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.
Contents |
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
- ↑ 1.0 1.1 1.2 1.3 (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.
- ↑ 2.0 2.1 2.2 2.3 (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.
- ↑ 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.
- ↑ 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.
- ↑ New Myostatin Blocker Makes Mouse Muscles 60 Percent Larger, MDA Research News, January 6, 2006
Cell signaling: TGF beta signaling pathway | |
|---|---|
| TGF beta superfamily of ligands | TGF beta family (TGF-β1, TGF-β2, TGF-β3) Bone morphogenetic proteins (BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10 , BMP15) Growth differentiation factors (GDF1, GDF2, GDF3, GDF5, GDF6, GDF7, Myostatin/GDF8, GDF9, GDF10, GDF11, GDF15) Other (Activin A and B/Inhibin A and B, Anti-müllerian hormone, Nodal) |
| TGF beta receptors | TGFBR1: Activin type 1 receptors (ACVR1, ACVR1B, ACVR1C) - ACVRL1 - BMPR1 (BMPR1A - BMPR1B) TGFBR2: Activin type 2 receptors (ACVR2A, ACVR2B) - AMHR2 - BMPR2 TGFBR3: betaglycan |
| Transducers/SMAD | R-SMAD (SMAD1, SMAD2, SMAD3, SMAD5, SMAD9) - I-SMAD (SMAD6, SMAD7) - SMAD4 |
| Ligand Inhibitors | Cerberus - Chordin - DAN - Decorin - Follistatin - Gremlin - Lefty - LTBP1 - Noggin - THBS1 |
| Coreceptors | BAMBI - Cripto |
| Other | SARA |
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