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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.

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. Myostatin, a TGF-beta superfamily member, is a negative regulator of muscle growth. 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). Two of these muscle groups (pectoralis and triceps) were increased in ACVR2B (null) mutants.

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

Clinical significance

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

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.

Inhibitors

• Stamulumab (MYO-029) myostatin Inhibitor

References

1. ^ 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. ^ 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

• Genes on human chromosome 2
• Genes on human chromosome 3
• GS domain
• TS domain
• S/T domain