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. 1996 Mar;16(3):1066–1073. doi: 10.1128/mcb.16.3.1066

Activation of signalling by the activin receptor complex.

L Attisano 1, J L Wrana 1, E Montalvo 1, J Massagué 1
PMCID: PMC231089  PMID: 8622651

Abstract

Activin exerts its effects by simultaneously binding to two types of p rotein serine/threonine kinase receptors, each type existing in various isoforms. Using the ActR-IB and ActR-IIB receptor isoforms, we have investigated the mechanism of activin receptor activation. ActR-IIB are phosphoproteins with demonstrable affinity for each other. However, activin addition strongly promotes an interaction between these two proteins. Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation, suggesting that this domain contains phosphorylation sites required for signalling. ActR-IB activation can be mimicked by mutation of Thr-206 to aspartic acid, which yields a construct, ActR-IB(T206D), that signals in the absence of ligand. Furthermore, the signalling activity of this mutant construct is undisturbed by overexpression of a dominant negative kinase-defective ActR-IIB construct, indicating that ActR-IB(T206D) can signal independently of ActR-IIB. The evidence suggests that ActR-IIB acts as a primary activin receptor and ActR-IB acts as a downstream transducer of activin signals.

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Selected References

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  1. Affolter M., Nellen D., Nussbaumer U., Basler K. Multiple requirements for the receptor serine/threonine kinase thick veins reveal novel functions of TGF beta homologs during Drosophila embryogenesis. Development. 1994 Nov;120(11):3105–3117. doi: 10.1242/dev.120.11.3105. [DOI] [PubMed] [Google Scholar]
  2. Andersson S., Davis D. L., Dahlbäck H., Jörnvall H., Russell D. W. Cloning, structure, and expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme. J Biol Chem. 1989 May 15;264(14):8222–8229. [PubMed] [Google Scholar]
  3. Attisano L., Cárcamo J., Ventura F., Weis F. M., Massagué J., Wrana J. L. Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell. 1993 Nov 19;75(4):671–680. doi: 10.1016/0092-8674(93)90488-c. [DOI] [PubMed] [Google Scholar]
  4. Attisano L., Wrana J. L., Cheifetz S., Massagué J. Novel activin receptors: distinct genes and alternative mRNA splicing generate a repertoire of serine/threonine kinase receptors. Cell. 1992 Jan 10;68(1):97–108. doi: 10.1016/0092-8674(92)90209-u. [DOI] [PubMed] [Google Scholar]
  5. Attisano L., Wrana J. L., López-Casillas F., Massagué J. TGF-beta receptors and actions. Biochim Biophys Acta. 1994 May 26;1222(1):71–80. doi: 10.1016/0167-4889(94)90026-4. [DOI] [PubMed] [Google Scholar]
  6. Brummel T. J., Twombly V., Marqués G., Wrana J. L., Newfeld S. J., Attisano L., Massagué J., O'Connor M. B., Gelbart W. M. Characterization and relationship of Dpp receptors encoded by the saxophone and thick veins genes in Drosophila. Cell. 1994 Jul 29;78(2):251–261. doi: 10.1016/0092-8674(94)90295-x. [DOI] [PubMed] [Google Scholar]
  7. Chen F., Weinberg R. A. Biochemical evidence for the autophosphorylation and transphosphorylation of transforming growth factor beta receptor kinases. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1565–1569. doi: 10.1073/pnas.92.5.1565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chen R. H., Moses H. L., Maruoka E. M., Derynck R., Kawabata M. Phosphorylation-dependent interaction of the cytoplasmic domains of the type I and type II transforming growth factor-beta receptors. J Biol Chem. 1995 May 19;270(20):12235–12241. doi: 10.1074/jbc.270.20.12235. [DOI] [PubMed] [Google Scholar]
  9. Childs S. R., Wrana J. L., Arora K., Attisano L., O'Connor M. B., Massagué J. Identification of a Drosophila activin receptor. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9475–9479. doi: 10.1073/pnas.90.20.9475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cowley S., Paterson H., Kemp P., Marshall C. J. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell. 1994 Jun 17;77(6):841–852. doi: 10.1016/0092-8674(94)90133-3. [DOI] [PubMed] [Google Scholar]
