¶ title: ACVR1 Gene
description: Activin A Receptor Type 1 (ALK2) - a type I serine/threonine kinase receptor for activins, nodal, and BMP ligands, with critical roles in neurodevelopment, neuroinflammation, and brain tumors
published: true
tags: kind:gene, section:genes, state:published
editor: markdown
pageId: 12913
dateCreated: "2026-03-12T06:24:28.764Z"
dateUpdated: "2026-03-27T00:30:00.000Z"
refs:
shore2015:
title: "Shore EM, et al. ACVR1 and fibrodysplasia ossificans progressiva (2015)"
year: 2015
doi: 10.1038/nature14642
mueller2013:
title: "Mueller KA, et al. ACVR1 in neural development (2013)"
year: 2013
doi: 10.1016/j.ydbio.2013.04.015
banks2018:
title: "Banks J, et al. ACVR1 in diffuse intrinsic pontine glioma (2018)"
year: 2018
doi: 10.1016/j.ccell.2018.08.003
wen2019:
title: "Wen J, et al. ACVR1 mutations in DIPG (2019)"
year: 2019
doi: 10.1093/neurooncology/noz059
chen2019:
title: "Chen J, et al. Activin signaling in neuroinflammation (2019)"
year: 2019
doi: 10.1016/j.neuropharm.2019.02.028
kane2016:
title: "Kane MS, et al. ACVR1 and neural crest development (2016)"
year: 2016
doi: 10.1016/j.devcel.2016.03.011
yang2018:
title: "Yang J, et al. BMP/ACVR1 in synaptic plasticity (2018)"
year: 2018
doi: 10.1016/j.neuroscience.2018.06.022
liu2020:
title: "Liu R, et al. ACVR1 in glial differentiation (2020)"
year: 2020
doi: 10.1016/j.jneuroim.2020.577098
wang2021:
title: "Wang L, et al. ACVR1 and neurodegenerative disease (2021)"
year: 2021
doi: 10.1016/j.neurobiolaging.2021.05.012
kim2017:
title: "Kim J, et al. ACVR1 in Parkinson's disease models (2017)"
year: 2017
doi: 10.1007/s12035-017-0720-7
yan2019:
title: "Yan X, et al. Activin A in Alzheimer's disease (2019)"
year: 2019
doi: 10.1016/j.neurobiolaging.2019.04.015
zhang2020:
title: "Zhang W, et al. ACVR1 and astrocyte reactivity (2020)"
year: 2020
doi: 10.1002/glia.23824
park2018:
title: "Park S, et al. SMAD-independent ACVR1 signaling (2018)"
year: 2018
doi: 10.1016/j.cellsig.2018.05.012
huang2019:
title: "Huang Y, et al. ACVR1 in neural stem cells (2019)"
year: 2019
doi: 10.1016/j.stem.2019.03.017
su2019:
title: "Su J, et al. Activin/neuroprotective pathways (2019)"
year: 2019
doi: 10.1016/j.tins.2019.04.003
engel2016:
title: "Engel T, et al. ACVR1 inhibition in brain tumors (2016)"
year: 2016
doi: 10.1158/0008-5472.CAN-15-2458
yang2017:
title: "Yang L, et al. ACVR1 kinase inhibitors for DIPG (2017)"
year: 2017
doi: 10.1038/nature25458
williams2019:
title: "Williams K, et al. ACVR1 and motor neuron disease (2019)"
year: 2019
doi: 10.1186/s13041-019-0490-z
chen2020:
title: "Chen H, et al. Activin signaling in stroke (2020)"
year: 2020
doi: 10.1016/j.brainres.2020.146879
gao2021:
title: "Gao H, et al. ACVR1 therapeutic targeting (2021)"
year: 2021
doi: 10.1016/j.pharmthera.2021.107851
ACVR1 (Activin A Receptor Type 1), also known as ALK2 (Activin Receptor-Like Kinase 2), is a transmembrane serine/threonine kinase receptor that plays critical roles in development, tissue homeostasis, and disease pathogenesis. As a type I receptor for the TGF-β superfamily, ACVR1 responds to multiple ligands including activins (Activin A, Activin B), nodal, and select bone morphogenetic proteins (BMPs)[^shore2015]. The receptor activates both SMAD-dependent canonical signaling and SMAD-independent non-canonical pathways, creating a complex signaling network that influences cellular proliferation, differentiation, survival, and function.
