Activin signaling as an emerging target for therapeutic interventions
Tóm tắt
After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-β (TGF-β) ligands such as myostatin, growth and differentiation factor-11 and nodal. Thus, although the activity of each ligand is distinct, they are also redundant, both physiologically and pathologically in vivo. Activin receptors activated by ligands phosphorylate the receptor-regulated Smads for TGF-β, Smad2 and 3. The Smad proteins then undergo multimerization with the co-mediator Smad4, and translocate into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. Signaling through receptors and Smads is controlled by multiple mechanisms including phosphorylation and other posttranslational modifications such as sumoylation, which affect potein localization, stability and transcriptional activity. Non-Smad signaling also plays an important role in activin signaling. Extracellularly, follistatin and related proteins bind to activins and related TGF-β ligands, and control the signaling and availability of ligands. The functions of activins through activin receptors are pleiotrophic, cell type-specific and contextual, and they are involved in the etiology and pathogenesis of a variety of diseases. Accordingly, activin signaling may be a target for therapeutic interventions. In this review, we summarize the current knowledge on activin signaling and discuss the potential roles of this pathway as a molecular target of therapy for metabolic diseases, musculoskeletal disorders, cancers and neural damages.
Tài liệu tham khảo
Tsuchida K, Nakatani M, Uezumi A, Murakami T, Cui X: Signal transduction pathway through activin receptors as a therapeutic target of musculoskeletal diseases and cancer. Endocr J. 2008, 55: 11-21. 10.1507/endocrj.KR-110.
Massagué J, Gomis RR: The logic of TGFbeta signaling. FEBS Lett. 2006, 580: 2811-2820. 10.1016/j.febslet.2006.04.033.
Anderson SB, Goldberg AL, Whitman M: Identification of a novel pool of extracellular pro-myostatin in skeletal muscle. J Biol Chem. 2008, 283: 7027-7035. 10.1074/jbc.M706678200.
Harrison CA, Gray PC, Vale WW, Robertson DM: Antagonists of activin signaling: mechanisms and potential biological applications. Trends Endocrinol Metab. 2005, 16: 73-78. 10.1016/j.tem.2005.01.003.
Lee SJ: Regulation of muscle mass by myostatin. Annu Rev Cell Dev Biol. 2004, 20: 61-86. 10.1146/annurev.cellbio.20.012103.135836.
Wu HH, Ivkovic S, Murray RC, Jaramillo S, Lyons KM, Johnson JE, Calof AL: Autoregulation of neurogenesis by GDF11. Neuron. 2003, 37: 197-207. 10.1016/S0896-6273(02)01172-8.
Oxburgh L, Chu GC, Michael SK, Robertson EJ: TGFbeta superfamily signals are required for morphogenesis of the kidney mesenchyme progenitor population. Development. 2004, 131: 4593-4605. 10.1242/dev.01324.
Dichmann DS, Yassin H, Serup P: Analysis of pancreatic endocrine development in GDF11-deficient mice. Dev Dyn. 2006, 235: 3016-3025. 10.1002/dvdy.20953.
Shen MM: Nodal signaling: developmental roles and regulation. Development. 2007, 134: 1023-1034. 10.1242/dev.000166.
Mathews LS, Vale WW: Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell. 1991, 65: 973-982. 10.1016/0092-8674(91)90549-E.
Feng XH, Derynck R: Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol. 2005, 21: 659-693. 10.1146/annurev.cellbio.21.022404.142018.
Gray PC, Harrison CA, Vale W: Cripto forms a complex with activin and type II activin receptors and can block activin signaling. Proc Natl Acad Sci USA. 2003, 100: 5193-5198. 10.1073/pnas.0531290100.
Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massagué J, Niehrs C: Silencing of TGF-beta signalling by the pseudoreceptor BAMBI. Nature. 1999, 401: 480-485. 10.1038/46794.
Sekiya T, Adachi S, Kohu K, Yamada T, Higuchi O, Furukawa Y, Nakamura Y, Nakamura T, Tashiro K, Kuhara S, et al.: Identification of BMP and activin membrane-bound inhibitor (BAMBI), an inhibitor of transforming growth factor-beta signaling, as a target of the beta-catenin pathway in colorectal tumor cells. J Biol Chem. 2004, 279: 6840-6846. 10.1074/jbc.M310876200.
Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL: SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell. 1998, 95: 779-791. 10.1016/S0092-8674(00)81701-8.
Wu G, Chen YG, Ozdamar B, Gyuricza CA, Chong PA, Wrana JL, Massague J, Shi Y: Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Science. 2000, 287: 92-97. 10.1126/science.287.5450.92.
Shoji H, Tsuchida K, Kishi H, Yamakawa N, Matsuzaki T, Liu Z, Nakamura T, Sugino H: Identification and characterization of a PDZ protein that interacts with activin type II receptors. J Biol Chem. 2000, 275: 5485-5492. 10.1074/jbc.275.8.5485.
Iida J, Ishizaki H, Okamoto-Tanaka M, Kawata A, Sumita K, Ohgake S, Sato Y, Yorifuji H, Nukina N, Ohashi K, et al.: Synaptic scaffolding molecule alpha is a scaffold to mediate N-methyl-D-aspartate receptor-dependent RhoA activation in dendrites. Mol Cell Biol. 2007, 27: 4388-4405. 10.1128/MCB.01901-06.
Kurisaki A, Inoue I, Kurisaki K, Yamakawa N, Tsuchida K, Sugino H: Activin induces long-lasting N-methyl-D-aspartate receptor activation via scaffolding PDZ protein activin receptor interacting protein 1. Neuroscience. 2008, 151: 1225-1235. 10.1016/j.neuroscience.2007.12.012.
Matsuzaki T, Hanai S, Kishi H, Liu Z, Bao Y, Kikuchi A, Tsuchida K, Sugino H: Regulation of endocytosis of activin type II receptors by a novel PDZ protein through Ral/Ral-binding protein 1-dependent pathway. J Biol Chem. 2002, 277: 19008-19018. 10.1074/jbc.M112472200.
Liu ZH, Tsuchida K, Matsuzaki T, Bao YL, Kurisaki A, Sugino H: Characterization of isoforms of activin receptor-interacting protein 2 that augment activin signaling. J Endocrinol. 2006, 189: 409-421. 10.1677/joe.1.06420.
Yamakawa N, Tsuchida K, Sugino H: The rasGAP-binding protein, Dok-1, mediates activin signaling via serine/threonine kinase receptors. Embo J. 2002, 21: 1684-1694. 10.1093/emboj/21.7.1684.
Inoue Y, Imamura T: Regulation of TGF-beta family signaling by E3 ubiquitin ligases. Cancer Sci. 2008, 99: 2107-2112. 10.1111/j.1349-7006.2008.00925.x.
Kang JS, Saunier EF, Akhurst RJ, Derynck R: The type I TGF-beta receptor is covalently modified and regulated by sumoylation. Nat Cell Biol. 2008, 10: 654-664. 10.1038/ncb1728.
Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J, Hu M, Davis CM, Wang J, Brunicardi FC, et al.: PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell. 2006, 125: 915-928. 10.1016/j.cell.2006.03.044.
Nakano A, Koinuma D, Miyazawa K, Uchida T, Saitoh M, Kawabata M, Hanai J, Akiyama H, Abe M, Miyazono K, et al.: Pin1 Down-regulates Transforming Growth Factor-{beta} (TGF-{beta}) Signaling by Inducing Degradation of Smad Proteins. J Biol Chem. 2009, 284: 6109-6115. 10.1074/jbc.M804659200.
Bao YL, Tsuchida K, Liu B, Kurisaki A, Matsuzaki T, Sugino H: Synergistic activity of activin A and basic fibroblast growth factor on tyrosine hydroxylase expression through Smad3 and ERK1/ERK2 MAPK signaling pathways. J Endocrinol. 2005, 184: 493-504. 10.1677/joe.1.05978.
de Guise C, Lacerte A, Rafiei S, Reynaud R, Roy M, Brue T, Lebrun JJ: Activin inhibits the human Pit-1 gene promoter through the p38 kinase pathway in a Smad-independent manner. Endocrinology. 2006, 147: 4351-4362. 10.1210/en.2006-0444.
