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Activins Family

Overview

Activins, members of the TGF-beta superfamily, are disulfide-linked dimeric proteins originally purified from gonadal fluids as proteins that stimulated pituitary follicle stimulating hormone (FSH) release. 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.

Activins Structure

Activin is a dimer composed of two identical or very similar beta subunits. However, in contrast to activin, the second component of the inhibin dimer is a more distantly-related alpha subunit. The activin protein complexes are both dimeric in structure, and, in each complex, the two monomers are linked to one another by a single disulfide bond. The following is a list of the most common activin complexes and their subunit composition:

Table 1. Activin complexes and their subunit composition

Class Activity Complex Dimer subunits
1 2
Activin stimulates FSH secretion Activin A βA βA
Activin AB βA βB
Activin B βB βB

In mammals, four beta subunits have been described, called activin βA, activin βB, activin βC and activin βE. A fifth subunit, activin βD, has been described in Xenopus laevis. Two activin βA subunits give rise to activin A, one βA, and one βB subunit gives rise to activin AB, and so on. Various, but not all theoretically possible, heterodimers have been described. The subunits are linked by a single covalent disulfide bond. The βC subunit is able to form activin heterodimers with βA or βB subunits.

Members of activins family

Table 2. Activins family related products

Activins Activin    
Activins Receptor Activin Receptor Type IA Activin RIIB ACVR1
ACVR1B ACVR1C ACVR2A
ACVR2B ACVRL1  
Activins Modulators Follistatin FSTL1 FSTL3
FSTL4 FSTL5  

Cellular functions

Activin is produced in the gonads, pituitary gland, placenta, and other organs:

  • In the ovarian follicle, activin increases FSH binding and FSH-induced aromatization. It participates in androgen synthesis enhancing LH action in the ovary and testis. In the male, activin enhances spermatogenesis.
  • Activin is strongly expressed in wounded skin, and overexpression of activin in epidermis of transgenic mice improves wound healing and enhances scar formation. Its action in wound repair and skin morphogenesis is through stimulation of keratinocytes and stromal cells in a dose-dependent manner.
  • Activin also regulates the morphogenesis of branching organs such as the prostate, lung, and especially the kidney. Activin A increases the expression level of type-I collagen suggesting that activin A acts as a potent activator of fibroblasts.
  • The lack of activin during development results in neural developmental defects.
  • The upregulation of Activin A drives pluripotent stem cells into a mesoendodermal fate, and thus provides a useful tool for stem cell differentiation and organoid formation.

Mechanism of action

As with other members of the superfamily, activins interact with two types of cell surface transmembrane receptors (Types I and II) which have intrinsic serine/threonine kinase activities in their cytoplasmic domains:

  • Activin type 1 receptors: ACVR1, ACVR1B, ACVR1C
  • Activin type 2 receptors: ACVR2A, ACVR2B

Activin binds to the Type II receptor and initiates a cascade reaction that leads to the recruitment, phosphorylation, and activation of Type I activin receptor. This then interacts with and then phosphorylates SMAD2 and SMAD3, two of the cytoplasmic SMAD proteins.

Smad3 then translocates to the nucleus and interacts with SMAD4 through multimerization, resulting in their modulation as transcription factor complexes responsible for the expression of a large variety of genes.

Role in disease

Activin A is more plentiful in the obese adipose tissue, compared to lean persons. Activin A promotes the proliferation of adipocyte progenitor cells, while inhibiting their differentiation into adipocytes. Activin A also increases inflammatory cytokines in macrophages.

A mutation in the gene for the activin receptor ACVR1 results in fibrodysplasia ossificans progressiva, a fatal disease that causes muscle and soft tissue to gradually be replaced by bone tissue. This condition is characterized by the formation of an extra skeleton that produces immobilization and eventually dies by suffocation. The mutation in ACVR1 causes activin A, which normally acts as an antagonist of the receptor and blocks osteogenesis (bone growth), to behave as an agonist of the receptor and to induce hyperactive bone growth. On 2 September 2015, Regeneron announced that they have developed an antibody for activin A that effectively cures the disease in an animal model of the condition.

Mutations in the ACVR1 gene have also been linked to cancer, especially diffuse intrinsic pontine glioma (DIPG).

In January 2017, the Journal of Translational Medicine reported that elevated Activin B levels with normal Activin A levels provided a biomarker for myalgic encephalomyelitis/chronic fatigue syndrome.

References:

1. Chen YG, Wang Q, Lin SL, et, al. "Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis". Experimental Biology and Medicine. May 2006; 231 (5): 534–44.
2. Sulyok S, Wankell M, Alzheimer C, et, al. "Activin: an important regulator of wound repair, fibrosis, and neuroprotection". Molecular and Cellular Endocrinology. October 2004; 225 (1–2): 127–32.
3. Xu P, Hall AK. "The role of activin in neuropeptide induction and pain sensation". Developmental Biology. November 2006; 299 (2): 303–9.
4. Pauklin S, Vallier L. "Activin/Nodal signalling in stem cells". Development. 2015; 142 (4): 607–19.

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