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, 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.
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]
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]
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]
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.
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 (ossification). It is the only known medical condition where one organ system changes into another. It is a severe, disabling disorder with no cure.
Bone morphogenetic protein 4 is a protein that in humans is encoded by BMP4 gene. BMP4 is found on chromosome 14q22-q23.
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.
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.
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.
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.
Activin receptor type-1B is a protein that in humans is encoded by the ACVR1B gene.
Activin receptor type-2A is a protein that in humans is encoded by the ACVR2A gene. ACVR2A is an activin type 2 receptor.
Activin receptor type-2B is a protein that in humans is encoded by the ACVR2B gene. ACVR2B is an activin type 2 receptor.
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.
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.
Bone morphogenetic protein receptor type-1B also known as CDw293 is a protein that in humans is encoded by the BMPR1B gene.
Serine/threonine-protein kinase receptor R3 is an enzyme that in humans is encoded by the ACVRL1 gene.
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.
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. It is taken by mouth.
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.
Frederick S. Kaplan is an American medical doctor specializing in research of musculoskeletal disorders such as fibrodysplasia ossificans progressiva (FOP).
Eileen M. Shore is an American medical researcher and geneticist specializing in research of muscoskeletal disorders such as fibrodysplasia ossificans progressiva.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.