Hirota M, Watanabe K, Hamada S, Sun Y, Strizzi L, Mancino M, Nagaoka T, Gonzales M, Seno M, Bianco C, Salomon DS: Smad2 functions as a co-activator of canonical Wnt/beta-catenin signaling pathway independent of Smad4 through histone acetyltransferase activity of p300. Cell Signal. 2008, 20: 1632-1641. 10.1016/j.cellsig.2008.05.003.
Wrighton KH, Lin X, Yu PB, Feng XH: Transforming Growth Factor {beta} Can Stimulate Smad1 Phosphorylation Independently of Bone Morphogenic Protein Receptors. J Biol Chem. 2009, 284: 9755-9763. 10.1074/jbc.M809223200.
Murakami M, Kawachi H, Ogawa K, Nishino Y, Funaba M: Receptor expression modulates the specificity of transforming growth factor-beta signaling pathways. Genes Cells. 2009, 14: 469-482. 10.1111/j.1365-2443.2009.01283.x.
Liu IM, Schilling SH, Knouse KA, Choy L, Derynck R, Wang XF: TGFbeta-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFbeta switch. Embo J. 2009, 28: 88-98. 10.1038/emboj.2008.266.
Nakamura T, Takio K, Eto Y, Shibai H, Titani K, Sugino H: Activin-binding protein from rat ovary is follistatin. Science. 1990, 247: 836-838. 10.1126/science.2106159.
Thompson TB, Lerch TF, Cook RW, Woodruff TK, Jardetzky TS: The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding. Dev Cell. 2005, 9: 535-543. 10.1016/j.devcel.2005.09.008.
Harrington AE, Morris-Triggs SA, Ruotolo BT, Robinson CV, Ohnuma S, Hyvonen M: Structural basis for the inhibition of activin signalling by follistatin. Embo J. 2006, 25: 1035-1045. 10.1038/sj.emboj.7601000.
Stamler R, Keutmann HT, Sidis Y, Kattamuri C, Schneyer A, Thompson TB: The structure of FSTL3.activin A complex. Differential binding of N-terminal domains influences follistatin-type antagonist specificity. J Biol Chem. 2008, 283: 32831-32838. 10.1074/jbc.M801266200.
Hill JJ, Davies MV, Pearson AA, Wang JH, Hewick RM, Wolfman NM, Qiu Y: The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. J Biol Chem. 2002, 277: 40735-40741. 10.1074/jbc.M206379200.
Matzuk MM, Lu N, Vogel H, Sellheyer K, Roop DR, Bradley A: Multiple defects and perinatal death in mice deficient in follistatin. Nature. 1995, 374: 360-363. 10.1038/374360a0.
Tsuchida K, Arai KY, Kuramoto Y, Yamakawa N, Hasegawa Y, Sugino H: Identification and characterization of a novel follistatin-like protein as a binding protein for the TGF-beta family. J Biol Chem. 2000, 275: 40788-40796. 10.1074/jbc.M006114200.
Hayette S, Gadoux M, Martel S, Bertrand S, Tigaud I, Magaud JP, Rimokh R: FLRG (follistatin-related gene), a new target of chromosomal rearrangement in malignant blood disorders. Oncogene. 1998, 16: 2949-2954. 10.1038/sj.onc.1201807.
Saito S, Sidis Y, Mukherjee A, Xia Y, Schneyer A: Differential biosynthesis and intracellular transport of follistatin isoforms and follistatin-like-3. Endocrinology. 2005, 146: 5052-5062. 10.1210/en.2005-0833.
Mukherjee A, Sidis Y, Mahan A, Raher MJ, Xia Y, Rosen ED, Bloch KD, Thomas MK, Schneyer AL: FSTL3 deletion reveals roles for TGF-beta family ligands in glucose and fat homeostasis in adults. Proc Natl Acad Sci USA. 2007, 104: 1348-1353. 10.1073/pnas.0607966104.
Frandsen U, Porneki AD, Floridon C, Abdallah BM, Kassem M: Activin B mediated induction of Pdx1 in human embryonic stem cell derived embryoid bodies. Biochem Biophys Res Commun. 2007, 362: 568-574. 10.1016/j.bbrc.2007.07.200.
Kim SK, Hebrok M, Li E, Oh SP, Schrewe H, Harmon EB, Lee JS, Melton DA: Activin receptor patterning of foregut organogenesis. Genes Dev. 2000, 14: 1866-1871.
Goto Y, Nomura M, Tanaka K, Kondo A, Morinaga H, Okabe T, Yanase T, Nawata H, Takayanagi R, Li E: Genetic interactions between activin type IIB receptor and Smad2 genes in asymmetrical patterning of the thoracic organs and the development of pancreas islets. Dev Dyn. 2007, 236: 2865-2874. 10.1002/dvdy.21303.
Kogame M, Matsuo S, Nakatani M, Kurisaki A, Nishitani H, Tsuchida K, Sugino H: ALK7 is a novel marker for adipocyte differentiation. J Med Invest. 2006, 53: 238-245. 10.2152/jmi.53.238.
Watanabe R, Shen ZP, Tsuda K, Yamada Y: Insulin gene is a target in activin receptor-like kinase 7 signaling pathway in pancreatic beta-cells. Biochem Biophys Res Commun. 2008, 377: 867-872. 10.1016/j.bbrc.2008.10.074.
Tsuchida K, Nakatani M, Yamakawa N, Hashimoto O, Hasegawa Y, Sugino H: Activin isoforms signal through type I receptor serine/threonine kinase ALK7. Mol Cell Endocrinol. 2004, 220: 59-65. 10.1016/j.mce.2004.03.009.
Andersson O, Korach-Andre M, Reissmann E, Ibanez CF, Bertolino P: Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity. Proc Natl Acad Sci USA. 2008, 105: 7252-7256. 10.1073/pnas.0800272105.
Shen JJ, Huang L, Li L, Jorgez C, Matzuk MM, Brown CW: Deficiency of growth differentiation factor 3 protects against diet-induced obesity by selectively acting on white adipose. Mol Endocrinol. 2009, 23: 113-123. 10.1210/me.2007-0322.
Allen DL, Cleary AS, Speaker KJ, Lindsay SF, Uyenishi J, Reed JM, Madden MC, Mehan RS: Myostatin, activin receptor IIb, and follistatin-like-3 gene expression are altered in adipose tissue and skeletal muscle of obese mice. Am J Physiol Endocrinol Metab. 2008, 294: E918-927. 10.1152/ajpendo.00798.2007.
Hittel DS, Berggren JR, Shearer J, Boyle K, Houmard JA: Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes. 2009, 58: 30-38. 10.2337/db08-0943.
McPherron AC, Lawler AM, Lee SJ: Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997, 387: 83-90. 10.1038/387083a0.
McPherron AC, Lee SJ: Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA. 1997, 94: 12457-12461. 10.1073/pnas.94.23.12457.
Clop A, Marcq F, Takeda H, Pirottin D, Tordoir X, Bibe B, Bouix J, Caiment F, Elsen JM, Eychenne F, et al.: A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet. 2006, 38: 813-818. 10.1038/ng1810.
Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS, Parker HG, Ostrander EA: A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genet. 2007, 3: e79-10.1371/journal.pgen.0030079.
Shelton GD, Engvall E: Gross muscle hypertrophy in whippet dogs is caused by a mutation in the myostatin gene. Neuromuscul Disord. 2007, 17: 721-722. 10.1016/j.nmd.2007.06.008.
Acosta J, Carpio Y, Borroto I, Gonzalez O, Estrada MP: Myostatin gene silenced by RNAi show a zebrafish giant phenotype. J Biotechnol. 2005, 119: 324-331. 10.1016/j.jbiotec.2005.04.023.
Schuelke M, Wagner KR, Stolz LE, Hubner C, Riebel T, Komen W, Braun T, Tobin JF, Lee SJ: Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004, 350: 2682-2688. 10.1056/NEJMoa040933.
