Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1993 Dec;13(12):7239–7247. doi: 10.1128/mcb.13.12.7239

Signaling activity of transforming growth factor beta type II receptors lacking specific domains in the cytoplasmic region.

R Wieser 1, L Attisano 1, J L Wrana 1, J Massagué 1
PMCID: PMC364794  PMID: 8246946

Abstract

The transforming growth factor beta (TGF-beta) type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that contains two inserts in the kinase region and a serine/threonine-rich C-terminal extension. T beta R-II is required for TGF-beta binding to the type I receptor, with which it forms a heteromeric receptor complex, and its kinase activity is required for signaling by this complex. We investigated the role of various cytoplasmic regions in T beta R-II by altering or deleting these regions and determining the signaling activity of the resulting products in cell lines made resistant to TGF-beta by inactivation of the endogenous T beta R-II. TGF-beta binding to receptor I and responsiveness to TGF-beta in these cells can be restored by transfection of wild-type T beta R-II. Using this system, we show that the kinase insert 1 and the C-terminal tail of T beta R-II, in contrast to the corresponding regions in most tyrosine kinase receptors, are not essential to specify ligand-induced responses. Insert 2 is necessary to support the catalytic activity of the receptor kinase, and its deletion yields a receptor that is unable to mediate any of the responses tested. However, substitution of this insert with insert 2 from the activin receptor, ActR-IIB, does not diminish the ability of T beta R-II to elicit these responses. A truncated T beta R-II lacking the cytoplasmic domain still binds TGF-beta, supports ligand binding to receptor I, and forms a complex with this receptor. However, TGF-beta binding to receptor I facilitated by this truncated T beta R-II fails to inhibit cell proliferation, activate extracellular matrix protein production, or activate transcription from a promoter containing TGF-beta-responsive elements. We conclude that the transcriptional and antiproliferative responses to TGF-beta require both components of a heteromeric receptor complex that differs from tyrosine kinase receptors in its mode of signaling.

Full text

PDF
7240

Images in this article

7242Image
on p.7242
7242Image
on p.7242
7243Image
on p.7243
7244Image
on p.7244
7245Image
on p.7245

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. 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]
  2. Boyd F. T., Massagué J. Transforming growth factor-beta inhibition of epithelial cell proliferation linked to the expression of a 53-kDa membrane receptor. J Biol Chem. 1989 Feb 5;264(4):2272–2278. [PubMed] [Google Scholar]
  3. Brand T., MacLellan W. R., Schneider M. D. A dominant-negative receptor for type beta transforming growth factors created by deletion of the kinase domain. J Biol Chem. 1993 Jun 5;268(16):11500–11503. [PubMed] [Google Scholar]
  4. Cheifetz S., Weatherbee J. A., Tsang M. L., Anderson J. K., Mole J. E., