Activin and inhibin are two closely related
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
complexes that have almost directly opposite biological effects. Identified in 1986,
activin enhances
FSH biosynthesis
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecul ...
and
secretion 440px
Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classic ...
, and participates in the regulation of the
menstrual cycle
The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs ...
. Many other functions have been found to be exerted by activin, including roles in cell proliferation,
differentiation,
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
,
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...
,
homeostasis
In biology, homeostasis ( British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
,
immune response
An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which coul ...
,
wound repair,
and
endocrine function. Conversely, inhibin downregulates FSH synthesis and inhibits FSH secretion. The existence of inhibin was hypothesized as early as 1916; however, it was not demonstrated to exist until
Neena Schwartz and
Cornelia Channing's work in the mid-1970s, after which both proteins were molecularly characterized ten years later.
Activin is a
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ( ...
composed of two identical or very similar beta subunits. Inhibin is also a dimer wherein the first component is a beta subunit similar or identical to the beta subunit in activin. However, in contrast to activin, the second component of the inhibin dimer is a more distantly-related alpha subunit.
Activin, inhibin and a number of other structurally related proteins such as
anti-Müllerian hormone,
bone morphogenetic protein, and
growth differentiation factor belong to the
TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other s ...
protein
superfamily
SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilies. Domains are functional, str ...
.
Structure
The activin and inhibin protein complexes are both dimeric in structure, and, in each complex, the two monomers are linked to one another by a single
disulfide bond.
In addition, both complexes are derived from the same family of related genes and proteins but differ in their subunit composition.
Below is a list of the most common inhibin and activin complexes and their subunit composition:
The alpha and beta subunits share approximately 25%
sequence similarity, whereas the similarity between beta subunits is approximately 65%.
In mammals, four beta subunits have been described, called activin β
A, activin β
B, activin β
C and activin β
E. Activin β
A and β
B are identical to the two beta subunits of inhibin. A fifth subunit, activin β
D, has been described in ''
Xenopus laevis
The African clawed frog (''Xenopus laevis'', also known as the xenopus, African clawed toad, African claw-toed frog or the ''platanna'') is a species of African aquatic frog of the family Pipidae. Its name is derived from the three short claws o ...
''. Two activin β
A subunits give rise to activin A, one β
A, and one β
B 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 β
A or β
B subunits but is unable to dimerize with inhibin α.
Function
Activin
Activin is produced in the
gonad
A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sp ...
s,
pituitary gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The h ...
,
placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
, and other organs:
* In the
ovarian follicle
An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with ...
, activin increases FSH binding and FSH-induced
aromatization. It participates in
androgen synthesis enhancing
LH action in the
ovary
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. ...
and
testis. In the male, activin enhances
spermatogenesis
Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubu ...
.
* Activin is strongly expressed in wounded
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different ...
, and overexpression of activin in
epidermis
The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rel ...
of
transgenic mice improves wound healing and enhances
scar
A scar (or scar tissue) is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a ...
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
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of ...
, and especially
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
. Activin A increased the expression level of
type-I collagen suggesting that activin A acts as a potent activator of
fibroblast
A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...
s.
* Lack of activin during development results in neural developmental defects.
*Upregulation of Activin A drives pluripotent
stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...
s into a mesoendodermal fate, and thus provides a useful tool for stem cell
differentiation and
organoid
An organoid is a miniaturized and simplified version of an organ produced in vitro in three dimensions that shows realistic micro-anatomy. They are derived from one or a few cells from a tissue, embryonic stem cells or induced pluripotent ste ...
formation.
Inhibin
In both females and males, inhibin inhibits
FSH production. Inhibin does not inhibit the secretion of GnRH from the hypothalamus.
However, the overall mechanism differs between the sexes:
In females
Inhibin is produced in the
gonads,
pituitary gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The h ...
,
placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
,
corpus luteum and other organs.
FSH stimulates the secretion of inhibin from the
granulosa cells of the ovarian follicles in the
ovaries
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
. In turn, inhibin suppresses FSH.
* ''Inhibin B'' reaches a peak in the early- to mid-
follicular phase
The follicular phase, also known as the preovulatory phase or proliferative phase, is the phase of the estrous cycle (or, in primates for example, the menstrual cycle) during which follicles in the ovary mature from primary follicle to a fully ...
