Activin type 2 receptors

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activin A receptor, type IIA
Identifiers
Symbol ACVR2A
Alt. symbolsACVR2
NCBI gene 92
HGNC 173
OMIM 102581
RefSeq NM_001616
UniProt P27037
Other data
Locus Chr. 2 q22.2-23.3
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Structures Swiss-model
Domains InterPro
activin A receptor, type IIB
Identifiers
Symbol ACVR2B
NCBI gene 93
HGNC 174
OMIM 602730
RefSeq NM_001106
UniProt Q13705
Other data
Locus Chr. 3 p22
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Structures Swiss-model
Domains InterPro

The activin type 2 receptors belong to a larger TGF-beta receptor family and modulate signals for transforming growth factor beta ligands. These receptors are involved in a host of physiological processes including, growth, cell differentiation, homeostasis, osteogenesis, apoptosis and many other functions. There are two activin type two receptors: ACVR2A and ACVR2B.

Contents

Despite the large amount of processes that these ligands regulate, they all operate through essentially the same pathway: A ligand binds to a type 2 receptor, which recruits and trans-phosphorylates a type I receptor. The type I receptor recruits a receptor regulated SMAD (R-SMAD) which it phosphorylates. The RSMAD then translocates to the nucleus where it functions as a transcription factor.

Function

Several ligands that signal through the activin type 2 receptors regulate muscle growth. [1] Myostatin, a TGF-beta superfamily member, is a negative regulator of muscle growth. [1] Myostatin binds to ACVR2B and to a lesser extent ACVR2A. In mice that were ACVR2A −/− (null) mutants there was an increase in all four muscle groups studied (pectoralis, triceps, quadriceps, and gastrocnemious/plantaris muscles). [1] Two of these muscle groups (pectoralis and triceps) were increased in ACVR2B −/− (null) mutants. [1]

Activin plays a significant role in reproduction. ACVR2 receptors are present in the testis during testicular development. [2] ACR2A and ACVR2B was found to be localized primarily in the gonocytes as well as in sertoli cells. [2] These cells are responsive to both autocrine and paracrine activin B signaling, which controls their proliferation. [2] Cells of the epididymis also have ACVR2A receptors present. ACVR2B receptors were found to be localized in the rete testis. [2]

Clinical significance

The ACVR2 gene is often found inactivated in prostate cancer and tumors with microsatellite instability. [3]

In a lab, it has been shown that truncated mutations in the ACVR2 gene causes a significant reduction in activin mediated cell signaling. In 58.1% of microsatellite unstable (MSI-H) colorectal cancers the ACVR2A gene has been found mutated. It also plays a role in non-MSI-H colorectal cancers. [4]

Inhibitors

Related Research Articles

<span class="mw-page-title-main">Paracrine signaling</span>

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">Myostatin</span> Mammalian and avian protein

Myostatin is a protein that in humans is encoded by the MSTN gene. Myostatin is a myokine that is produced and released by myocytes and acts on muscle cells to inhibit muscle growth. Myostatin is a secreted growth differentiation factor that is a member of the TGF beta protein family.

<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.

<span class="mw-page-title-main">Mothers against decapentaplegic homolog 3</span> Protein-coding gene in humans

Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.

<span class="mw-page-title-main">Mothers against decapentaplegic homolog 7</span> Protein-coding gene in the species Homo sapiens

Mothers against decapentaplegic homolog 7 or SMAD7 is a protein that in humans is encoded by the SMAD7 gene.

Smads comprise a family of structurally similar proteins that are the main signal transducers for receptors of the transforming growth factor beta (TGF-B) superfamily, which are critically important for regulating cell development and growth. The abbreviation refers to the homologies to the Caenorhabditis elegans SMA and MAD family of genes in Drosophila.

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">Follistatin</span> Mammalian protein found in Homo sapiens

Follistatin also known as activin-binding protein is a protein that in humans is encoded by the FST gene. Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals.

<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 the species Homo sapiens

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

<span class="mw-page-title-main">ACVR1</span> Protein-coding gene

Activin A receptor, type I (ACVR1) is a protein which in humans is encoded by the ACVR1 gene; also known as ALK-2. ACVR1 has been linked to the 2q23-24 region of the genome. 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 disease characterized by the formation of heterotopic bone throughout the body. It is a bone morphogenetic protein receptor, type 1.

<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">Endoglin</span> Protein-coding gene in the species Homo sapiens

Endoglin (ENG) is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex. It is also commonly referred to as CD105, END, FLJ41744, HHT1, ORW and ORW1. It has a crucial role in angiogenesis, therefore, making it an important protein for tumor growth, survival and metastasis of cancer cells to other locations in the body.

<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">ACVRL1</span> Protein-coding gene in the species Homo sapiens

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

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

Inhibin beta C chain is a protein that in humans is encoded by the INHBC gene.

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

Inhibin, beta B, also known as INHBB, is a protein which in humans is encoded by the INHBB gene. INHBB is a subunit of both activin and inhibin, two closely related glycoproteins with opposing biological effects.

<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.

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.

References

  1. 1 2 3 4 Lee SJ, Reed LA, Davies MV, Girgenrath S, Goad ME, Tomkinson KN, Wright JF, Barker C, Ehrmantraut G, Holmstrom J, Trowell B, Gertz B, Jiang MS, Sebald SM, Matzuk M, Li E, Liang LF, Quattlebaum E, Stotish RL, Wolfman NM (December 2005). "Regulation of muscle growth by multiple ligands signaling through activin type II receptors". Proc. Natl. Acad. Sci. U.S.A. 102 (50): 18117–22. Bibcode:2005PNAS..10218117L. doi: 10.1073/pnas.0505996102 . PMC   1306793 . PMID   16330774.
  2. 1 2 3 4 Anderson RA, Cambray N, Hartley PS, McNeilly AS (June 2002). "Expression and localization of inhibin alpha, inhibin/activin betaA and betaB and the activin type II and inhibin beta-glycan receptors in the developing human testis". Reproduction. 123 (6): 779–88. doi: 10.1530/rep.0.1230779 . PMID   12052232.
  3. Rossi MR, Ionov Y, Bakin AV, Cowell JK (December 2005). "Truncating mutations in the ACVR2 gene attenuates activin signaling in prostate cancer cells". Cancer Genet. Cytogenet. 163 (2): 123–9. doi:10.1016/j.cancergencyto.2005.05.007. PMID   16337854.
  4. Olaru A, Mori Y, Yin J, Wang S, Kimos MC, Perry K, Xu Y, Sato F, Selaru FM, Deacu E, Sterian A, Shibata D, Abraham JM, Meltzer SJ (December 2003). "Loss of heterozygosity and mutational analyses of the ACTRII gene locus in human colorectal tumors". Lab. Invest. 83 (12): 1867–71. doi: 10.1097/01.LAB.0000106723.75567.72 . PMID   14691305.
  5. New Myostatin Blocker Makes Mouse Muscles 60 Percent Larger Archived 2007-09-27 at the Wayback Machine , MDA Research News, January 6, 2006