Activin

SUBCHAPTER 33B

Activin Hiroyuki Kaneko

Abbreviation: none Additional names: erythroid differentiation factor (EDF)

Synthesis and Release

A member of transforming growth factor (TGF)-β superfamily, produced in a wide range of tissues. Exerts pluripotent effects on tissue growth and function in an autocrine/paracrine manner.

Each β-subunit is independently encoded. Gene location and the mRNAs encoding precursor proteins are described in subchapter 33A. In the promoter region, the bovine βA-subunit gene has an AP-2 binding site and the rat βB-subunit gene has SP1 and AP-2 binding sites.

Discovery Activin was initially isolated from follicular fluid as a stimulator for follicle-stimulating hormone (FSH) secretion in 1986 [1]. Also independently isolated from a human monocytic cell line (THP-1 cell) as a differentiation factor for erythroleukemic cells in 1987 [2].

Gene, mRNA, and Precursor

Tissue Distribution of mRNA βA- and βB-subunit genes are widely expressed (Table 33B.1). The βC-subunit gene is expressed in the liver, lung, epididymis, testis, ovary, uterus, pituitary, adrenal gland, and prostate. The βE-subunit gene is highly expressed in the liver.

Tissue Content Adult rat, testis, activin A, 150 (pg/testis).

Plasma Concentrations Structure Structural Features Activins are disulfide-linked dimers composed of βA- and βAsubunits (activin A), βB- and βB-subunits (activin B), or βAand βB-subunits (activin AB) (see Figure 33A.1 in Subchapter 33A). Mature βA- and βB-subunits have nine cysteine residues that are required for inter- and intramolecular disulfide bonds. Unlike the inhibin α-subunit, β-subunits lack glycosylation sites. Amino acid sequences of the mature βA- and βB-subunits are highly conserved among species (see E-Figures 33A.2 and 33A.3 in Subchapter 33A). Additionally, genes encoding the βC-subunit [3] and the βE-subunit [4] have been identified in mammals, and the βD-subunit gene [5] in Xenopus laevis, potentially giving rise to more activin/inhibin isoforms.

Primary Structure Amino acid sequences of the human β-subunits are shown in Figure 33A.2 in Subchapter 33A.

Properties Mr 25,000 28,000 (mature activin). Additional Mr forms (70,000 110,000) exist in follicular fluid due to the processing of the largest precursor form (Mr 110,000). These larger molecular species have no biological activity. pI 4.0 5.0. Stable in 8 M urea. Dissociated to two subunits in 2% (v/v) 2-mercaptoethanol.

Human menstrual 400 4000.

cycle

300 500

(pg/ml),

pregnancy

Regulation of Synthesis and Release FSH and cAMP enhance the expression of the βB-subunit gene in rat Sertoli cells and the βA-subunit gene in rat granulosa cells, less effectively as compared to the inhibin α-subunit gene. Bacterial lipopolysaccharide (LPS) or interleukin (IL)-1 promotes βA-subunit gene expression and activin A production in rat Sertoli cells and sheep monocytes. Table 33B.1 Expression of β-subunit mRNAs Cells or Tissues

mRNA

Species

hypothalamus pituitary cell granulosa cell follicle cell luteal cell endometrium early embryo

βA and βB βA and βB βA and βB βA and βB βA βA and βB βA βA, βB, and βD βA and βB βA and/or βB βA and βB βA and βB βA and βB βA and βB βB βA and βB βA βA

rat various mammals various mammals, zebrafish, goldfish human, primate human, primate, sheep cattle frog various mammals various mammals various mammals human human, sheep human human, rat human various mammals human

Sertoli cell Leydig cell male germ cell prostate adenocortex cell hepatocyte pancreas kidney bone marrow macrophage, T cell

Y. Takei, H. Ando, & K. Tsutsui (Eds): Handbook of Hormones. DOI: http://dx.doi.org/10.1016/B978-0-12-801028-0.00188-4 © 2016 Elsevier Inc. All rights reserved.

295

P A R T I Peptides and Proteins in Vertebrates

Figure 33B.1 Structure of activin receptor.

The expression of the βA-subunit gene in the adrenocortical cells is stimulated by adrenocorticotropic hormone (ACTH).

Receptors Structure and Subtype Two types of activin receptors are identified: type I (ActRIB, also known as activin receptor-like kinase 4 (ALK4) [6] and ActRIC (ALK7) [7]) and type II (ActRIIA [8] and ActRIIB [9]). Both types of activin receptors have approximately 500 aa residues, consisting of a cysteine rich extracellular domain (B110 aa residues) with ligand binding activity, a transmembrane domain (B26 aa residues), and an intracellular domain (B360 aa residues) that contains serine/threonine kinase activity (Figure 33B.1 and E-Figure 33B.1). The type II receptors bind activin with high affinity, but the type I receptor (ALK4) is unable to bind activin in the absence of the type II receptor.

Signal Transduction Pathway Activin binds primarily the type II receptor and cooperatively recruits the type I receptor, which forms a ternary receptor complex. In the receptor complex, the type II receptor phosphorylates and activates the type I receptor. The activated type I receptor then phosphorylates the cytoplasmic transcription factors, Smad2 and Smad3, resulting in the formation of a complex with Smad4. The Smad complex then moves to the nucleus, leading to activation or repression of target genes.

Agonists Recombinant and purified activins.

Antagonists Antibodies to ActRII, follistatin, follistatin-related protein-3 (FRP-3), inhibin.

Biological Functions

Table 33B.2 Effects of Activin on Various Cells or Tissues Cells or Tissues

Species

Effects

Ref

GnRH neuron gonadotroph somatotroph lactotrophs granulosa cell premature

cell line rat rat rat

mGnRH production mFSH production kbasal or GRF stimulated GH production, kTRH-stimulated PRL production

[10] [11] [12] [13]

mFSH-induced aromatase activity mFSH-induced progesterone production minhibin production mFSH receptor expression mproliferation mature kbasal or LH-stimulated progesterone production luteinized human anti-luteinization (FSH receptorm, LH receptork) theca cell rat kLH-induced androgen production oocyte zebrafish mgerminal vesicle breakdown (GVBD) rat mGVBD embryo frog mesodermal and neural tissue induction cattle mearly embryonic development Sertoli cell rat mproliferation Leydig cell rat kLH-induced androgen production spermatogonia rat mDNA synthesis bone marrow human mcolony formation of erythroid and multipotential progenitor cells endothelial human kproliferation cell pancreatic cell human minsulin production, mβ-cell differentiation hepatocyte rat kEGF induced DNA synthesis rat rat rat rat rat rat

[14] [15] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [20] [26] [27] [28] [29] [30]

LPS induces a rapid increase in the circulating activin A, far earlier than with IL-6 but concurrently with tumor necrosis factor α (TNF-α). The activin response, occurring through the Toll-like receptor 4 signaling pathway, promotes an inflammatory reaction by stimulation of monocytes and macrophages to produce IL-6, TNF-α, and prostaglandin E2.

Use for Diagnosis and Treatment None.

Target Cells/Tissues and Functions Activin A and B have paracrine and autocrine actions throughout the endocrine, reproductive, immune, and hematopoietic systems in adult animals (Table 33B.2) [10 30]. Activin is an inducer of dorsal mesodermal and neural tissues in Xenopus embryos. βC- and βE-subunit genes are expressed in several tissues; however, their biological functions have not been fully clarified.

Phenotype of Gene-Modified Animals βA-subunit gene null mice die perinatally. The lacking of activin type II receptor expression lowers the growth of testis and ovary, most likely through disruption of FSH production [31]. Overexpression of the βA-subunit gene results in degeneration of seminiferous tubules.

Pathophysiological Implications Clinical Implications Activin A expression is increased in several inflammatory diseases. Elevation in the concentrations of serum activin is noted in patients with septicemia. Experimental exposure to 296

References 1. Ling N, Ying SY, Ueno N, et al. Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin. Nature. 1986;321:779 782. 2. Eto Y, Tsuji T, Takezawa M, et al. Purification and characterization of erythroid differentiation factor (EDF) isolated from human leukemia cell line THP-1. Biochem Biophys Res Commun. 1987;142:1095 1103. 3. Lau AL, Nishimori K, Matzuk MM. Structural analysis of the mouse activin beta C gene. Biochem Biophys Acta. 1996;1307:145 148. 4. Fang J, Yin W, Smiley E, et al. Molecular cloning of the mouse activin beta E subunit gene. Biochem Biophys Res Commun. 1996;228:669 674. 5. Oda S, Nishimatsu S, Murakami K, et al. Molecular cloning and functional analysis of a new activin beta subunit: a dorsal mesoderm-inducing activity in Xenopus. Biochem Biophys Res Commun. 1995;210:581 588. 6. Attisano L, Ca´rcamo J, Ventura F, et al. Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell. 1993;75:671 680. 7. Tsuchida K, Sawchenko PE, Nishikawa S, et al. Molecular cloning of a novel type I receptor serine/threonine kinase for the TGF beta superfamily from rat brain. Mol Cell Neurosci. 1996;7:467 478.

S U B C H A P T E R 3 3 B Activin 8. Mathews LS, Vale WW. Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell. 1991;65:973 982. 9. Attisano L, Wrana JL, Cheifetz S, et al. Novel activin receptors: distinct genes and alternative mRNA splicing generate a repertoire of serine/threonine kinase receptors. Cell. 1992;68:97 108. 10. Gonza´lez-Mancho´n C, Bilezikjian LM, Corrigan AZ, et al. ActivinA modulates gonadotropin-releasing hormone secretion from a gonadotropin-releasing hormone-secreting neuronal cell line. Neuroendocrinology. 1991;54:373 377. 11. Vale W, Rivier J, Vaughan J, et al. Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid. Nature. 1986;321:776 779. 12. Billestrup N, Gonza´lez-Mancho´n C, Potter E, et al. Inhibition of somatotroph growth and growth hormone biosynthesis by activin in vitro. Mol Endocrinol. 1990;4:356 362. 13. Kitaoka M, Kojima I, Ogata E. Activin-A: a modulator of multiple types of anterior pituitary cells. Biochem Biophys Res Commun. 1988;157:48 54. 14. Hutchinson LA, Findlay JK, de Vos FL, et al. Effects of bovine inhibin, transforming growth factor-beta and bovine Activin-A on granulosa cell differentiation. Biochem Biophys Res Commun. 1987;146:1405 1412. 15. Sugino H, Nakamura T, Hasegawa Y, et al. Erythroid differentiation factor can modulate follicular granulosa cell functions. Biochem Biophys Res Commun. 1988;153:281 288. 16. Hasegawa Y, Miyamoto K, Abe Y, et al. Induction of follicle stimulating hormone receptor by erythroid differentiation factor on rat granulosa cell. Biochem Biophys Res Commun. 1988;156:668 674. 17. Kaipia A, Toppari J, Huhtaniemi I, et al. Sex difference in the action of activin-A on cell proliferation of differentiating rat gonad. Endocrinology. 1994;134:2165 2170. 18. Miro´ F, Smyth CD, Hillier SG. Development-related effects of recombinant activin on steroid synthesis in rat granulosa cells. Endocrinology. 1991;129:3388 3394. 19. Myers M, van den Driesche S, McNeilly AS, et al. Activin A reduces luteinisation of human luteinised granulosa cells and has opposing effects to human chorionic gonadotropin in vitro. J Endocrinol. 2008;199:201 212.

