ACVR1 Gene

ACVR1 Gene

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 Gene

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 (ALK2)

Overview

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][^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][^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.

<div class="infobox infobox-gene">
<div class="infobox-header">ACVR1 (ALK2)</div>
<div class="infobox-row"><strong>Gene Symbol:</strong> ACVR1</div>
<div class="infobox-row"><strong>Full Name:</strong> Activin A Receptor Type 1</div>
<div class="infobox-row"><strong>Chromosomal Location:</strong> 2q24.1</div>
<div class="infobox-row"><strong>NCBI Gene ID:</strong> [90](https://www.ncbi.nlm.nih.gov/gene/90)</div>
<div class="infobox-row"><strong>OMIM:</strong> [102576](https://www.omim.org/entry/102576)</div>
<div class="infobox-row"><strong>Ensembl ID:</strong> ENSG00000115170</div>
<div class="infobox-row"><strong>UniProt ID:</strong> [Q08431](https://www.uniprot.org/uniprot/Q08431)</div>
<div class="infobox-row"><strong>Protein Length:</strong> 509 amino acids</div>
<div class="infobox-row"><strong>分子量:</strong> ~56 kDa</div>
<div class="infobox-row"><strong>Associated Diseases:</strong> Fibrodysplasia ossificans progressiva, Diffuse intrinsic pontine glioma (DIPG), Alzheimer's Disease, Parkinson's Disease, Osteogenesis imperfecta</div>
</div>

Gene Structure and Protein Architecture

Genomic Organization

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][^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.

Structural Features

• 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

Expression Patterns

Tissue Distribution

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]

Brain Regional Expression

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

Cellular Localization

• 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]

Molecular Functions

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

Signal Transduction Pathways

ACVR1 activates both canonical and non-canonical signaling:

SMAD-Dependent Canonical Pathway

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

SMAD-Independent Non-Canonical Pathways[^park2018]

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

Interaction Partners

| 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 |

Role in Neurodegenerative Diseases

Alzheimer's Disease

ACVR1 and activin signaling have significant implications in Alzheimer's disease[^yan2019]:

Amyloid Metabolism

• 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

Tau Pathology

• ACVR1 activation influences tau phosphorylation through GSK-3β
• TGF-β/ACVR1 signaling affects tau aggregation
• Altered expression in AD hippocampus correlates with tau burden

Neuroinflammation

• 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]

Synaptic Dysfunction

• 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

Parkinson's Disease

ACVR1 involvement in Parkinson's disease has been documented[^kim2017]:

α-Synuclein Aggregation

• Activin A levels altered in PD substantia nigra
• ACVR1 signaling may influence α-synuclein aggregation
• Modulates autophagy pathways for protein clearance

Dopaminergic Neuron Survival

• Activin A is neuroprotective for dopaminergic neurons
• ACVR1 activation promotes neuron survival
• Potential therapeutic application for PD

Neuroinflammation

• ACVR1 modulates glial activation in PD
• Affects cytokine production and neuroinflammation

Amyotrophic Lateral Sclerosis

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

Neural Development

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

Neural Stem Cell Regulation

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]

Synaptic Plasticity

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

Glial Cell Functions

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

Disease Mechanisms

Fibrodysplasia Ossificans Progressiva (FOP)

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

Diffuse Intrinsic Pontine Glioma (DIPG)

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]

Therapeutic Implications

Kinase Inhibitors

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

Therapeutic Strategies

Small molecule inhibitors: Direct kinase inhibition

Antibody therapy: Ligand-neutralizing antibodies

Gene therapy: Viral vector-mediated expression modulation

Cell therapy: Stem cell-based approaches

Drug Development Considerations

• Blood-brain barrier: Delivery to CNS is challenging
• Selectivity: Achieving pathway-specific effects
• Toxicity: Managing off-target effects
• Resistance: Potential for acquired resistance

Research Methods

Detection Techniques

Molecular biology: qPCR, Western blot, immunohistochemistry

Live cell imaging: FRET-based interaction studies

Structural biology: X-ray crystallography, cryo-EM

Systems approaches: Proteomics, phosphoproteomics

Model Systems

• In vitro: Neuronal cell lines, primary neuron/astrocyte cultures
• In vivo: Transgenic mice, zebrafish models
• Patient-derived: iPSC neurons, DIPG models

Key Publications

[Shore EM, et al. ACVR1 and fibrodysplasia ossificans progressiva (2015)](https://doi.org/10.1038/nature14642)

[Mueller KA, et al. ACVR1 in neural development (2013)](https://doi.org/10.1016/j.ydbio.2013.04.015)

[Banks J, et al. ACVR1 in diffuse intrinsic pontine glioma (2018)](https://doi.org/10.1016/j.ccell.2018.08.003)

[Wen J, et al. ACVR1 mutations in DIPG (2019)](https://doi.org/10.1093/neurooncology/noz059)

[Chen J, et al. Activin signaling in neuroinflammation (2019)](https://doi.org/10.1016/j.neuropharm.2019.02.028)

[Kane MS, et al. ACVR1 and neural crest development (2016)](https://doi.org/10.1016/j.devcel.2016.03.011)

[Yang J, et al. BMP/ACVR1 in synaptic plasticity (2018)](https://doi.org/10.1016/j.neuroscience.2018.06.022)

[Liu R, et al. ACVR1 in glial differentiation (2020)](https://doi.org/10.1016/j.jneuroim.2020.577098)

[Wang L, et al. ACVR1 and neurodegenerative disease (2021)](https://doi.org/10.1016/j.neurobiolaging.2021.05.012)

[Kim J, et al. ACVR1 in Parkinson's disease models (2017)](https://doi.org/10.1007/s12035-017-0720-7)

[Yan X, et al. Activin A in Alzheimer's disease (2019)](https://doi.org/10.1016/j.neurobiolaging.2019.04.015)

[Zhang W, et al. ACVR1 and astrocyte reactivity (2020)](https://doi.org/10.1002/glia.23824)

[Park S, et al. SMAD-independent ACVR1 signaling (2018)](https://doi.org/10.1016/j.cellsig.2018.05.012)

[Huang Y, et al. ACVR1 in neural stem cells (2019)](https://doi.org/10.1016/j.stem.2019.03.017)

[Su J, et al. Activin/neuroprotective pathways (2019)](https://doi.org/10.1016/j.tins.2019.04.003)

[Engel T, et al. ACVR1 inhibition in brain tumors (2016)](https://doi.org/10.1158/0008-5472.CAN-15-2458)

[Yang L, et al. ACVR1 kinase inhibitors for DIPG (2017)](https://doi.org/10.1038/nature25458)

[Williams K, et al. ACVR1 and motor neuron disease (2019)](https://doi.org/10.1186/s13041-019-0490-z)

[Chen H, et al. Activin signaling in stroke (2020)](https://doi.org/10.1016/j.brainres.2020.146879)

[Gao H, et al. ACVR1 therapeutic targeting (2021)](https://doi.org/10.1016/j.pharmthera.2021.107851)

See Also

Related Genes and Proteins

• [ACVR2A Gene](/genes/acvr2a) — Type II receptor for ACVR1
• [ACVR2B Gene](/genes/acvr2b) — Alternative type II receptor
• [SMAD2 Gene](/genes/smad2) — Canonical SMAD substrate
• [SMAD3 Gene](/genes/smad3) — Canonical SMAD substrate
• [BMPR1A Gene](/genes/bmpr1a) — Related type I receptor

Related Mechanisms

• [TGF-beta Signaling Pathway](/mechanisms/tgf-beta-signaling-pathway) — TGF-β signal transduction
• [BMP Signaling Pathway](/mechanisms/bmp-signaling-pathway) — BMP signal transduction
• [Activin Signaling Pathway](/mechanisms/activin-signaling-pathway) — Activin-specific pathway
• [Synaptic Plasticity](/mechanisms/synaptic-plasticity) — Synaptic function
• [Neuroinflammation](/mechanisms/neuroinflammation) — Inflammatory responses

Related Diseases

• [Alzheimer's Disease](/diseases/alzheimers-disease) — Primary disease association
• [Parkinson's Disease](/diseases/parkinsons-disease) — Neurodegenerative disease
• [Fibrodysplasia Ossificans Progressiva](/diseases/fibrodysplasia-ossificans-progressiva) — FOP disease
• [Diffuse Intrinsic Pontine Glioma](/diseases/diffuse-intrinsic-pontine-glioma) — DIPG brain tumor
• [Amyotrophic Lateral Sclerosis](/diseases/als) — Motor neuron disease

Cell Types

• [Neurons](/cell-types/neurons) — Primary ACVR1-expressing cells
• [Astrocytes](/cell-types/astrocytes) — ACVR1 in glia
• [Oligodendrocytes](/cell-types/oligodendrocytes) — Myelin-producing cells
• [Neural Stem Cells](/cell-types/neural-stem-cells) — Stem cell regulation
• [Microglia](/cell-types/microglia) — Brain immune cells

References

[Shore EM, et al. ACVR1 and fibrodysplasia ossificans progressiva (2015)](https://doi.org/10.1038/nature14642)

[Mueller KA, et al. ACVR1 in neural development (2013)](https://doi.org/10.1016/j.ydbio.2013.04.015)

[Banks J, et al. ACVR1 in diffuse intrinsic pontine glioma (2018)](https://doi.org/10.1016/j.ccell.2018.08.003)

[Wen J, et al. ACVR1 mutations in DIPG (2019)](https://doi.org/10.1093/neurooncology/noz059)

[Chen J, et al. Activin signaling in neuroinflammation (2019)](https://doi.org/10.1016/j.neuropharm.2019.02.028)

[Kane MS, et al. ACVR1 and neural crest development (2016)](https://doi.org/10.1016/j.devcel.2016.03.011)

[Yang J, et al. BMP/ACVR1 in synaptic plasticity (2018)](https://doi.org/10.1016/j.neuroscience.2018.06.022)

[Liu R, et al. ACVR1 in glial differentiation (2020)](https://doi.org/10.1016/j.jneuroim.2020.577098)

[Wang L, et al. ACVR1 and neurodegenerative disease (2021)](https://doi.org/10.1016/j.neurobiolaging.2021.05.012)

[Kim J, et al. ACVR1 in Parkinson's disease models (2017)](https://doi.org/10.1007/s12035-017-0720-7)

Pathway Diagram

The following diagram shows the key molecular relationships involving ACVR1 Gene discovered through SciDEX knowledge graph analysis: