ACVR1

Official Full Name

activin A receptor type 1

Organism

Homo sapiens

GeneID

Background

Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I ( I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. This gene encodes activin A type I receptor which signals a particular transcriptional response in concert with activin type II receptors. Mutations in this gene are associated with fibrodysplasia ossificans progressive. [provided by RefSeq, Jul 2008]

Synonyms

FOP; ALK2; SKR1; TSRI; ACTRI; ACVR1A; ACVRLK2;

Bio Chemical Class

Kinase

Protein Sequence

MVDGVMILPVLIMIALPSPSMEDEKPKVNPKLYMCVCEGLSCGNEDHCEGQQCFSSLSINDGFHVYQKGCFQVYEQGKMTCKTPPSPGQAVECCQGDWCNRNITAQLPTKGKSFPGTQNFHLEVGLIILSVVFAVCLLACLLGVALRKFKRRNQERLNPRDVEYGTIEGLITTNVGDSTLADLLDHSCTSGSGSGLPFLVQRTVARQITLLECVGKGRYGEVWRGSWQGENVAVKIFSSRDEKSWFRETELYNTVMLRHENILGFIASDMTSRHSSTQLWLITHYHEMGSLYDYLQLTTLDTVSCLRIVLSIASGLAHLHIEIFGTQGKPAIAHRDLKSKNILVKKNGQCCIADLGLAVMHSQSTNQLDVGNNPRVGTKRYMAPEVLDETIQVDCFDSYKRVDIWAFGLVLWEVARRMVSNGIVEDYKPPFYDVVPNDPSFEDMRKVVCVDQQRPNIPNRWFSDPTLTSLAKLMKECWYQNPSARLTALRIKKTLTKIDNSLDKLKTDC

Open

Disease

Anemia, Multiple myeloma, Myelodysplastic syndrome, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

Signaling networks that govern homeostasis, differentiation, and development use ACVR1 (ALK2). A TGF-β superfamily member is encoded by ACVR1 on chromosome 2q23-q24. This family includes dimeric growth and differentiation agents bone morphogenetic proteins and activins.

ACVR1 has intracellular, transmembrane, and extracellular ligand-binding domains. It is predominantly type I in heterotetrameric complexes with type II receptors ACVR2A and ACVR2B. ACVR1's kinase domain phosphorylates SMAD1, SMAD5, and SMAD8 proteins following ligand binding, which provide gene expression signals. ACVR1 is required for a variety of physiological and developmental processes because of its complicated signaling system.

Biological Significance of ACVR1

ACVR1's biological roles go beyond signal transduction. It is necessary for ossification, neurogenesis, and reproductive system development. ACVR1 is important for bone and cartilage growth via regulating BMP signaling pathways. Cell growth, differentiation, and death are affected by receptor activation.

In addition, ACVR1 regulates the equilibrium between BMP and TGF-β/activin signaling pathways. Although it mostly promotes BMP signaling, it may also inhibit TGF-β/activin pathways by disrupting activin binding to type II receptors. This dual function emphasizes ACVR1's role in cellular homeostasis and environmental response.

Figure 1 shows the major ACVR1 signal transduction system, including type I and type II receptor contacts, ligand binding, and SMAD protein-activated conventional and non-canonical signaling pathways. Figure 1. Schematic representation of main ACVR1 signal transduction. (Valer JA, et al., 2019)

ACVR1 in Human Diseases

Fibrodysplasia Ossificans Progressiva (FOP)

ACVR1's importance in human health was originally recognized in the context of FOP, an uncommon and devastating genetic condition known as "stone man syndrome." One in two million people have this illness, which turns muscles and tendons into bone. Trauma or damage causes heterotopic ossification. FOP is caused by ACVR1 gene mutations that disrupt BMP signaling pathways. Over 95% of FOP patients have the c.617G>A (Arg206His) gain-of-function mutation. This mutation hyperactivates the ACVR1 receptor, causing soft tissue injury and inflammatory responses to be dysregulated.

Neurological Implications

ACVR1 also affects the central nervous system and FOP, according to current study. FOP patients' neurological symptoms show ACVR1 regulates neurodevelopment. In diffuse intrinsic pontine glioma, a particularly aggressive brain tumor in children, 25% of individuals have ACVR1 somatic mutations. This shows the importance of BMP signaling in bone development, neurogenesis, and neuroplasticity.

Cardiovascular Health

ACVR1 is important for cardiovascular development as well as skeletal and neurological development. Deletions of ACVR1 alter cardiac differentiation gene expression and heart and valve development. Disrupted valve formation may lead to cardiovascular disease and congenital heart abnormalities. These results highlight ACVR1's role in cardiovascular health.

Hematopoiesis, Anemia

ACVR1 regulates Sonic Hedgehog (Shh), which primitive hematopoietic cells need to grow. Maintaining hematopoietic stem cell activity requires BMP-Shh interaction. Recent studies have linked Shh axis dysregulation to bone marrow fibrosis in myelofibrosis (MF). ACVR1 also affects hepcidin and hemoglobin levels in iron homeostasis. In MF, ACVR1's activity affects erythropoiesis and anemia.

Genetic Interactions

The link between ACVR1 and other genes is also significant. Hepcidin synthesis increases due to pathogenic mutations in the matriptase-2 gene TMPRSS6, causing iron-refractory iron-deficient anemia. This shows the complex gene connections that regulate hepcidin and affect erythropoiesis iron availability.

References:

Valer JA, Sánchez-de-Diego C, Pimenta-Lopes C, et al. ACVR1 Function in Health and Disease. Cells. 2019;8(11):1366.
Duminuco A, Chifotides HT, et al. ACVR1: A Novel Therapeutic Target to Treat Anemia in Myelofibrosis. Cancers (Basel). 2023;16(1):154.
Yu X, Ton AN, Niu Z, et al. ACVR1-activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans. Pain. 2023;164(1):43-58.

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