20. Hsueh AJ, Dahl KD, Vaughan J, et al. Heterodimers and homodimers of inhibin subunits have different paracrine action in the modulation of luteinizing hormone-stimulated androgen biosynthesis. Proc Natl Acad Sci USA. 1987;84:5082 5086. 21. Wu T, Patel H, Mukai S, et al. Activin, inhibin, and follistatin in zebrafish ovary: expression and role in oocyte maturation. Biol Reprod. 2000;62:1585 1592. 22. Itoh M, Igarashi M, Yamada K, et al. Activin A stimulates meiotic maturation of the rat oocyte in vitro. Biochem Biophys Res Commun. 1990;166:1479 1484. 23. Thomsen G, Woolf T, Whitman M, et al. Activins are expressed early in Xenopus embryogenesis and can induce axial mesoderm and anterior structures. Cell. 1990;63:485 493. 24. Yoshioka K, Kamomae H. Recombinant human activin A stimulates development of bovine one-cell embryos matured and fertilized in vitro. Mol Reprod Dev. 1996;45:151 156. 25. Boitani C, Stefanini M, Fragale A, et al. Activin stimulates Sertoli cell proliferation in a defined period of rat testis development. Endocrinology. 1995;136:5438 5444. 26. Hakovirta H, Kaipia A, So¨der O, et al. Effects of activin-A, inhibinA, and transforming growth factor-beta 1 on stage-specific deoxyribonucleic acid synthesis during rat seminiferous epithelial cycle. Endocrinology. 1993;133:1664 1668. 27. Broxmeyer HE, Lu L, Cooper S, et al. Selective and indirect modulation of human multipotential and erythroid hematopoietic progenitor cell proliferation by recombinant human activin and inhibin. Proc Natl Acad Sci USA. 1988;85:9052 9056. 28. McCarthy SA, Bicknell R. Inhibition of vascular endothelial cell growth by activin-A. J Biol Chem. 1993;268:23066 23071. 29. Demeterco C, Beattie GM, Dib SA, et al. A role for activin A and betacellulin in human fetal pancreatic cell differentiation and growth. J Clin Endocrinol Metab. 2000;85:3892 3897. 30. Yasuda H, Mine T, Shibata H, et al. Activin A: an autocrine inhibitor of initiation of DNA synthesis in rat hepatocytes. J Clin Invest. 1993;92:1491 1496. 31. Matzuk MM, Kumar TR, Bradley A. Different phenotypes for mice deficient in either activins or activin receptor type II. Nature. 1996;374:356 360.

Supplemental Information

E-Figure 33B.1 Primary structure of the human type I activin receptor. The signal peptide is underlined and the transmembrane domain is shaded. The extracellular domain is indicated in red. The intracellular serine/threonine kinase domain is indicated in yellow.

297

P A R T I Peptides and Proteins in Vertebrates E-Table 33B.1 Activin Receptor Genes Receptor Type

Species

Gene

cDNA

Type I receptor Human Rat House mouse Cattle Chicken Atlantic salmon Starlet sea anemone

NM_001105 L19341, NM_024486 NM_007394

Human Rat House mouse Grass carp Atlantic salmon

BC000254 NM_199230 NM_007395

Rat

NM_139090

U58095 AJ318064, NM_204560 NM_001141639 JQ959546

IB

FJ198046 NM_001140568

IC Type II receptor Human Rat House AH001839 mouse Cattle Sheep Starlet sea anemone Red abalone

X77533, M93415 S48190

Human Chimpanzee Rat House mouse Cattle Chicken

D31770 AK306416 NM_031571, S48190 BC138823, NM_123799

L21717 L19442 AY496946 KF661329

IIA

X. laevis European seabass

U43208, NM_174227 D3189, U312229, NM_205367 NM_001090592 HE967321

Human

AH006936, AB008681

IIB AF060199, AF060200, AF060201, AF0602002

Rat House mouse Pig Cattle AH005863 Sheep Chicken X. laevis European seabass Grass carp Zebrafish Rainbow trout

e33B-2

M87067, L10640 M84120, NM_007397, BC106189, NM_031554 AY705387 U57707, NM_174495 JX422071 U31223 M88594, NM_001090580 HE967322 FJ198047 BC164219, BC097042, BC044131, AF069500 NM_001190941, HM143891