ACVR1

Activin A receptor, type I (ACVR1) is a protein which in humans is encoded by the ACVR1 gene; it is also known as ALK-2 (activin receptor-like kinase-2).^[5] ACVR1 has been linked to the 2q23-24 region of the genome.^[6] This protein is important in the bone morphogenic protein (BMP) pathway that is responsible for the development and repair of the skeletal system. While knockout models with this gene are in progress, the ACVR1 gene has been connected to fibrodysplasia ossificans progressiva, an extremely rare progressive genetic disease characterized by heterotopic ossification of muscles, tendons, and ligaments.^[7] It is a bone morphogenetic protein receptor, type 1.

ACVR1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3H9R, 3MTF, 3OOM, 3Q4U, 4BGG, 4C02, 4DYM
Identifiers
Aliases	ACVR1, ACTRI, ACVR1A, ACVRLK2, ALK2, FOP, SKR1, TSRI, activin A receptor type 1
External IDs	OMIM: 102576; MGI: 87911; HomoloGene: 7; GeneCards: ACVR1; OMA:ACVR1 - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q24.1 Start 157,736,251 bp[1] End 157,876,330 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2|2 C1.1 Start 58,278,656 bp[2] End 58,457,169 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in cartilage tissue synovial joint saphenous vein stromal cell of endometrium urethra islet of Langerhans secondary oocyte periodontal fiber ventricular zone synovial membrane Top expressed in atrioventricular valve endocardial cushion calvaria vas deferens atrium ureter dermis semi-lunar valve ankle vestibular membrane of cochlear duct More reference expression data BioGPS n/a
Gene ontology Molecular function transferase activity protein kinase activity activin receptor activity, type I nucleotide binding protein homodimerization activity growth factor binding activin binding metal ion binding kinase activity peptide hormone binding protein serine/threonine kinase activity transmembrane receptor protein serine/threonine kinase activity transforming growth factor beta receptor activity, type I protein binding ATP binding transforming growth factor beta binding SMAD binding transforming growth factor beta-activated receptor activity BMP receptor activity Cellular component integral component of membrane membrane apical part of cell integral component of plasma membrane activin receptor complex receptor complex Biological process germ cell development pathway-restricted SMAD protein phosphorylation positive regulation of bone mineralization phosphorylation positive regulation of cell migration mesoderm formation gastrulation with mouth forming second negative regulation of extrinsic apoptotic signaling pathway endocardial cushion cell fate commitment cellular response to BMP stimulus in utero embryonic development positive regulation of determination of dorsal identity mitral valve morphogenesis smooth muscle cell differentiation BMP signaling pathway positive regulation of transcription, DNA-templated protein phosphorylation negative regulation of activin receptor signaling pathway heart development determination of left/right symmetry positive regulation of osteoblast differentiation transmembrane receptor protein serine/threonine kinase signaling pathway acute inflammatory response gastrulation embryonic heart tube morphogenesis neural crest cell migration cardiac muscle cell fate commitment branching involved in blood vessel morphogenesis negative regulation of signal transduction regulation of ossification peptidyl-threonine phosphorylation mesoderm development transforming growth factor beta receptor signaling pathway pharyngeal system development activin receptor signaling pathway outflow tract septum morphogenesis atrioventricular valve morphogenesis endocardial cushion morphogenesis endocardial cushion fusion atrial septum primum morphogenesis positive regulation of pathway-restricted SMAD protein phosphorylation positive regulation of transcription by RNA polymerase II ventricular septum morphogenesis BMP signaling pathway involved in heart development positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation G1/S transition of mitotic cell cycle pattern specification process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 90 11477 Ensembl ENSG00000115170 ENSMUSG00000026836 UniProt Q04771 P37172 RefSeq (mRNA) NM_001105 NM_001111067 NM_001347663 NM_001347664 NM_001347665 NM_001347666 NM_001347667 NM_001110204 NM_001110205 NM_007394 NM_001355048 NM_001355049 RefSeq (protein) NP_001096 NP_001104537 NP_001334592 NP_001334593 NP_001334594 NP_001334595 NP_001334596 NP_001103674 NP_001103675 NP_031420 NP_001341977 NP_001341978 Location (UCSC) Chr 2: 157.74 – 157.88 Mb Chr 2: 58.28 – 58.46 Mb PubMed search [3] [4]
Wikidata
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Function

Activins are dimeric growth and differentiation factors that 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 that 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; 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 that signals a particular transcriptional response in concert with activin type II receptors.^[8]

Signaling

ACVR1 transduces signals of BMPs. BMPs bind either ACVR2A/ACVR2B or a BMPR2 and then form a complex with ACVR1. These go on to recruit the R-SMADs SMAD1, SMAD2, SMAD3 or SMAD6.^[9]

Clinical significance

Gain-of-function mutations in the gene ACVR1/ALK2 is responsible for the genetic disease fibrodysplasia ossificans progressiva (FOP).^[10] The typical FOP patient has the amino acid arginine substituted for the amino acid histidine at position 206 in this protein.^[10][11] This substitution causes a change in the critical glycine-serine activation domain of the protein that will then cause the protein to bind its inhibitory ligand (FKBP12) less tightly, and thus overactivate the BMP/SMAD pathway.^[6] The result of this overactivation is that endothelial cells transform to mesenchymal stem cells and then to bone.^[12] Atypical mutations involving other residues work similarly, thereby causing the protein to be stuck in its active conformation despite no BMP being present.^[13]

Mutations in the ACVR1 gene have also been linked to cancer, especially diffuse intrinsic pontine glioma (DIPG).^[14][15][16]