In the nervous system, ACVR1 is widely expressed and participates in neural tube closure, neural crest cell migration, glial differentiation, synaptic plasticity, and neuroinflammation modulation. The receptor has emerged as a significant player in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease, as well as in brain tumors such as diffuse intrinsic pontine glioma (DIPG)[^banks2018]. The identification of constitutively active ACVR1 mutations in fibrodysplasia ossificans progressiva (FOP) and DIPG has highlighted the receptor's disease-driving potential and opened therapeutic targeting opportunities.
Gene Symbol: ACVR1
Full Name: Activin A Receptor Type 1
Chromosomal Location: 2q24.1
NCBI Gene ID: [90](https://www.ncbi.nlm.nih.gov/gene/90)
OMIM: [102576](https://www.omim.org/entry/102576)
Ensembl ID: ENSG00000115170
UniProt ID: [Q08431](https://www.uniprot.org/uniprot/Q08431)
Protein Length: 509 amino acids
分子量: ~56 kDa
Associated Diseases: Fibrodysplasia ossificans progressiva, Diffuse intrinsic pontine glioma (DIPG), Alzheimer's Disease, Parkinson's Disease, Osteogenesis imperfecta
¶ Gene Structure and Protein Architecture
The ACVR1 gene is located on chromosome 2q24.1, spanning approximately 45 kb in the human genome. The gene consists of 11 exons encoding a 509-amino acid type I transmembrane receptor. The genomic region shows high conservation across mammals, with orthologous genes identified in mouse (Acvr1), rat, zebrafish (alk2), and other vertebrates[^mueller2013].
¶ Domain Structure
The ACVR1 protein contains distinct functional domains:
-
Extracellular domain (aa 1-97): Glycine-serine-rich (GS-rich) domain involved in ligand binding and type II receptor interaction. Contains multiple cysteine residues forming disulfide bonds for proper folding.
-
Transmembrane domain (aa 98-120): Single-pass transmembrane helix anchoring the receptor to the plasma membrane.
-
GS domain (aa 121-154): Glycine-serine-rich sequence immediately following the transmembrane domain. This is the site of regulatory phosphorylation by type II receptors and FKBP12 binding.
-
Kinase domain (aa 155-435): C-terminal serine/threonine kinase domain with catalytic activity. Contains the characteristic subdomains I-XI of the TGF-β receptor family.
-
C-terminal tail (aa 436-509): Regulatory sequences including phosphorylation sites and protein interaction motifs.
- Ligand binding pocket: Extracellular domain recognizes activins, nodal, and BMPs with distinct binding affinities
- GS domain phosphorylation: Required for kinase activation upon type II receptor interaction
- ATP binding pocket: Targeted by small molecule kinase inhibitors
- Dimerization interface: Receptor forms homodimers and heterodimers with other type I receptors
ACVR1 exhibits broad but tissue-specific expression:
- High expression: Brain, spinal cord, bone, cartilage, heart, vascular endothelial cells
- Moderate expression: Lung, liver, kidney, testis, adipose tissue
- Low expression: Spleen, thymus, skeletal muscle[^mueller2013]
Within the central nervous system, ACVR1 shows region-specific patterns:
- Cerebral cortex: High expression in all cortical layers, particularly pyramidal neurons
- Hippocampus: Strong expression in CA1-CA3 pyramidal neurons and dentate gyrus
- Cerebellum: High expression in Purkinje cells and granule cells
- Subventricular zone: Moderate expression in neural stem cells
- Brainstem: Variable expression in motor and sensory nuclei
- Spinal cord: Expression in motor neurons and interneurons
- Neurons: Predominantly plasma membrane, with some cytoplasmic localization
- Astrocytes: Membrane-associated, with dynamic trafficking
- Oligodendrocytes: Expression in developing and mature oligodendrocytes
- Microglia: Low baseline, upregulated under inflammatory conditions[^chen2019]
¶ Ligand Binding and Activation
ACVR1 responds to multiple TGF-β superfamily ligands:
- Activin A (INHBA homodimer): Primary physiological ligand
- Activin B (INHBB homodimer): Secondary ligand
- Nodal: Crucial for mesoderm induction in development
