Biology:Activin and inhibin

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Short description: Regulators of feedback on FSH-production
inhibin, alpha
Identifiers
SymbolINHA
NCBI gene3623
HGNC6065
OMIM147380
RefSeqNM_002191
UniProtP05111
Other data
LocusChr. 2 q33-qter
inhibin, beta A
Peptide hormones - 2ARV.png
The Activin dimer, from 2ARV.pdb
Identifiers
SymbolINHBA
Alt. symbolsactivin A
NCBI gene3624
HGNC6066
OMIM147290
RefSeqNM_002192
UniProtP08476
Other data
LocusChr. 7 p15-p13
inhibin, beta B
Identifiers
SymbolINHBB
Alt. symbolsactivin B
NCBI gene3625
HGNC6067
OMIM147390
RefSeqNM_002193
UniProtP09529
Other data
LocusChr. 2 cen-q13
inhibin, beta C
Identifiers
SymbolINHBC
Alt. symbolsactivin C
NCBI gene3626
HGNC6068
OMIM601233
RefSeqNM_005538
UniProtP55103
Other data
LocusChr. 12 q13
inhibin, beta E
Identifiers
SymbolINHBE
Alt. symbolsactivin E
NCBI gene83729
HGNC24029
OMIM612031
RefSeqNM_031479
UniProtP58166
Other data
LocusChr. 12 q13.2

Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986,[1][2] 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,[3] metabolism, homeostasis, immune response, wound repair,[4] and endocrine function. Conversely, inhibin downregulates FSH synthesis and inhibits FSH secretion.[5] 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.[6]

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.[7][8] 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 protein superfamily.[9]

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.[10] In addition, both complexes are derived from the same family of related genes and proteins but differ in their subunit composition.[7] 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%.[9]

In mammals, four beta subunits have been described, called activin βA, activin βB, activin βC and activin βE. Activin βA and βB are identical to the two beta subunits of inhibin. 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.[11][12] The subunits are linked by a single covalent disulfide bond.

The βC subunit is able to form activin heterodimers with βA or βB subunits but is unable to dimerize with inhibin α.[13]

Function

Activin

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.[14]
  • Activin also regulates the morphogenesis of branching organs such as the prostate, lung, and especially kidney. Activin A increased the expression level of type-I collagen 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 formation.[15]

Inhibin

In both females and males, inhibin inhibits FSH production. Inhibin does not inhibit the secretion of GnRH from the hypothalamus.[16][17] However, the overall mechanism differs between the sexes:

In females

Inhibin is produced in the gonads, pituitary gland, placenta, corpus luteum and other organs.

FSH stimulates the secretion of inhibin from the granulosa cells of the ovarian follicles in the ovaries. In turn, inhibin suppresses FSH.

  • Inhibin B reaches a peak in the early- to mid-follicular phase, 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,[18] located in the seminiferous tubules inside the testes. Androgens stimulate inhibin production; this protein may also help to locally regulate spermatogenesis.[19]

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 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.

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.[8]

Clinical significance

Activin

Activin A is more plentiful in the adipose tissue of obese, compared to lean persons.[20] Activin A promotes the proliferation of adipocyte progenitor cells, while inhibiting their differentiation into adipocytes.[20] Activin A also increases inflammatory cytokines in macrophages.[20]

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.[21] This condition is characterized by the formation of an extra skeleton that produces immobilization and eventually death by suffocation.[21] 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.[21] On 2 September 2015, Regeneron Pharmaceuticals announced that they had developed an antibody for activin A that effectively cures the disease in an animal model of the condition.[22]

Mutations in the ACVR1 gene have also been linked to cancer, especially diffuse intrinsic pontine glioma(DIPG).[23][24][25]

Elevated Activin B levels with normal Activin A levels provided a possible biomarker for myalgic encephalomyelitis / chronic fatigue syndrome.[26]

Activin A is overexpressed in many cancers. It was shown to promote tumorigenesis by hampering the adaptive anti-tumor immune response in melanoma.[27]

