Activin and inhibin explained

inhibin, alpha
Hgncid:6065
Symbol:INHA
Entrezgene:3623
Omim:147380
Refseq:NM_002191
Uniprot:P05111
Chromosome:2
Arm:q
Band:33-qter
Altsymbols:activin A
Hgncid:6066
Chromosome:7
Arm:p
Locussupplementarydata:15-p13
Omim:147290
Entrezgene:3624
Refseq:NM_002192
Uniprot:P08476
Altsymbols:activin B
Hgncid:6067
Chromosome:2
Locussupplementarydata:cen-q13
Omim:147390
Entrezgene:3625
Refseq:NM_002193
Uniprot:P09529
inhibin, beta C
Hgncid:6068
Symbol:INHBC
Altsymbols:activin C
Entrezgene:3626
Omim:601233
Refseq:NM_005538
Uniprot:P55103
Chromosome:12
Arm:q
Band:13
inhibin, beta E
Hgncid:24029
Symbol:INHBE
Altsymbols:activin E
Entrezgene:83729
Omim:612031
Refseq:NM_031479
Uniprot:P58166
Chromosome:12
Arm:q
Band:13.2

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.

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.[9] 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:

ClassActivityComplexDimer subunits
12
Inhibininhibits FSH secretionInhibin AαβA
Inhibin BαβB
Activinstimulates FSH secretionActivin AβAβA
Activin ABβAβB
Activin BβBβB

The alpha and beta subunits share approximately 25% sequence similarity, whereas the similarity between beta subunits is approximately 65%.[10]

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:

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 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. Activin A promotes the proliferation of adipocyte progenitor cells, while inhibiting their differentiation into adipocytes.[20] 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.[21] 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 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]

