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 ...
complex
Complex commonly refers to:
* Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe
** Complex system, a system composed of many components which may interact with each ...
es that have almost directly opposite biological effects. 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
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 c ...
,
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 could ...
,
wound repair
Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.
In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
,
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
Neena Betty Schwartz (December 10, 1926 – April 15, 2018) was an American endocrinologist and William Deering Professor of Endocrinology Emerita in the Department of Neurobiology at Northwestern University. She was best known for her work on ...
and
Cornelia Channing
Cornelia "Nina" Channing (1938–1985) was an American professor of physiology at the University of Maryland School of Medicine. Her research focused on endocrinology and fertility; along with longtime collaborators Neena Schwartz and Darrell Wa ...
's work in the mid-1970s, after which both proteins were molecularly characterized ten years later.
Activin is a
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
Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differen ...
,
bone morphogenetic protein, and
growth differentiation factor Growth differentiation factors (GDFs) are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in development.
Types
Several members of this subfamily have been described, and name ...
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 sign ...
protein
superfamily.
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 biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
.
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
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
, 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 ...
''. 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
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 ...
,
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 t ...
, activin increases FSH binding and FSH-induced
aromatization
Aromatization is a chemical reaction in which an aromatic system is formed from a single nonaromatic precursor. Typically aromatization is achieved by dehydrogenation of existing cyclic compounds, illustrated by the conversion of cyclohexane int ...
. It participates in
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
synthesis enhancing
LH action in the
ovary and
testis
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 testostero ...
. In the male, activin enhances
spermatogenesis.
* 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 de ...
, and overexpression of activin in
epidermis 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 n ...
formation. Its action in wound repair and skin
morphogenesis
Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...
is through stimulation of
keratinocyte
Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells.
Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...
s and
stromal cell
Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa ...
s in a dose-dependent manner.
* Activin also regulates the
morphogenesis
Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...
of branching organs such as the
prostate
The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, chemically, and phys ...
,
lung, 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
Type I collagen is the most abundant collagen of the human body. It forms large, eosinophilic fibers known as collagen fibers.
It is present in scar tissue, the end product when tissue heals by repair, as well as tendons, ligaments, the endomys ...
suggesting that activin A acts as a potent activator of
fibroblasts.
* Lack of activin during development results in neural developmental defects.
*Upregulation of Activin A drives pluripotent
stem cells 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 stem ...
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
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 sper ...
,
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 ...
,
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 cell
A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete (called an oocyte or egg) in the ovary of mammals.
Structure and function
In the primordial ovarian follicle, and la ...
s 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, and a second peak at
ovulation
Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...
.
* ''Inhibin A'' reaches its peak in the mid-
luteal phase
The corpus luteum (Latin for "yellow body"; plural corpora lutea) is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is th ...
.
Inhibin secretion is diminished by
GnRH
Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and releas ...
, and enhanced by
insulin-like growth factor
The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF " ...
-1 (IGF-1).
In males
It is secreted from the
Sertoli cell
Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis (the production of sperm) as a structural component of the seminiferous tubules. They are activated by follicle-stimu ...
s, located in the
seminiferous tubules
Seminiferous tubules are located within the testes, and are the specific location of meiosis, and the subsequent creation of male gametes, namely spermatozoa. Structure
The epithelium of the tubule consists of a type of sustentacular cells known ...
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
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
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.
Mechanism of action
Activin
As with other members of the superfamily, activins interact with two types of cell surface
transmembrane receptor
Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral me ...
s (Types I and II) which have intrinsic
serine/threonine kinase
A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human prote ...
activities in their cytoplasmic domains:
*
Activin type 1 receptors:
ACVR1
Activin A receptor, type I (ACVR1) is a protein which in humans is encoded by the ''ACVR1'' gene; also known as ALK-2 (activin receptor-like kinase-2). ACVR1 has been linked to the 2q23-24 region of the genome. This protein is important in the bo ...
,
ACVR1B,
ACVR1C
*
Activin type 2 receptors
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, ...
:
ACVR2A
Activin receptor type-2A is a protein that in humans is encoded by the ''ACVR2A'' gene.
ACVR2A is an activin type 2 receptor.
Function
This gene encodes activin A type II receptor. Activins are dimeric growth and differentiation factors which ...
,
ACVR2B
Activin receptor type-2B is a protein that in humans is encoded by the ''ACVR2B'' gene. ACVR2B is an activin type 2 receptor.
Function
Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-bet ...
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
Mothers against decapentaplegic homolog 2 also known as SMAD family member 2 or SMAD2 is a protein that in humans is encoded by the ''SMAD2'' gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the ''Dros ...
and
SMAD3
Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.
SMAD3 is a member of the SMAD family of proteins. It acts as a mediator of the signals initiated by t ...
, two of the cytoplasmic
SMAD proteins.
Smad3 then translocates to the nucleus and interacts with
SMAD4
SMAD4, also called SMAD family member 4, Mothers against decapentaplegic homolog 4, or DPC4 (Deleted in Pancreatic Cancer-4) is a highly conserved protein present in all metazoans. It belongs to the SMAD family of transcription factor proteins, ...
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
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...
of obese, compared to lean persons.
Activin A promotes the proliferation of
adipocyte progenitor cell
A progenitor cell is a biological cell that can differentiate into a specific cell type. Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than progenitor cells. Progenitor cells can only differ ...
s, 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 autocrin ...
s in
macrophages.
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 replication, DNA or viral repl ...
in the gene for the activin receptor
ACVR1
Activin A receptor, type I (ACVR1) is a protein which in humans is encoded by the ''ACVR1'' gene; also known as ALK-2 (activin receptor-like kinase-2). ACVR1 has been linked to the 2q23-24 region of the genome. This protein is important in the bo ...
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 mus ...
, 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
Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts funct ...
(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 the ...
for
activin A
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual c ...
that effectively cures the disease in an
animal model
An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...
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
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
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
Adaptation, in biology, is the process or trait by which organisms or population better match their environment
Adaptation may also refer to:
Arts
* Adaptation (arts), a transfer of a work of art from one medium to another
** Film adaptation, a ...
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
Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnant are almost ...
) 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 dis ...
. 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 c ...
.
Inhibin B may be used as a marker of
spermatogenesis 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