  11. Cárcamo J., Weis F. M., Ventura F., Wieser R., Wrana J. L., Attisano L., Massagué J. Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin. Mol Cell Biol. 1994 Jun;14(6):3810–3821. doi: 10.1128/mcb.14.6.3810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cárcamo J., Zentella A., Massagué J. Disruption of transforming growth factor beta signaling by a mutation that prevents transphosphorylation within the receptor complex. Mol Cell Biol. 1995 Mar;15(3):1573–1581. doi: 10.1128/mcb.15.3.1573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ebner R., Chen R. H., Lawler S., Zioncheck T., Derynck R. Determination of type I receptor specificity by the type II receptors for TGF-beta or activin. Science. 1993 Nov 5;262(5135):900–902. doi: 10.1126/science.8235612. [DOI] [PubMed] [Google Scholar]
  14. Eto Y., Tsuji T., Takezawa M., Takano S., Yokogawa Y., Shibai H. Purification and characterization of erythroid differentiation factor (EDF) isolated from human leukemia cell line THP-1. Biochem Biophys Res Commun. 1987 Feb 13;142(3):1095–1103. doi: 10.1016/0006-291x(87)91528-2. [DOI] [PubMed] [Google Scholar]
  15. Ferguson E. L., Anderson K. V. Decapentaplegic acts as a morphogen to organize dorsal-ventral pattern in the Drosophila embryo. Cell. 1992 Oct 30;71(3):451–461. doi: 10.1016/0092-8674(92)90514-d. [DOI] [PubMed] [Google Scholar]
  16. Franzén P., ten Dijke P., Ichijo H., Yamashita H., Schulz P., Heldin C. H., Miyazono K. Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor. Cell. 1993 Nov 19;75(4):681–692. doi: 10.1016/0092-8674(93)90489-d. [DOI] [PubMed] [Google Scholar]
  17. Gonzalez-Manchon C., Vale W. Activin-A, inhibin and transforming growth factor-beta modulate growth of two gonadal cell lines. Endocrinology. 1989 Sep;125(3):1666–1672. doi: 10.1210/endo-125-3-1666. [DOI] [PubMed] [Google Scholar]
  18. H tten G., Neidhardt H., Schneider C., Pohl J. Cloning of a new member of the TGF-beta family: a putative new activin beta C chain. Biochem Biophys Res Commun. 1995 Jan 17;206(2):608–613. doi: 10.1006/bbrc.1995.1086. [DOI] [PubMed] [Google Scholar]
  19. He W. W., Gustafson M. L., Hirobe S., Donahoe P. K. Developmental expression of four novel serine/threonine kinase receptors homologous to the activin/transforming growth factor-beta type II receptor family. Dev Dyn. 1993 Feb;196(2):133–142. doi: 10.1002/aja.1001960207. [DOI] [PubMed] [Google Scholar]
  20. Heldin C. H. Dimerization of cell surface receptors in signal transduction. Cell. 1995 Jan 27;80(2):213–223. doi: 10.1016/0092-8674(95)90404-2. [DOI] [PubMed] [Google Scholar]
  21. Hemmati-Brivanlou A., Melton D. A. A truncated activin receptor inhibits mesoderm induction and formation of axial structures in Xenopus embryos. Nature. 1992 Oct 15;359(6396):609–614. doi: 10.1038/359609a0. [DOI] [PubMed] [Google Scholar]
  22. Inagaki M., Moustakas A., Lin H. Y., Lodish H. F., Carr B. I. Growth inhibition by transforming growth factor beta (TGF-beta) type I is restored in TGF-beta-resistant hepatoma cells after expression of TGF-beta receptor type II cDNA. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5359–5363. doi: 10.1073/pnas.90.11.5359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kawabata M., Chytil A., Moses H. L. Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor. J Biol Chem. 1995 Mar 10;270(10):5625–5630. doi: 10.1074/jbc.270.10.5625. [DOI] [PubMed] [Google Scholar]
  24. Kessler D. S., Melton D. A. Vertebrate embryonic induction: mesodermal and neural patterning. Science. 1994 Oct 28;266(5185):596–604. doi: 10.1126/science.7939714. [DOI] [PubMed] [Google Scholar]
  25. Kingsley D. M. What do BMPs do in mammals? Clues from the mouse short-ear mutation. Trends Genet. 1994 Jan;10(1):16–21. doi: 10.1016/0168-9525(94)90014-0. [DOI] [PubMed] [Google Scholar]
  26. Laiho M., Weis M. B., Massagué J. Concomitant loss of transforming growth factor (TGF)-beta receptor types I and II in TGF-beta-resistant cell mutants implicates both receptor types in signal transduction. J Biol Chem. 1990 Oct 25;265(30):18518–18524. [PubMed] [Google Scholar]