Bogdanovich S, Krag TO, Barton ER, Morris LD, Whittemore LA, Ahima RS, Khurana TS: Functional improvement of dystrophic muscle by myostatin blockade. Nature. 2002, 420: 418-421. 10.1038/nature01154.
Wagner KR, McPherron AC, Winik N, Lee SJ: Loss of myostatin attenuates severity of muscular dystrophy in mdx mice. Ann Neurol. 2002, 52: 832-836. 10.1002/ana.10385.
Bogdanovich S, Perkins KJ, Krag TO, Whittemore LA, Khurana TS: Myostatin propeptide-mediated amelioration of dystrophic pathophysiology. Faseb J. 2005, 19: 543-549. 10.1096/fj.04-2796com.
Ohsawa Y, Hagiwara H, Nakatani M, Yasue A, Moriyama K, Murakami T, Tsuchida K, Noji S, Sunada Y: Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition. J Clin Invest. 2006, 116: 2924-2934. 10.1172/JCI28520.
Bartoli M, Poupiot J, Vulin A, Fougerousse F, Arandel L, Daniele N, Roudaut C, Noulet F, Garcia L, Danos O, Richard I: AAV-mediated delivery of a mutated myostatin propeptide ameliorates calpain 3 but not alpha-sarcoglycan deficiency. Gene Ther. 2007, 14 (9): 733-740. 10.1038/sj.gt.3302928.
Parsons SA, Millay DP, Sargent MA, McNally EM, Molkentin JD: Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdle muscular dystrophy. Am J Pathol. 2006, 168: 1975-1985. 10.2353/ajpath.2006.051316.
Nakatani M, Takehara Y, Sugino H, Matsumoto M, Hashimoto O, Hasegawa Y, Murakami T, Uezumi A, Takeda S, Noji S, et al.: Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice. Faseb J. 2008, 22: 477-487. 10.1096/fj.07-8673com.
Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR: Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle Nerve. 2009, 39: 283-296. 10.1002/mus.21244.
Li ZB, Kollias HD, Wagner KR: Myostatin directly regulates skeletal muscle fibrosis. J Biol Chem. 2008, 283: 19371-19378. 10.1074/jbc.M802585200.
Li ZF, Shelton GD, Engvall E: Elimination of myostatin does not combat muscular dystrophy in dy mice but increases postnatal lethality. Am J Pathol. 2005, 166: 491-497.
Lee SJ, Reed LA, Davies MV, Girgenrath S, Goad ME, Tomkinson KN, Wright JF, Barker C, Ehrmantraut G, Holmstrom J, et al.: Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci USA. 2005, 102: 18117-18122. 10.1073/pnas.0505996102.
Souza TA, Chen X, Guo Y, Sava P, Zhang J, Hill JJ, Yaworsky PJ, Qiu Y: Proteomic identification and functional validation of activins and bone morphogenetic protein 11 as candidate novel muscle mass regulators. Mol Endocrinol. 2008, 22: 2689-2702. 10.1210/me.2008-0290.
Holzbaur EL, Howland DS, Weber N, Wallace K, She Y, Kwak S, Tchistiakova LA, Murphy E, Hinson J, Karim R, et al.: Myostatin inhibition slows muscle atrophy in rodent models of amyotrophic lateral sclerosis. Neurobiol Dis. 2006, 23: 697-707. 10.1016/j.nbd.2006.05.009.
Rose FF Jr, Mattis VB, Rindt H, Lorson CL: Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy. Hum Mol Genet. 2009, 18: 997-1005. 10.1093/hmg/ddn426.
Mahmoudabady M, Mathieu M, Dewachter L, Hadad I, Ray L, Jespers P, Brimioulle S, Naeije R, McEntee K: Activin-A, transforming growth factor-beta, and myostatin signaling pathway in experimental dilated cardiomyopathy. J Card Fail. 2008, 14: 703-709. 10.1016/j.cardfail.2008.05.003.
Cohn RD, Liang HY, Shetty R, Abraham T, Wagner KR: Myostatin does not regulate cardiac hypertrophy or fibrosis. Neuromuscul Disord. 2007, 17: 290-296. 10.1016/j.nmd.2007.01.011.
Sugatani T, Alvarez UM, Hruska KA: Activin A stimulates IkappaB-alpha/NFkappaB and RANK expression for osteoclast differentiation, but not AKT survival pathway in osteoclast precursors. J Cell Biochem. 2003, 90: 59-67. 10.1002/jcb.10613.
Deal C: Potential new drug targets for osteoporosis. Nat Clin Pract Rheumatol. 2009, 5: 20-27. 10.1038/ncprheum0977.
Pearsall RS, Canalis E, Cornwall-Brady M, Underwood KW, Haigis B, Ucran J, Kumar R, Pobre E, Grinberg A, Werner ED, et al.: A soluble activin type IIA receptor induces bone formation and improves skeletal integrity. Proc Natl Acad Sci USA. 2008, 105: 7082-7087. 10.1073/pnas.0711263105.
Perrien DS, Akel NS, Edwards PK, Carver AA, Bendre MS, Swain FL, Skinner RA, Hogue WR, Nicks KM, Pierson TM, et al.: Inhibin A is an endocrine stimulator of bone mass and strength. Endocrinology. 2007, 148: 1654-1665. 10.1210/en.2006-0848.
Yu PB, Deng DY, Lai CS, Hong CC, Cuny GD, Bouxsein ML, Hong DW, McManus PM, Katagiri T, Sachidanandan C, et al.: BMP type I receptor inhibition reduces heterotopic ossification. Nat Med. 2008, 14: 1363-1369. 10.1038/nm.1888.
Adkins HB, Bianco C, Schiffer SG, Rayhorn P, Zafari M, Cheung AE, Orozco O, Olson D, De Luca A, Chen LL, et al.: Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo. J Clin Invest. 2003, 112: 575-587.
Razanajaona D, Joguet S, Ay AS, Treilleux I, Goddard-Leon S, Bartholin L, Rimokh R: Silencing of FLRG, an antagonist of activin, inhibits human breast tumor cell growth. Cancer Res. 2007, 67: 7223-7229. 10.1158/0008-5472.CAN-07-0805.
Hempen PM, Zhang L, Bansal RK, Iacobuzio-Donahue CA, Murphy KM, Maitra A, Vogelstein B, Whitehead RH, Markowitz SD, Willson JK, et al.: Evidence of selection for clones having genetic inactivation of the activin A type II receptor (ACVR2) gene in gastrointestinal cancers. Cancer Res. 2003, 63: 994-999.
Su GH, Bansal R, Murphy KM, Montgomery E, Yeo CJ, Hruban RH, Kern SE: ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma. Proc Natl Acad Sci USA. 2001, 98: 3254-3257. 10.1073/pnas.051484398.
Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996, 271: 350-353. 10.1126/science.271.5247.350.
Matzuk MM, Finegold MJ, Mather JP, Krummen L, Lu H, Bradley A: Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice. Proc Natl Acad Sci USA. 1994, 91: 8817-8821. 10.1073/pnas.91.19.8817.
Leto G, Incorvaia L, Badalamenti G, Tumminello FM, Gebbia N, Flandina C, Crescimanno M, Rini G: Activin A circulating levels in patients with bone metastasis from breast or prostate cancer. Clin Exp Metastasis. 2006, 23: 117-122. 10.1007/s10585-006-9010-5.
Li Q, Kumar R, Underwood K, O'Connor AE, Loveland KL, Seehra JS, Matzuk MM: Prevention of cachexia-like syndrome development and reduction of tumor progression in inhibin-deficient mice following administration of a chimeric activin receptor type II-murine Fc protein. Mol Hum Reprod. 2007, 13: 675-683. 10.1093/molehr/gam055.
Ehata S, Hanyu A, Fujime M, Katsuno Y, Fukunaga E, Goto K, Ishikawa Y, Nomura K, Yokoo H, Shimizu T, et al.: Ki2 a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci. 6894, 98 (1): 127-133. 10.1111/j.1349-7006.2006.00357.x.
Ogino H, Yano S, Kakiuchi S, Muguruma H, Ikuta K, Hanibuchi M, Uehara H, Tsuchida K, Sugino H, Sone S: Follistatin suppresses the production of experimental multiple-organ metastasis by small cell lung cancer cells in natural killer cell-depleted SCID mice. Clin Cancer Res. 2008, 14: 660-667. 10.1158/1078-0432.CCR-07-1221.
Hjelmeland MD, Hjelmeland AB, Sathornsumetee S, Reese ED, Herbstreith MH, Laping NJ, Friedman HS, Bigner DD, Wang XF, Rich JN: SB-43 a small molecule transforming growth factor-beta-receptor antagonist, inhibits human glioma cell line proliferation and motility. Mol Cancer Ther. 1542, 3: 737-745.
Halder SK, Beauchamp RD, Datta PK: A specific inhibitor of TGF-beta receptor kinase, SB-43 as a potent antitumor agent for human cancers. Neoplasia. 1542, 7: 509-521. 10.1593/neo.04640.
Futakuchi M, Nannuru KC, Varney ML, Sadanandam A, Nakao K, Asai K, Shirai T, Sato SY, Singh RK: Transforming growth factor-beta signaling at the tumor-bone interface promotes mammary tumor growth and osteoclast activation. Cancer Sci. 2009, 100: 71-81. 10.1111/j.1349-7006.2008.01012.x.
Uhl M, Aulwurm S, Wischhusen J, Weiler M, Ma JY, Almirez R, Mangadu R, Liu YW, Platten M, Herrlinger U, et al.: SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res. 2004, 64: 7954-7961. 10.1158/0008-5472.CAN-04-1013.
Roberts VJ, Barth SL: Expression of messenger ribonucleic acids encoding the inhibin/activin system during mid- and late-gestation rat embryogenesis. Endocrinology. 1994, 134: 914-923. 10.1210/en.134.2.914.
Trudeau VL, Theodosis DT, Poulain DA: Activin facilitates neuronal development in the rat amygdala. Neurosci Lett. 1997, 237: 33-36. 10.1016/S0304-3940(97)00796-9.
Andreasson K, Worley PF: Induction of beta-A activin expression by synaptic activity and during neocortical development. Neuroscience. 1995, 69: 781-796. 10.1016/0306-4522(95)00245-E.
Inokuchi K, Kato A, Hiraia K, Hishinuma F, Inoue M, Ozawa F: Increase in activin beta A mRNA in rat hippocampus during long-term potentiation. FEBS Lett. 1996, 382: 48-52. 10.1016/0014-5793(96)00135-4.
Shoji-Kasai Y, Ageta H, Hasegawa Y, Tsuchida K, Sugino H, Inokuchi K: Activin increases the number of synaptic contacts and the length of dendritic spine necks by modulating spinal actin dynamics. J Cell Sci. 2007, 120: 3830-3837. 10.1242/jcs.012450.
Lai M, Gluckman P, Dragunow M, Hughes PE: Focal brain injury increases activin betaA mRNA expression in hippocampal neurons. Neuroreport. 1997, 8: 2691-2694. 10.1097/00001756-199708180-00011.
Foster JA, Puchowicz MJ, McIntyre DC, Herkenham M: Activin mRNA induced during amygdala kindling shows a spatiotemporal progression that tracks the spread of seizures. J Comp Neurol. 2004, 476: 91-102. 10.1002/cne.20197.
Hughes PE, Alexi T, Williams CE, Clark RG, Gluckman PD: Administration of recombinant human Activin-A has powerful neurotrophic effects on select striatal phenotypes in the quinolinic acid lesion model of Huntington's disease. Neuroscience. 1999, 92: 197-209. 10.1016/S0306-4522(98)00724-6.
Wu DD, Lai M, Hughes PE, Sirimanne E, Gluckman PD, Williams CE: Expression of the activin axis and neuronal rescue effects of recombinant activin A following hypoxic-ischemic brain injury in the infant rat. Brain Res. 1999, 835: 369-378. 10.1016/S0006-8993(99)01638-8.