, and a second peak at
ovulation.
* ''Inhibin A'' reaches its peak in the mid-
luteal phase.
Inhibin secretion is diminished by
GnRH, and enhanced by
insulin-like growth factor-1 (IGF-1).
In males
It is secreted from the
Sertoli cells, located in the
seminiferous tubules inside the
testes
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoste ...
.
Androgens stimulate inhibin production; this
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
may also help to locally regulate
spermatogenesis
Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubu ...
.
Mechanism of action
Activin
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
Activin receptor type-1B is a protein that in humans is encoded by the ''ACVR1B'' gene.
ACVR1B or ALK-4 acts as a transducer of activin or activin-like ligands (e.g., inhibin) signals. Activin binds to either ACVR2A or ACVR2B and then forms a c ...
,
ACVR1C
The activin A receptor also known as ACVR1C or ALK-7 is a protein that in humans is encoded by the ACVR1C gene. ACVR1C is a type I receptor for the TGFB family of signaling molecules.
ACVR1C transduces signals of Nodal. Nodal binds to ACVR2B ...
*
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
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
complexes responsible for the expression of a large variety of genes.
Inhibin
In contrast to activin, much less is known about the mechanism of action of inhibin, but may involve competing with activin for binding to activin receptors and/or binding to inhibin-specific receptors.
Clinical significance
Activin
Activin A is more plentiful in the
adipose tissue of obese, compared to lean persons.
Activin A promotes the proliferation of
adipocyte
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
progenitor cells, while inhibiting their
differentiation into adipocytes.
Activin A also increases inflammatory
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s in
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
s.
A
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
in the gene for the activin receptor
ACVR1 results in
fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva (; FOP; also called Münchmeyer disease and formerly called myositis ossificans progressiva or Stoneman disease) is an extremely rare connective tissue disease in which fibrous connective tissue such as mu ...
, 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 death 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 Pharmaceuticals
Regeneron Pharmaceuticals, Inc. is an American biotechnology company headquartered in Westchester County, New York. The company was founded in 1988. Originally focused on neurotrophic factors and their regenerative capabilities, giving rise to ...
announced that they had developed an
antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of t ...
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).
Elevated Activin B levels with normal Activin A levels provided a possible
biomarker for
myalgic encephalomyelitis/chronic fatigue syndrome.
Activin A is overexpressed in many
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s. It was shown to promote
tumorigenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
by hampering the
adaptive anti-tumor immune response in
melanoma.
Inhibin
Quantification of inhibin A is part of the prenatal
quad screen that can be administered during pregnancy at a gestational age of 16–18 weeks. An elevated inhibin A (along with an increased
beta-hCG, decreased
AFP, and a decreased
estriol) is suggestive of the presence of a fetus with
Down syndrome
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual d ...
. As a screening test, abnormal quad screen test results need to be followed up with more definitive tests.
It also has been used as a marker for
ovarian cancer
Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...
.
Inhibin B may be used as a marker of
spermatogenesis
Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubu ...
function and
male infertility
Male infertility refers to a sexually mature male's inability to impregnate a fertile female. In humans it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen ...
. The mean serum inhibin B level is significantly higher among fertile men (approximately 140 pg/mL) than in infertile men (approximately 80 pg/mL).
In men with
azoospermia
Azoospermia is the medical condition of a man whose semen contains no sperm. It is associated with male infertility, but many forms are amenable to medical treatment. In humans, azoospermia affects about 1% of the male population and may be seen ...
, a positive test for inhibin B slightly raises the chances for successfully achieving pregnancy through
testicular sperm extraction
Testicular sperm extraction (TESE) is a surgical procedure in which a small portion of tissue is removed from the testicle and any viable sperm cells from that tissue are extracted for use in further procedures, most commonly intracytoplasmic sperm ...
(TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval
I 0.56–0.74) and a specificity of 0.83 (CI: 0.64–0.93) for prediction the presence of sperm in the testes in non-obstructive azoospermia.
References
External links
*
*
*
{{DEFAULTSORT:Activin And Inhibin
Mammal reproductive system
Hormones of the ovary
Peptide hormones
TGFβ domain
Human female endocrine system