  27. Letsou A., Arora K., Wrana J. L., Simin K., Twombly V., Jamal J., Staehling-Hampton K., Hoffmann F. M., Gelbart W. M., Massagué J. Drosophila Dpp signaling is mediated by the punt gene product: a dual ligand-binding type II receptor of the TGF beta receptor family. Cell. 1995 Mar 24;80(6):899–908. doi: 10.1016/0092-8674(95)90293-7. [DOI] [PubMed] [Google Scholar]
  28. Liu F., Ventura F., Doody J., Massagué J. Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol Cell Biol. 1995 Jul;15(7):3479–3486. doi: 10.1128/mcb.15.7.3479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mansour S. J., Matten W. T., Hermann A. S., Candia J. M., Rong S., Fukasawa K., Vande Woude G. F., Ahn N. G. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science. 1994 Aug 12;265(5174):966–970. doi: 10.1126/science.8052857. [DOI] [PubMed] [Google Scholar]
  30. Massagué J., Attisano L., Wrana J. L. The TGF-beta family and its composite receptors. Trends Cell Biol. 1994 May;4(5):172–178. doi: 10.1016/0962-8924(94)90202-x. [DOI] [PubMed] [Google Scholar]
  31. Mathews L. S., Vale W. W. Characterization of type II activin receptors. Binding, processing, and phosphorylation. J Biol Chem. 1993 Sep 5;268(25):19013–19018. [PubMed] [Google Scholar]
  32. Mathews L. S., Vale W. W. Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell. 1991 Jun 14;65(6):973–982. doi: 10.1016/0092-8674(91)90549-e. [DOI] [PubMed] [Google Scholar]
  33. Mathews L. S., Vale W. W., Kintner C. R. Cloning of a second type of activin receptor and functional characterization in Xenopus embryos. Science. 1992 Mar 27;255(5052):1702–1705. doi: 10.1126/science.1313188. [DOI] [PubMed] [Google Scholar]
  34. Matsuzaki K., Xu J., Wang F., McKeehan W. L., Krummen L., Kan M. A widely expressed transmembrane serine/threonine kinase that does not bind activin, inhibin, transforming growth factor beta, or bone morphogenic factor. J Biol Chem. 1993 Jun 15;268(17):12719–12723. [PubMed] [Google Scholar]
  35. McCarthy S. A., Bicknell R. Inhibition of vascular endothelial cell growth by activin-A. J Biol Chem. 1993 Nov 5;268(31):23066–23071. [PubMed] [Google Scholar]
  36. Mitrani E., Ziv T., Thomsen G., Shimoni Y., Melton D. A., Bril A. Activin can induce the formation of axial structures and is expressed in the hypoblast of the chick. Cell. 1990 Nov 2;63(3):495–501. doi: 10.1016/0092-8674(90)90446-l. [DOI] [PubMed] [Google Scholar]
  37. Miyazono K., Ten Dijke P., Ichijo H., Heldin C. H. Receptors for transforming growth factor-beta. Adv Immunol. 1994;55:181–220. [PubMed] [Google Scholar]
  38. Ogawa Y., Schmidt D. K., Nathan R. M., Armstrong R. M., Miller K. L., Sawamura S. J., Ziman J. M., Erickson K. L., de Leon E. R., Rosen D. M. Bovine bone activin enhances bone morphogenetic protein-induced ectopic bone formation. J Biol Chem. 1992 Jul 15;267(20):14233–14237. [PubMed] [Google Scholar]
  39. Padgett R. W., St Johnston R. D., Gelbart W. M. A transcript from a Drosophila pattern gene predicts a protein homologous to the transforming growth factor-beta family. Nature. 1987 Jan 1;325(6099):81–84. doi: 10.1038/325081a0. [DOI] [PubMed] [Google Scholar]
  40. Pagès G., Brunet A., L'Allemain G., Pouysségur J. Constitutive mutant and putative regulatory serine phosphorylation site of mammalian MAP kinase kinase (MEK1). EMBO J. 1994 Jul 1;13(13):3003–3010. doi: 10.1002/j.1460-2075.1994.tb06599.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Panganiban G. E., Reuter R., Scott M. P., Hoffmann F. M. A Drosophila growth factor homolog, decapentaplegic, regulates homeotic gene expression within and across germ layers during midgut morphogenesis. Development. 1990 Dec;110(4):1041–1050. doi: 10.1242/dev.110.4.1041. [DOI] [PubMed] [Google Scholar]
  42. Penton A., Chen Y., Staehling-Hampton K., Wrana J. L., Attisano L., Szidonya J., Cassill J. A., Massagué J., Hoffmann F. M. Identification of two bone morphogenetic protein type I receptors in Drosophila and evidence that Brk25D is a decapentaplegic receptor. Cell. 1994 Jul 29;78(2):239–250. doi: 10.1016/0092-8674(94)90294-1. [DOI] [PubMed] [Google Scholar]
