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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)
End	157,876,330 bp
Gene location (Mouse)
Chr.	Chromosome 2 (mouse)
End	58,457,169 bp
RNA expression pattern
	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
	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
	90
	11477
	ENSG00000115170
	ENSMUSG00000026836
	Q04771
	P37172
NM_001105; NM_001111067; NM_001347663; NM_001347664; NM_001347665;
	NM_001347666; NM_001347667
	NM_001110204; NM_001110205; NM_007394; NM_001355048; NM_001355049
NP_001096; NP_001104537; NP_001334592; NP_001334593; NP_001334594;
	NP_001334595; NP_001334596
	NP_001103674; NP_001103675; NP_031420; NP_001341977; NP_001341978
	Wikidata
View/Edit Human	View/Edit Mouse

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.

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]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000115170 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000026836 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ten Dijke P, Ichijo H, Franzén P, Schulz P, Saras J, Toyoshima H, Heldin CH, Miyazono K (October 1993). "Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity". Oncogene. 8 (10): 2879–87. PMID 8397373.
^ ^a ^b Pignolo RJ, Shore EM, Kaplan FS (June 2013). "Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons". Pediatr Endocrinol Rev. 10 Suppl 2 (2): 437–48. PMC 3995352. PMID 23858627.
^ de Ruiter RD, Smilde BJ, Pals G, Bravenboer N, Knaus P, Schoenmaker T, et al. (2021). "Fibrodysplasia Ossificans Progressiva: What Have We Achieved and Where Are We Now? Follow-up to the 2015 Lorentz Workshop". Front Endocrinol (Lausanne). 12: 732728. doi:10.3389/fendo.2021.732728. PMC 8631510. PMID 34858325.
^ "Entrez Gene: ACVR1 (activin A receptor, type I)".
^ Inman GJ, Nicolás FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ, Hill CS (July 2002). "SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7". Molecular Pharmacology. 62 (1): 65–74. doi:10.1124/mol.62.1.65. PMID 12065756. S2CID 15185199.
^ ^a ^b Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS (May 2006). "A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva". Nature Genetics. 38 (5): 525–7. doi:10.1038/ng1783. PMID 16642017. S2CID 41579747.
^ "News Release of FOP's Cause". Archived from the original on 2012-01-13. Retrieved 2012-02-29.
^ van Dinther M, Visser N, de Gorter DJ, Doorn J, Goumans MJ, de Boer J, ten Dijke P (June 2010). "ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation". Journal of Bone and Mineral Research. 25 (6): 1208–15. doi:10.1359/jbmr.091110. PMID 19929436. S2CID 207269687.
^ Petrie KA, Lee WH, Bullock AN, Pointon JJ, Smith R, Russell RG, Brown MA, Wordsworth BP, Triffitt JT (2009). "Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients". PLOS ONE. 4 (3): e5005. Bibcode:2009PLoSO...4.5005P. doi:10.1371/journal.pone.0005005. PMC 2658887. PMID 19330033.
^ Taylor KR, Mackay A, Truffaux N, Butterfield YS, Morozova O, Philippe C, Castel D, Grasso CS, Vinci M, Carvalho D, Carcaboso AM, de Torres C, Cruz O, Mora J, Entz-Werle N, Ingram WJ, Monje M, Hargrave D, Bullock AN, Puget S, Yip S, Jones C, Grill J (May 2014). "Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma". Nature Genetics. 46 (5): 457–61. doi:10.1038/ng.2925. PMC 4018681. PMID 24705252.
^ "Cure Brain Cancer - News - Multiple Breakthroughs in Childhood Brain Cancer DIPG". Cure Brain Cancer Foundation.
^ Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M, et al. (May 2014). "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations". Nature Genetics. 46 (5): 451–6. doi:10.1038/ng.2936. PMC 3997489. PMID 24705254.

External links

Human ACVR1 genome location and ACVR1 gene details page in the UCSC Genome Browser.
Overview of all the structural information available in the PDB for UniProt: Q04771 (Human Activin receptor type-1) at the PDBe-KB.