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.[28] 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.[29][30]

Inhibin B may be used as a marker of spermatogenesis function and male infertility. The mean serum inhibin B level is significantly higher among fertile men (approximately 140 pg/mL) than in infertile men (approximately 80 pg/mL).[31] In men with azoospermia, a positive test for inhibin B slightly raises the chances for successfully achieving pregnancy through testicular sperm extraction (TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval [CI]: 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.[32]

References

  1. ↑ "Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid". Nature 321 (6072): 776–9. 1986. doi:10.1038/321776a0. PMID 3012369. Bibcode: 1986Natur.321..776V. 
  2. ↑ "Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin". Nature 321 (6072): 779–82. 1986. doi:10.1038/321779a0. PMID 3086749. Bibcode: 1986Natur.321..779L. 
  3. ↑ "Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis". Experimental Biology and Medicine 231 (5): 534–44. May 2006. doi:10.1177/153537020623100507. PMID 16636301. http://www.ebmonline.org/cgi/pmidlookup?view=long&pmid=16636301. 
  4. ↑ "Activin: an important regulator of wound repair, fibrosis, and neuroprotection". Molecular and Cellular Endocrinology 225 (1–2): 127–32. October 2004. doi:10.1016/j.mce.2004.07.011. PMID 15451577. 
  5. ↑ "Do cycle disturbances explain the age-related decline of female fertility? Cycle characteristics of women aged over 40 years compared with a reference population of young women". Human Reproduction 18 (3): 495–501. March 2003. doi:10.1093/humrep/deg138. PMID 12615813. 
  6. ↑ "Inhibin at 90: from discovery to clinical application, a historical review". Endocrine Reviews 35 (5): 747–94. October 2014. doi:10.1210/er.2014-1003. PMID 25051334. 
  7. ↑ 7.0 7.1 "Inhibin: definition and nomenclature, including related substances". The Journal of Clinical Endocrinology and Metabolism 66 (4): 885–6. April 1988. PMID 3346366. 
  8. ↑ 8.0 8.1 "Inhibin/activin and ovarian cancer". Endocrine-Related Cancer 11 (1): 35–49. March 2004. doi:10.1677/erc.0.0110035. PMID 15027884. 
  9. ↑ 9.0 9.1 "The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms". Genes & Development 8 (2): 133–46. Jan 1994. doi:10.1101/gad.8.2.133. PMID 8299934. 
  10. ↑ "Inhibins and activins: chemical properties and biological activity". Proceedings of the Society for Experimental Biology and Medicine 186 (3): 253–64. December 1987. doi:10.3181/00379727-186-42611a. PMID 3122219. 
  11. ↑ "The role of activin in neuropeptide induction and pain sensation". Developmental Biology 299 (2): 303–9. November 2006. doi:10.1016/j.ydbio.2006.08.026. PMID 16973148. 
  12. ↑ "Activins and activin antagonists in hepatocellular carcinoma". World Journal of Gastroenterology 14 (11): 1699–709. March 2008. doi:10.3748/wjg.14.1699. PMID 18350601. 
  13. ↑ "Localization of activin beta(A)-, beta(B)-, and beta(C)-subunits in humanprostate and evidence for formation of new activin heterodimers of beta(C)-subunit". The Journal of Clinical Endocrinology and Metabolism 85 (12): 4851–8. December 2000. doi:10.1210/jcem.85.12.7052. PMID 11134153. 
  14. ↑ Bamberger, Casimir; Schärer, Agnes; Antsiferova, Maria; Tychsen, Birte; Pankow, Sandra; Müller, Mischa; Rülicke, Thomas; Paus, Ralf et al. (2021-03-09). "Activin Controls Skin Morphogenesis and Wound Repair Predominantly via Stromal Cells and in a Concentration-Dependent Manner via Keratinocytes". The American Journal of Pathology 167 (3): 733–747. doi:10.1016/S0002-9440(10)62047-0. PMID 16127153. 