  43. Petraglia F., Vaughan J., Vale W. Inhibin and activin modulate the release of gonadotropin-releasing hormone, human chorionic gonadotropin, and progesterone from cultured human placental cells. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5114–5117. doi: 10.1073/pnas.86.13.5114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Ruberte E., Marty T., Nellen D., Affolter M., Basler K. An absolute requirement for both the type II and type I receptors, punt and thick veins, for dpp signaling in vivo. Cell. 1995 Mar 24;80(6):889–897. doi: 10.1016/0092-8674(95)90292-9. [DOI] [PubMed] [Google Scholar]
  45. Smith J. C. Mesoderm-inducing factors in early vertebrate development. EMBO J. 1993 Dec;12(12):4463–4470. doi: 10.1002/j.1460-2075.1993.tb06135.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Taylor S. S., Radzio-Andzelm E. Three protein kinase structures define a common motif. Structure. 1994 May 15;2(5):345–355. doi: 10.1016/s0969-2126(00)00036-8. [DOI] [PubMed] [Google Scholar]
  47. Tsuchida K., Mathews L. S., Vale W. W. Cloning and characterization of a transmembrane serine kinase that acts as an activin type I receptor. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11242–11246. doi: 10.1073/pnas.90.23.11242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Ullrich A., Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990 Apr 20;61(2):203–212. doi: 10.1016/0092-8674(90)90801-k. [DOI] [PubMed] [Google Scholar]
  49. Ventura F., Doody J., Liu F., Wrana J. L., Massagué J. Reconstitution and transphosphorylation of TGF-beta receptor complexes. EMBO J. 1994 Dec 1;13(23):5581–5589. doi: 10.1002/j.1460-2075.1994.tb06895.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Vivien D., Attisano L., Wrana J. L., Massagué J. Signaling activity of homologous and heterologous transforming growth factor-beta receptor kinase complexes. J Biol Chem. 1995 Mar 31;270(13):7134–7141. doi: 10.1074/jbc.270.13.7134. [DOI] [PubMed] [Google Scholar]
  51. Wharton K. A., Ray R. P., Gelbart W. M. An activity gradient of decapentaplegic is necessary for the specification of dorsal pattern elements in the Drosophila embryo. Development. 1993 Feb;117(2):807–822. doi: 10.1242/dev.117.2.807. [DOI] [PubMed] [Google Scholar]
  52. Wieser R., Wrana J. L., Massagué J. GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J. 1995 May 15;14(10):2199–2208. doi: 10.1002/j.1460-2075.1995.tb07214.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Wilson I. A., Niman H. L., Houghten R. A., Cherenson A. R., Connolly M. L., Lerner R. A. The structure of an antigenic determinant in a protein. Cell. 1984 Jul;37(3):767–778. doi: 10.1016/0092-8674(84)90412-4. [DOI] [PubMed] [Google Scholar]
  54. Wrana J. L., Attisano L., Cárcamo J., Zentella A., Doody J., Laiho M., Wang X. F., Massagué J. TGF beta signals through a heteromeric protein kinase receptor complex. Cell. 1992 Dec 11;71(6):1003–1014. doi: 10.1016/0092-8674(92)90395-s. [DOI] [PubMed] [Google Scholar]
  55. Wrana J. L., Attisano L., Wieser R., Ventura F., Massagué J. Mechanism of activation of the TGF-beta receptor. Nature. 1994 Aug 4;370(6488):341–347. doi: 10.1038/370341a0. [DOI] [PubMed] [Google Scholar]
  56. Wrana J. L., Tran H., Attisano L., Arora K., Childs S. R., Massagué J., O'Connor M. B. Two distinct transmembrane serine/threonine kinases from Drosophila melanogaster form an activin receptor complex. Mol Cell Biol. 1994 Feb;14(2):944–950. doi: 10.1128/mcb.14.2.944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Yamashita H., ten Dijke P., Huylebroeck D., Sampath T. K., Andries M., Smith J. C., Heldin C. H., Miyazono K. Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects. J Cell Biol. 1995 Jul;130(1):217–226. doi: 10.1083/jcb.130.1.217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Yasuda H., Mine T., Shibata H., Eto Y., Hasegawa Y., Takeuchi T., Asano S., Kojima I. Activin A: an autocrine inhibitor of initiation of DNA synthesis in rat hepatocytes. J Clin Invest. 1993 Sep;92(3):1491–1496. doi: 10.1172/JCI116727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. ten Dijke P., Yamashita H., Ichijo H., Franzén P., Laiho M., Miyazono K., Heldin C. H. Characterization of type I receptors for transforming growth factor-beta and activin. Science. 1994 Apr 1;264(5155):101–104. doi: 10.1126/science.8140412. [DOI] [PubMed] [Google Scholar]

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