Tretter YP, Hertel M, Munz B, ten Bruggencate G, Werner S, Alzheimer C: Induction of activin A is essential for the neuroprotective action of basic fibroblast growth factor in vivo. Nat Med. 2000, 6: 812-815. 10.1038/77548.
Muller MR, Zheng F, Werner S, Alzheimer C: Transgenic mice expressing dominant-negative activin receptor IB in forebrain neurons reveal novel functions of activin at glutamatergic synapses. J Biol Chem. 2006, 281: 29076-29084. 10.1074/jbc.M604959200.
Ageta H, Murayama A, Migishima R, Kida S, Tsuchida K, Yokoyama M, Inokuchi K: Activin in the brain modulates anxiety-related behavior and adult neurogenesis. PLoS ONE. 2008, 3: e1869-10.1371/journal.pone.0001869.
Zheng F, Adelsberger H, Muller MR, Fritschy JM, Werner S, Alzheimer C: Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior. Mol Psychiatry. 2009, 14: 332-346. 10.1038/sj.mp.4002131.
Dow AL, Russell DS, Duman RS: Regulation of activin mRNA and Smad2 phosphorylation by antidepressant treatment in the rat brain: effects in behavioral models. J Neurosci. 2005, 25: 4908-4916. 10.1523/JNEUROSCI.5155-04.2005.
Asashima M, Michiue T, Kurisaki A: Elucidation of the role of activin in organogenesis using a multiple organ induction system with amphibian and mouse undifferentiated cells in vitro. Dev Growth Differ. 2008, 50 (Suppl 1): S35-45.
Phillips BW, Hentze H, Rust WL, Chen QP, Chipperfield H, Tan EK, Abraham S, Sadasivam A, Soong PL, Wang ST, et al.: Directed differentiation of human embryonic stem cells into the pancreatic endocrine lineage. Stem Cells Dev. 2007, 16: 561-578. 10.1089/scd.2007.0029.
Xiao L, Yuan X, Sharkis SJ: Activin A maintains self-renewal and regulates fibroblast growth factor, Wnt, and bone morphogenic protein pathways in human embryonic stem cells. Stem Cells. 2006, 24: 1476-1486. 10.1634/stemcells.2005-0299.
Xu RH, Sampsell-Barron TL, Gu F, Root S, Peck RM, Pan G, Yu J, Antosiewicz-Bourget J, Tian S, Stewart R, Thomson JA: NANOG is a direct target of TGFbeta/activin-mediated SMAD signaling in human ESCs. Cell Stem Cell. 2008, 3: 196-206. 10.1016/j.stem.2008.07.001.
Minetti GC, Colussi C, Adami R, Serra C, Mozzetta C, Parente V, Fortuni S, Straino S, Sampaolesi M, Di Padova M, et al.: Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors. Nat Med. 2006, 12: 1147-1150. 10.1038/nm1479.
Pisconti A, Brunelli S, Di Padova M, De Palma C, Deponti D, Baesso S, Sartorelli V, Cossu G, Clementi E: Follistatin induction by nitric oxide through cyclic GMP: a tightly regulated signaling pathway that controls myoblast fusion. J Cell Biol. 2006, 172: 233-244. 10.1083/jcb.200507083.
Zimmers TA, Davies MV, Koniaris LG, Haynes P, Esquela AF, Tomkinson KN, McPherron AC, Wolfman NM, Lee SJ: Induction of cachexia in mice by systemically administered myostatin. Science. 2002, 296: 1486-1488. 10.1126/science.1069525.
Colussi C, Gaetano C, Capogrossi MC: AAV-dependent targeting of myostatin function: follistatin strikes back at muscular dystrophy. Gene Ther. 2008, 15: 1075-1076. 10.1038/gt.2008.95.
Kinouchi N, Ohsawa Y, Ishimaru N, Ohuchi H, Sunada Y, Hayashi Y, Tanimoto Y, Moriyama K, Noji S: Atelocollagen-mediated local and systemic applications of myostatin-targeting siRNA increase skeletal muscle mass. Gene Ther. 2008, 15: 1126-1130. 10.1038/gt.2008.24.