  15. ↑ "Activin/Nodal signalling in stem cells". Development 142 (4): 607–19. 2015. doi:10.1242/dev.091769. PMID 25670788. 
  16. ↑ "Inhibins in female and male reproductive physiology: role in gametogenesis, conception, implantation and early pregnancy". Human Reproduction Update 11 (2): 123–35. 2005. doi:10.1093/humupd/dmh057. PMID 15618291. 
  17. ↑ First Aid for the USMLE Step 1. McGraw Hill. 2012. p. 534. ISBN 978-0-07-177636-3. https://archive.org/details/firstaidforusmle2011leta. 
  18. ↑ "Stimulation of Sertoli cell inhibin secretion by the testicular paracrine factor PModS". Molecular and Cellular Endocrinology 66 (2): 239–49. October 1989. doi:10.1016/0303-7207(89)90036-1. PMID 2515083. 
  19. ↑ "Inhibin B in male reproduction: pathophysiology and clinical relevance". European Journal of Endocrinology 145 (5): 561–71. November 2001. doi:10.1530/eje.0.1450561. PMID 11720872. 
  20. ↑ 20.0 20.1 20.2 "Activin a plays a critical role in proliferation and differentiation of human adipose progenitors". Diabetes 59 (10): 2513–2521. 2010. doi:10.2337/db10-0013. PMID 20530742. PMC 3279533. http://diabetes.diabetesjournals.org/content/59/10/2513.long. 
  21. ↑ 21.0 21.1 21.2 "A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva". Nature Genetics 38 (5): 525–527. May 2006. doi:10.1038/ng1783. PMID 16642017. 
  22. ↑ Julie Steenhuysen (2 September 2015). "Regeneron scientists discover key to excess bone growth in rare disease". Reuters. http://mobile.reuters.com/article/idUSKCN0R222Z20150902. 
  23. ↑ "Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma". Nature Genetics 46 (5): 457–61. May 2014. doi:10.1038/ng.2925. PMID 24705252. 
  24. ↑ "Cure Brain Cancer - News - Multiple Breakthroughs in Childhood Brain Cancer DIPG". Cure Brain Cancer Foundation. http://www.curebraincancer.org.au/news/1044/multiple-breakthroughs-in-childhood-brain-cancer. 
  25. ↑ "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations". Nature Genetics 46 (5): 451–6. May 2014. doi:10.1038/ng.2936. PMID 24705254. 
  26. ↑ "Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study". Journal of Translational Medicine 15 (1): 60. March 2017. doi:10.1186/s12967-017-1161-4. PMID 28302133. 
  27. ↑ "Paracrine Activin-A Signaling Promotes Melanoma Growth and Metastasis through Immune Evasion". The Journal of Investigative Dermatology 137 (12): 2578–2587. December 2017. doi:10.1016/j.jid.2017.07.845. PMID 28844941. 
  28. ↑ "Dimeric inhibin A as a marker for Down's syndrome in early pregnancy". The New England Journal of Medicine 334 (19): 1231–6. May 1996. doi:10.1056/NEJM199605093341904. PMID 8606718. 
  29. ↑ "Inhibin as a diagnostic marker for ovarian cancer". Cancer Letters 249 (1): 14–7. April 2007. doi:10.1016/j.canlet.2006.12.017. PMID 17320281. 
  30. ↑ "Inhibins and ovarian cancer". Molecular and Cellular Endocrinology 225 (1–2): 65–71. October 2004. doi:10.1016/j.mce.2004.02.014. PMID 15451569. 
  31. ↑ "Inhibin B reference data for fertile and infertile men in Northeast America". Fertility and Sterility 92 (6): 1920–3. December 2009. doi:10.1016/j.fertnstert.2008.09.033. PMID 19006797. 
  32. ↑ "Inhibin B and anti-Mullerian hormone as markers of persistent spermatogenesis in men with non-obstructive azoospermia: a meta-analysis of diagnostic accuracy studies". Human Reproduction Update 16 (6): 713–24. 2010. doi:10.1093/humupd/dmq024. PMID 20601364. 

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