVR2B signaling are under development. A 2018 study established a high-sensitivity electrophoretic method capable of detecting activin receptor II-Fc fusion proteins at ng/mL levels in human blood, providing pharmacokinetic support for sACVR2B-Fc-based drugs. Updated serum detection platforms have improved quantification of therapeutic agents such as Sotatercept and Luspatercept, supporting individualized dosing.

Challenges and Future Directions

Despite promising therapeutic potential, ACVR2B-targeted therapies face several challenges. Drug specificity is a key issue—current sACVR2B-Fc agents block multiple ligands (activins, GDF8, GDF11), which may lead to unintended effects. For example, in bovine inhibin immunization studies, high antigen doses improved fertility (71.1% conception in the 1.5 mg group) but also caused a 15.6% twin pregnancy rate, indicating reproductive side effects. Future strategies should include development of ligand-specific monoclonal antibodies or allosteric modulators for more precise intervention.

Tissue-targeted delivery is another major challenge. To avoid systemic suppression effects (e.g., immune dysfunction), researchers are exploring liver- and muscle-targeted nanoparticle systems. Combination therapies involving ACVR2B inhibitors and agents like GLP-1 receptor agonists or immune checkpoint inhibitors are also being investigated for enhanced efficacy.

With the advancement of CRISPR gene editing, in situ modulation of ACVR2B expression is becoming feasible. In animal models, muscle-specific overexpression of a dominant-negative ACVR2B mutant effectively prevented denervation-induced atrophy without systemic side effects. This strategy offers a promising path for treating degenerative muscle diseases.