Activin type 2 receptors

The Activin type 2 receptors modulate signals for ligands belonging to the Transforming growth factor beta superfamily of ligands. These include: Activin (or Inhibin), Bone morphogenetic proteins and Nodal. They 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 two receptor, which recruits and trans-phosphorylate 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.

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Functions

Several ligands that signal through the Activin type II 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].

Disease

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

In the 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]

Related

• Stamulumab (MYO-029) Myostatin Inhibitor^[5]

References

1. ^ ^{a b c d} (Dec 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. Entrez PubMed 16330774.
2. ^ ^{a b c d} (Jun 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" (pdf). Reproduction. 123 (6). Retrieved on 2006-07-11.
3. ^ Rossi MR, Ionov Y, Bakin AV, Cowell JK (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, et al (2003). "Loss of heterozygosity and mutational analyses of the ACTRII gene locus in human colorectal tumors". Lab. Invest. 83 (12): 1867–71. PMID 14691305.
5. ^ New Myostatin Blocker Makes Mouse Muscles 60 Percent Larger, MDA Research News, January 6, 2006