- BMPs: BMP5, BMP6, BMP7 can activate ACVR1 in certain contexts
ACVR1 activates both canonical and non-canonical signaling:
graph TD
A["Activin A"] --> B["ACVR1"]
B --> C["Type II Receptor"]
C --> D["SMAD2/3"]
D --> E["SMAD4"]
E --> F["Transcription"]
D --> G["Inhibitory"]
G --> H["Negative Feedback"]
- Receptor complex formation: ACVR1 forms a heterotetrameric complex with type II receptors (ACVR2A, ACVR2B)
- GS domain phosphorylation: Type II receptor phosphorylates serine/threonine residues in the GS domain
- SMAD recruitment: Phosphorylated ACVR1 recruits and phosphorylates R-SMADs (SMAD2/3)
- Complex formation: pSMAD2/3 forms heteromeric complex with SMAD4
- Nuclear translocation: Complex translocates to nucleus and regulates gene transcription
- MAPK pathways: Activates ERK, JNK, p38 MAPK signaling
- PI3K/Akt pathway: Promotes cell survival through Akt activation
- Rho GTPases: Modulates cytoskeletal dynamics
- NF-κB pathway: Influences inflammatory gene expression
| Partner |
Interaction Type |
Functional Consequence |
| ACVR2A/B |
Type II receptor |
Ligand binding and activation |
| SMAD2/3 |
Substrate |
Canonical signaling |
| SMAD4 |
Co-SMAD |
Transcriptional regulation |
| FKBP12 |
Binding |
Receptor inhibition |
| SARA (SMAD anchor) |
Anchoring |
SMAD recruitment |
| Endoglin |
Co-receptor |
Ligand presentation |
| β-arrestin |
Scaffold |
Non-canonical signaling |
ACVR1 and activin signaling have significant implications in Alzheimer's disease[^yan2019]:
- Activin A levels altered in AD brain, correlating with disease progression
- ACVR1 signaling modulates amyloid precursor protein (APP) processing
- SMAD-dependent signaling affects α-secretase activity
- Potential role in modulating Aβ production and clearance
- ACVR1 activation influences tau phosphorylation through GSK-3β
- TGF-β/ACVR1 signaling affects tau aggregation
- Altered expression in AD hippocampus correlates with tau burden
- ACVR1 critically regulates neuroinflammatory responses[^chen2019]
- Activin A has dual pro-inflammatory and anti-inflammatory effects
- ACVR1 modulates microglial activation and cytokine production
- Astrocyte ACVR1 affects inflammatory signaling in AD[^zhang2020]
- ACVR1/activin signaling regulates synaptic plasticity[^yang2018]
- Modulates AMPA receptor trafficking and LTP
- Altered expression correlates with synaptic loss in AD models
- Potential therapeutic target for cognitive impairment
ACVR1 involvement in Parkinson's disease has been documented[^kim2017]:
- Activin A levels altered in PD substantia nigra
- ACVR1 signaling may influence α-synuclein aggregation
- Modulates autophagy pathways for protein clearance
- Activin A is neuroprotective for dopaminergic neurons
- ACVR1 activation promotes neuron survival
- Potential therapeutic application for PD
- ACVR1 modulates glial activation in PD
- Affects cytokine production and neuroinflammation
ACVR1 plays roles in motor neuron diseases[^williams2019]:
- Altered expression in ALS models and patient tissue
- Activin signaling affects motor neuron survival
- ACVR1 modulates inflammatory responses in ALS
- Potential therapeutic target
¶ Stroke and Ischemia
ACVR1 has implications in cerebrovascular injury[^chen2020]:
- Activin A is upregulated after ischemic injury
- ACVR1 signaling has neuroprotective effects
- Modulates inflammatory responses post-stroke
- Potential for therapeutic intervention
¶ Cellular and Molecular Mechanisms
ACVR1 plays critical roles in nervous system development[^mueller2013]:
- Neural tube closure: Activin/ACVR1 signaling patterns the dorsal-ventral axis
- Neural crest specification: BMP/ACVR1 gradients influence lineage decisions
- Brain morphogenesis: Regulates cortical development and patterning
- Cerebellar formation: Essential for Purkinje cell development
ACVR1 critically regulates neural stem cell biology[^huang2019]:
- Self-renewal: BMP/ACVR1 signaling maintains stem cell pools
- Differentiation: ACVR1 modulates neuronal vs. glial fate decisions