External links

Notes and References

  1. Vale W, Rivier J, Vaughan J, McClintock R, Corrigan A, Woo W, Karr D, Spiess J . Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid . Nature . 321 . 6072 . 776–9 . 1986 . 3012369 . 10.1038/321776a0 . 1986Natur.321..776V . 4365045 .
  2. Ling N, Ying SY, Ueno N, Shimasaki S, Esch F, Hotta M, Guillemin R . Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin . Nature . 321 . 6072 . 779–82 . 1986 . 3086749 . 10.1038/321779a0 . 1986Natur.321..779L . 38100413 .
  3. Chen YG, Wang Q, Lin SL, Chang CD, Chuang J, Chung J, Ying SY . Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis . Experimental Biology and Medicine . 231 . 5 . 534–44 . May 2006 . 16636301 . 10.1177/153537020623100507 . 39050907 .
  4. Sulyok S, Wankell M, Alzheimer C, Werner S . Activin: an important regulator of wound repair, fibrosis, and neuroprotection . Molecular and Cellular Endocrinology . 225 . 1–2 . 127–32 . October 2004 . 15451577 . 10.1016/j.mce.2004.07.011 . 6943949 .
  5. van Zonneveld P, Scheffer GJ, Broekmans FJ, Blankenstein MA, de Jong FH, Looman CW, Habbema JD, te Velde ER . 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 . 12615813 . 10.1093/humrep/deg138 . free .
  6. Makanji Y, Zhu J, Mishra R, Holmquist C, Wong WP, Schwartz NB, Mayo KE, Woodruff TK . Inhibin at 90: from discovery to clinical application, a historical review . Endocrine Reviews . 35 . 5 . 747–94 . October 2014 . 25051334 . 10.1210/er.2014-1003 . 4167436.
  7. Burger HG, Igarashi M . Inhibin: definition and nomenclature, including related substances . The Journal of Clinical Endocrinology and Metabolism . 66 . 4 . 885–6 . April 1988 . 3346366 .
  8. Robertson DM, Burger HG, Fuller PJ . 12202820 . Inhibin/activin and ovarian cancer . Endocrine-Related Cancer . 11 . 1 . 35–49 . March 2004 . 15027884 . 10.1677/erc.0.0110035 . free .
  9. Ying SY . Inhibins and activins: chemical properties and biological activity . Proceedings of the Society for Experimental Biology and Medicine . 186 . 3 . 253–64 . December 1987 . 3122219 . 10.3181/00379727-186-42611a . 36872324 .
  10. Kingsley DM . 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 . 8299934 . 10.1101/gad.8.2.133 . free .
  11. Xu P, Hall AK . The role of activin in neuropeptide induction and pain sensation . Developmental Biology . 299 . 2 . 303–9 . November 2006 . 16973148 . 10.1016/j.ydbio.2006.08.026 .
  12. Deli A, Kreidl E, Santifaller S, Trotter B, Seir K, Berger W, Schulte-Hermann R, Rodgarkia-Dara C, Grusch M . Activins and activin antagonists in hepatocellular carcinoma . World Journal of Gastroenterology . 14 . 11 . 1699–709 . March 2008 . 18350601 . 2695910 . 10.3748/wjg.14.1699 . free .
  13. Mellor SL, Cranfield M, Ries R, Pedersen J, Cancilla B, de Kretser D, Groome NP, Mason AJ, Risbridger GP . 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 . 10.1210/jcem.85.12.7052 . 11134153 . free .
  14. Bamberger . Casimir . Schärer . Agnes . Antsiferova . Maria . Tychsen . Birte . Pankow . Sandra . Müller . Mischa . Rülicke . Thomas . Paus . Ralf . Werner . Sabine . 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 . 2021-03-09 . 733–747 . 16127153 . 10.1016/S0002-9440(10)62047-0 . 1698729 .
  15. Pauklin S, Vallier L . Activin/Nodal signalling in stem cells . Development . 142 . 4 . 607–19 . 2015 . 25670788 . 10.1242/dev.091769 . free .
  16. Luisi S, Florio P, Reis FM, Petraglia F . Inhibins in female and male reproductive physiology: role in gametogenesis, conception, implantation and early pregnancy . Human Reproduction Update . 11 . 2 . 123–35 . 2005 . 15618291 . 10.1093/humupd/dmh057 .
  17. Book: Le T, Bhushan V, Hofmann J . First Aid for the USMLE Step 1 . limited . 2012 . McGraw Hill . 534 . 978-0-07-177636-3 .
  18. Skinner MK, McLachlan RI, Bremner WJ . Stimulation of Sertoli cell inhibin secretion by the testicular paracrine factor PModS . Molecular and Cellular Endocrinology . 66 . 2 . 239–49 . October 1989 . 2515083 . 10.1016/0303-7207(89)90036-1 . 1773/4395 . 21885326 . free .
  19. Meachem SJ, Nieschlag E, Simoni M . Inhibin B in male reproduction: pathophysiology and clinical relevance . European Journal of Endocrinology. 145 . 5 . 561–71 . November 2001 . 11720872 . 10.1530/eje.0.1450561 . free .
  20. Zaragosi LE, Wdziekonski B, Villageois P, Keophiphath M, Maumus M, Tchkonia T, Bourlier V, Mohsen-Kanson T, Ladoux A, Elabd C, Scheideler M, Trajanoski Z, Takashima Y, Amri EZ, Lacasa D, Sengenes C, Ailhaud G, Clément K, Bouloumie A, Kirkland JL, Dani C . Activin a plays a critical role in proliferation and differentiation of human adipose progenitors . . 59 . 10 . 2513–2521 . 2010 . 10.2337/db10-0013 . 3279533 . 20530742 .
  21. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS . 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 . 16642017 . 10.1038/ng1783 . 41579747 .
  22. Web site: Regeneron scientists discover key to excess bone growth in rare disease . Julie Steenhuysen . Reuters . 2 September 2015.
  23. Taylor KR, Mackay A, Truffaux N, Butterfield YS, Morozova O, Philippe C, Castel D, Grasso CS, Vinci M, Carvalho D, Carcaboso AM, de Torres C, Cruz O, Mora J, Entz-Werle N, Ingram WJ, Monje M, Hargrave D, Bullock AN, Puget S, Yip S, Jones C, Grill J . Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma . Nature Genetics . 46 . 5 . 457–61 . May 2014 . 24705252 . 4018681 . 10.1038/ng.2925 .
  24. Web site: Cure Brain Cancer - News - Multiple Breakthroughs in Childhood Brain Cancer DIPG . Cure Brain Cancer Foundation .
  25. Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M, Morrison A, Lewis P, Bouffet E, Bartels U, Zuccaro J, Agnihotri S, Ryall S, Barszczyk M, Chornenkyy Y, Bourgey M, Bourque G, Montpetit A, Cordero F, Castelo-Branco P, Mangerel J, Tabori U, Ho KC, Huang A, Taylor KR, Mackay A, Bendel AE, Nazarian J, Fangusaro JR, Karajannis MA, Zagzag D, Foreman NK, Donson A, Hegert JV, Smith A, Chan J, Lafay-Cousin L, Dunn S, Hukin J, Dunham C, Scheinemann K, Michaud J, Zelcer S, Ramsay D, Cain J, Brennan C, Souweidane MM, Jones C, Allis CD, Brudno M, Becher O, Hawkins C . Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations . Nature Genetics . 46 . 5 . 451–6 . May 2014 . 24705254 . 10.1038/ng.2936 . 3997489.
  26. Lidbury BA, Kita B, Lewis DP, Hayward S, Ludlow H, Hedger MP, de Kretser DM . 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 . 28302133 . 5353946 . 10.1186/s12967-017-1161-4 . free .
  27. Donovan P, Dubey OA, Kallioinen S, Rogers KW, Muehlethaler K, Müller P, Rimoldi D, Constam DB . Paracrine Activin-A Signaling Promotes Melanoma Growth and Metastasis through Immune Evasion . The Journal of Investigative Dermatology . 137 . 12 . 2578–2587 . December 2017 . 28844941 . 10.1016/j.jid.2017.07.845 . free .
  28. Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, Groome NP, Macri JN, Connor JM . 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 . 8606718 . 10.1056/NEJM199605093341904 . free .
  29. Robertson DM, Pruysers E, Jobling T . Inhibin as a diagnostic marker for ovarian cancer . Cancer Letters . 249 . 1 . 14–7 . April 2007 . 17320281 . 10.1016/j.canlet.2006.12.017 .
  30. Robertson DM, Pruysers E, Burger HG, Jobling T, McNeilage J, Healy D . Inhibins and ovarian cancer . Molecular and Cellular Endocrinology . 225 . 1–2 . 65–71 . October 2004 . 15451569 . 10.1016/j.mce.2004.02.014 . 33801243 .
  31. Myers GM, Lambert-Messerlian GM, Sigman M . Inhibin B reference data for fertile and infertile men in Northeast America . Fertility and Sterility . 92 . 6 . 1920–3 . December 2009 . 19006797 . 10.1016/j.fertnstert.2008.09.033 . free .
  32. Toulis KA, Iliadou PK, Venetis CA, Tsametis C, Tarlatzis BC, Papadimas I, Goulis DG . 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 . 20601364 . 10.1093/humupd/dmq024 . free .

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