ACVR1

Last updated
ACVR1
Protein ACVR1 PDB 3H9R.png
Available structures
PDB Ortholog search: PDBe RCSB
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
Orthologs
SpeciesHumanMouse
Entrez

90

11477

Ensembl

ENSG00000115170

ENSMUSG00000026836

UniProt

Q04771

P37172

RefSeq (mRNA)

NM_001110204
NM_001110205
NM_007394
NM_001355048
NM_001355049

Contents

RefSeq (protein)

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
View/Edit Human View/Edit Mouse

Activin A receptor, type I (ACVR1) is a protein which in humans is encoded by the ACVR1 gene; 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 which is responsible for the development and repair of the skeletal system. While knock-out models with this gene are in progress, the ACVR1 gene has been connected to fibrodysplasia ossificans progressiva, a very 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 which 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 which 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; and 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 which 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. [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 causes a change in the critical glycine-serine activation domain of the protein which will cause the protein to bind its inhibitory ligand (FKBP12) less tightly, and thus over-activate the BMP/SMAD pathway. [6] The result of this over-activation is that endothelial cells transform to mesenchymal stem cells and then to bone. [12] Atypical mutations involving other residues work similarly - 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]

Related Research Articles

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

<span class="mw-page-title-main">Fibrodysplasia ossificans progressiva</span> Rare connective tissue disease

Fibrodysplasia ossificans progressiva, also called Münchmeyer disease or formerly myositis ossificans progressiva, is an extremely rare connective tissue disease in which fibrous connective tissue such as muscle, tendons, and ligaments turn into bone tissue. It is the only known medical condition where one organ system changes into another. It is a severe, disabling disorder with no cure or treatment.

<span class="mw-page-title-main">Bone morphogenetic protein 4</span> Human protein and coding gene

Bone morphogenetic protein 4 is a protein that in humans is encoded by BMP4 gene. BMP4 is found on chromosome 14q22-q23.

<span class="mw-page-title-main">Mothers against decapentaplegic homolog 2</span> Protein-coding gene in the species Homo sapiens

Mothers against decapentaplegic homolog 2 also known as SMAD family member 2 or SMAD2 is a protein that in humans is encoded by the SMAD2 gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways.

The transforming growth factor beta (TGFB) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, cell migration, apoptosis, cellular homeostasis and other cellular functions. The TGFB signaling pathways are conserved. In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression.

<span class="mw-page-title-main">BMPR2</span> Protein-coding gene in the species Homo sapiens

Bone morphogenetic protein receptor type II or BMPR2 is a serine/threonine receptor kinase encoded by the BMPR2 gene. It binds bone morphogenetic proteins, members of the TGF beta superfamily of ligands, which are involved in paracrine signaling. BMPs are involved in a host of cellular functions including osteogenesis, cell growth and cell differentiation. Signaling in the BMP pathway begins with the binding of a BMP to the type II receptor. This causes the recruitment of a BMP type I receptor, which the type II receptor phosphorylates. The type I receptor phosphorylates an R-SMAD, a transcriptional regulator.

<span class="mw-page-title-main">BMPR1A</span> Bone morphogenetic protein receptor

The bone morphogenetic protein receptor, type IA also known as BMPR1A is a protein which in humans is encoded by the BMPR1A gene. BMPR1A has also been designated as CD292.

<span class="mw-page-title-main">ACVR1C</span> Protein-coding gene in the species Homo sapiens

The activin A receptor also known as ACVR1C or ALK-7 is a protein that in humans is encoded by the ACVR1C gene. ACVR1C is a type I receptor for the TGFB family of signaling molecules.

<span class="mw-page-title-main">ACVR1B</span> Protein-coding gene in humans

Activin receptor type-1B is a protein that in humans is encoded by the ACVR1B gene.

<span class="mw-page-title-main">ACVR2A</span> Protein-coding gene in the species Homo sapiens

Activin receptor type-2A is a protein that in humans is encoded by the ACVR2A gene. ACVR2A is an activin type 2 receptor.

<span class="mw-page-title-main">ACVR2B</span> Protein-coding gene in the species Homo sapiens

Activin receptor type-2B is a protein that in humans is encoded by the ACVR2B gene. ACVR2B is an activin type 2 receptor.

<span class="mw-page-title-main">TGF beta receptor 1</span> Protein-coding gene in the species Homo sapiens

Transforming growth factor beta receptor I is a membrane-bound TGF beta receptor protein of the TGF-beta receptor family for the TGF beta superfamily of signaling ligands. TGFBR1 is its human gene.

<span class="mw-page-title-main">GDF2</span> Protein-coding gene in the species Homo sapiens

Growth differentiation factor 2 (GDF2) also known as bone morphogenetic protein (BMP)-9 is a protein that in humans is encoded by the GDF2 gene. GDF2 belongs to the transforming growth factor beta superfamily.

<span class="mw-page-title-main">BMPR1B</span> Protein-coding gene in the species Homo sapiens

Bone morphogenetic protein receptor type-1B also known as CDw293 is a protein that in humans is encoded by the BMPR1B gene.

<span class="mw-page-title-main">ACVRL1</span> Protein-coding gene in humans

Serine/threonine-protein kinase receptor R3 is an enzyme that in humans is encoded by the ACVRL1 gene.

<span class="mw-page-title-main">Activin and inhibin</span> Regulators of feedback on FSH-production

Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual cycle. Many other functions have been found to be exerted by activin, including roles in cell proliferation, differentiation, apoptosis, metabolism, homeostasis, immune response, wound repair, and endocrine function. Conversely, inhibin downregulates FSH synthesis and inhibits FSH secretion. The existence of inhibin was hypothesized as early as 1916; however, it was not demonstrated to exist until Neena Schwartz and Cornelia Channing's work in the mid-1970s, after which both proteins were molecularly characterized ten years later.

<span class="mw-page-title-main">Palovarotene</span> Chemical compound

Palovarotene, sold under the brand name Sohonos, is a medication used for the treatment of heterotopic ossification and fibrodysplasia ossificans progressiva. It is a highly selective retinoic acid receptor gamma (RARγ) agonist.

The transforming growth factor beta (TGFβ) receptors are a family of serine/threonine kinase receptors involved in TGF beta signaling pathway. These receptors bind growth factor and cytokine signaling proteins in the TGF-beta family such as TGFβs, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), activin and inhibin, myostatin, anti-Müllerian hormone (AMH), and NODAL.

<span class="mw-page-title-main">Frederick Kaplan</span> American medical researcher

Frederick S. Kaplan is an American medical doctor specializing in research of musculoskeletal disorders such as fibrodysplasia ossificans progressiva (FOP).

<span class="mw-page-title-main">Eileen Shore</span> American medical researcher

Eileen M. Shore is an American medical researcher and geneticist specializing in research of muscoskeletal disorders such as fibrodysplasia ossificans progressiva.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000115170 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026836 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ 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.
  6. 1 2 Pignolo RJ, Shore EM, Kaplan FS (June 2013). "Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons". Pediatr Endocrinol Rev. 10 Suppl 2 (0 2): 437–48. PMC   3995352 . PMID   23858627.
  7. ↑ 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.
  8. ↑ "Entrez Gene: ACVR1 (activin A receptor, type I)".
  9. ↑ 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.
  10. 1 2 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.
  11. ↑ "News Release of FOP's Cause". Archived from the original on 2012-01-13. Retrieved 2012-02-29.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ "Cure Brain Cancer - News - Multiple Breakthroughs in Childhood Brain Cancer DIPG". Cure Brain Cancer Foundation.
  16. ↑ 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.

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