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).{{cite journal | vauthors = ten Dijke P, Ichijo H, Franzén P, Schulz P, Saras J, Toyoshima H, Heldin CH, Miyazono K | title = Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity | journal = Oncogene | volume = 8 | issue = 10 | pages = 2879–87 | date = October 1993 | pmid = 8397373 }} ACVR1 has been linked to the 2q23-24 region of the genome.{{cite journal | vauthors = Pignolo RJ, Shore EM, Kaplan FS | title = Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons | journal = Pediatr Endocrinol Rev | volume = 10 Suppl 2 | issue = 2 | pages = 437–48 | date = June 2013 | pmid = 23858627 | pmc = 3995352 }} 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.{{cite journal | vauthors = de Ruiter RD, Smilde BJ, Pals G, Bravenboer N, Knaus P, Schoenmaker T, Botman E, Sánchez-Duffhues G, Pacifici M, Pignolo RJ, Shore EM, van Egmond M, Van Oosterwyck H, Kaplan FS, Hsiao EC, Yu PB, Bocciardi R, De Cunto CL, Longo Ribeiro Delai P, de Vries TJ, Hilderbrandt S, Jaspers RT, Keen R, Koolwijk P, Morhart R, Netelenbos JC, Rustemeyer T, Scott C, Stockklausner C, Ten Dijke P, Triffit J, Ventura F, Ravazzolo R, Micha D, Eekhoff EM|display-authors = 6 | title = Fibrodysplasia Ossificans Progressiva: What Have We Achieved and Where Are We Now? Follow-up to the 2015 Lorentz Workshop | journal = Front Endocrinol (Lausanne) | volume = 12 | issue = | pages = 732728 | date = 2021 | pmid = 34858325 | pmc = 8631510 | doi = 10.3389/fendo.2021.732728 |doi-access = free }} 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.{{cite web | title = Entrez Gene: ACVR1 (activin A receptor, type I) | url =https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=90}}

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.{{cite journal | vauthors = Inman GJ, Nicolás FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ, Hill CS | title = 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 | journal = Molecular Pharmacology | volume = 62 | issue = 1 | pages = 65–74 | date = July 2002 | pmid = 12065756 | doi = 10.1124/mol.62.1.65 | s2cid = 15185199 }}

Clinical significance

Gain-of-function mutations in the gene ACVR1/ALK2 is responsible for the genetic disease fibrodysplasia ossificans progressiva (FOP).{{cite journal | vauthors = 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 | title = A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva | journal = Nature Genetics | volume = 38 | issue = 5 | pages = 525–7 | date = May 2006 | pmid = 16642017 | doi = 10.1038/ng1783 | s2cid = 41579747 }} The typical FOP patient has the amino acid arginine substituted for the amino acid histidine at position 206 in this protein.{{Cite web |url=http://www.uphs.upenn.edu/news/News_Releases/apr06/FOP.htm |title=News Release of FOP's Cause |access-date=2012-02-29 |archive-url=https://web.archive.org/web/20120113213418/http://www.uphs.upenn.edu/news/News_Releases/apr06/FOP.htm |archive-date=2012-01-13 |url-status=dead }} 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. The result of this overactivation is that endothelial cells transform to mesenchymal stem cells and then to bone.{{cite journal | vauthors = van Dinther M, Visser N, de Gorter DJ, Doorn J, Goumans MJ, de Boer J, ten Dijke P | title = 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 = Journal of Bone and Mineral Research | volume = 25 | issue = 6 | pages = 1208–15 | date = June 2010 | pmid = 19929436 | doi = 10.1359/jbmr.091110 | s2cid = 207269687 | doi-access = free }} Atypical mutations involving other residues work similarly, thereby causing the protein to be stuck in its active conformation despite no BMP being present.{{cite journal | vauthors = Petrie KA, Lee WH, Bullock AN, Pointon JJ, Smith R, Russell RG, Brown MA, Wordsworth BP, Triffitt JT | title = Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients | journal = PLOS ONE | volume = 4 | issue = 3 | pages = e5005 | date = 2009 | pmid = 19330033 | pmc = 2658887 | doi = 10.1371/journal.pone.0005005|bibcode=2009PLoSO...4.5005P |doi-access=free }}

Mutations in the ACVR1 gene have also been linked to cancer, especially diffuse intrinsic pontine glioma (DIPG).{{cite journal | vauthors = 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 | title = Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma | journal = Nature Genetics | volume = 46 | issue = 5 | pages = 457–61 | date = May 2014 | pmid = 24705252 | pmc = 4018681 | doi = 10.1038/ng.2925 }}{{cite web | url = http://www.curebraincancer.org.au/news/1044/multiple-breakthroughs-in-childhood-brain-cancer | title = Cure Brain Cancer - News - Multiple Breakthroughs in Childhood Brain Cancer DIPG | publisher = Cure Brain Cancer Foundation }}{{cite journal | vauthors = Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M, Morrison A, Lewis P, Bouffet E, Bartels U, Zuccaro J, Agnihotri S, Ryall S, Barszczyk M, Chornenkyy Y, Bourgey M, Bourque G, Montpetit A, Cordero F, Castelo-Branco P, Mangerel J, Tabori U, Ho KC, Huang A, Taylor KR, Mackay A, Bendel AE, Nazarian J, Fangusaro JR, Karajannis MA, Zagzag D, Foreman NK, Donson A, Hegert JV, Smith A, Chan J, Lafay-Cousin L, Dunn S, Hukin J, Dunham C, Scheinemann K, Michaud J, Zelcer S, Ramsay D, Cain J, Brennan C, Souweidane MM, Jones C, Allis CD, Brudno M, Becher O, Hawkins C | display-authors = 6 | title = Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations | journal = Nature Genetics | volume = 46 | issue = 5 | pages = 451–6 | date = May 2014 | pmid = 24705254 | pmc = 3997489 | doi = 10.1038/ng.2936 }}

References

External links

{{UCSC gene info|ACVR1}}
{{PDBe-KB2|Q04771|Human Activin receptor type-1}}

Category:GS domain

Category:TS domain

Category:S/T domain

Category:Human proteins

Category:EC 2.7.11