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Activin type 2 receptors

From Wikipedia, the free encyclopedia
Protein family
activin A receptor, type IIA
Identifiers
SymbolACVR2A
Alt. symbolsACVR2
NCBI gene92
HGNC173
OMIM102581
RefSeqNM_001616
UniProtP27037
Other data
LocusChr. 2q22.2-23.3
Search for
StructuresSwiss-model
DomainsInterPro
activin A receptor, type IIB
Identifiers
SymbolACVR2B
NCBI gene93
HGNC174
OMIM602730
RefSeqNM_001106
UniProtQ13705
Other data
LocusChr. 3p22
Search for
StructuresSwiss-model
DomainsInterPro

Theactivin type 2 receptors belong to a largerTGF-beta receptor family and modulate signals fortransforming growth factor beta ligands. These receptors are involved in a host ofphysiological processes including,growth,cell differentiation,homeostasis,osteogenesis,apoptosis and many other functions. There are two activin type two receptors:ACVR2A andACVR2B.

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

Function

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Severalligands that signal through the activin type 2 receptors regulatemuscle 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, andgastrocnemious/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 thegonocytes as well as insertoli cells.[2] These cells are responsive to both autocrine and paracrine activin B signaling, which controls their proliferation.[2] Cells of theepididymis also have ACVR2A receptors present. ACVR2B receptors were found to be localized in the rete testis.[2]

Clinical significance

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The ACVR2 gene is often found inactivated inprostate cancer and tumors withmicrosatellite 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

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References

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  1. ^abcdLee 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. ^abcdAnderson 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 LargerArchived 2007-09-27 at theWayback Machine,MDA Research News, January 6, 2006
TGF beta superfamily of ligands
Ligand ofACVR orTGFBR
Ligand ofBMPR
TGF beta receptors
(Activin,BMP,family)
TGFBR1:
TGFBR2:
TGFBR3:
Transducers/SMAD
Ligand inhibitors
Coreceptors
Other
Type I cytokine receptor
Receptor protein serine/threonine kinase
Receptor tyrosine kinase
Tumor necrosis factor receptor
Ig superfamily
Other/ungrouped
Type I
ALK1 (ACVRL1)
ALK2 (ACVR1A)
ALK3 (BMPR1A)
ALK4 (ACVR1B)
ALK5 (TGFβR1)
ALK6 (BMPR1B)
ALK7 (ACVR1C)
Type II
TGFβR2
BMPR2
ACVR2A (ACVR2)
ACVR2B
AMHR2 (AMHR)
Type III
TGFβR3 (β-glycan)
Unsorted
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