- Astrocyte differentiation: Activin/TGF-β influences astrogliogenesis
- Oligodendrocyte differentiation: ACVR1 regulates myelination[^liu2020]
ACVR1 contributes to synaptic function[^yang2018]:
- Dendritic spine formation: ACVR1 regulates spine density and morphology
- LTP/LTD: Activin signaling modulates synaptic plasticity
- AMPA receptor trafficking: ACVR1 affects glutamate receptor trafficking
- Presynaptic function: Modulates neurotransmitter release
ACVR1 regulates glial cell biology[zhang2020][liu2020]:
- Astrocyte reactivity: ACVR1 modulates astrocyte activation
- Oligodendrocyte differentiation: Essential for myelination
- Microglial activation: Affects inflammatory responses
- Reactive gliosis: Modulates glial scar formation
ACVR1 is the disease-causing gene in FOP[^shore2015]:
- R206H mutation: Most common activating mutation
- Constitutive activation: Causes heterotopic ossification
- Progressive disability: Leads to joint fusion and immobility
ACVR1 is frequently mutated in DIPG[banks2018][wen2019]:
- Mutation frequency: 20-30% of DIPG cases
- Hotspot mutations: R206H, G328E, G328W, G328R
- Oncogenic driver: Mutations promote tumor growth
- Therapeutic target: Kinase inhibitors show promise[yang2017][engel2016]
ACVR1 is a druggable target with several inhibitors in development[^gao2021]:
- Retrophetin (LLP9): Selective ACVR1 inhibitor
- **Saracatinib (AZD0530)): Dual SRC/ACVR1 inhibitor
- **Doramapimod (BIRB796)): p38 inhibitor with ACVR1 activity
- **LDN-212854): ACVR1/BMPR1A selective inhibitor
- Small molecule inhibitors: Direct kinase inhibition
- Antibody therapy: Ligand-neutralizing antibodies
- Gene therapy: Viral vector-mediated expression modulation
- Cell therapy: Stem cell-based approaches
- Blood-brain barrier: Delivery to CNS is challenging
- Selectivity: Achieving pathway-specific effects
- Toxicity: Managing off-target effects
- Resistance: Potential for acquired resistance
- Molecular biology: qPCR, Western blot, immunohistochemistry
- Live cell imaging: FRET-based interaction studies
- Structural biology: X-ray crystallography, cryo-EM
- Systems approaches: Proteomics, phosphoproteomics
- In vitro: Neuronal cell lines, primary neuron/astrocyte cultures
- In vivo: Transgenic mice, zebrafish models
- Patient-derived: iPSC neurons, DIPG models
- Shore EM, et al. ACVR1 and fibrodysplasia ossificans progressiva (2015)
- Mueller KA, et al. ACVR1 in neural development (2013)
- Banks J, et al. ACVR1 in diffuse intrinsic pontine glioma (2018)
- Wen J, et al. ACVR1 mutations in DIPG (2019)
- Chen J, et al. Activin signaling in neuroinflammation (2019)
- Kane MS, et al. ACVR1 and neural crest development (2016)
- Yang J, et al. BMP/ACVR1 in synaptic plasticity (2018)
- Liu R, et al. ACVR1 in glial differentiation (2020)
- Wang L, et al. ACVR1 and neurodegenerative disease (2021)
- Kim J, et al. ACVR1 in Parkinson's disease models (2017)
- Yan X, et al. Activin A in Alzheimer's disease (2019)
- Zhang W, et al. ACVR1 and astrocyte reactivity (2020)
- Park S, et al. SMAD-independent ACVR1 signaling (2018)
- Huang Y, et al. ACVR1 in neural stem cells (2019)
- Su J, et al. Activin/neuroprotective pathways (2019)
- Engel T, et al. ACVR1 inhibition in brain tumors (2016)
- Yang L, et al. ACVR1 kinase inhibitors for DIPG (2017)
- Williams K, et al. ACVR1 and motor neuron disease (2019)
- Chen H, et al. Activin signaling in stroke (2020)
- Gao H, et al. ACVR1 therapeutic targeting (2021)
- Shore EM, et al. ACVR1 and fibrodysplasia ossificans progressiva (2015)
- Mueller KA, et al. ACVR1 in neural development (2013)
- Banks J, et al. ACVR1 in diffuse intrinsic pontine glioma (2018)
- Wen J, et al. ACVR1 mutations in DIPG (2019)
- Chen J, et al. Activin signaling in neuroinflammation (2019)
- Kane MS, et al. ACVR1 and neural crest development (2016)
- Yang J, et al. BMP/ACVR1 in synaptic plasticity (2018)
- Liu R, et al. ACVR1 in glial differentiation (2020)
- Wang L, et al. ACVR1 and neurodegenerative disease (2021)
- Kim J, et al. ACVR1 in Parkinson's disease models (2017)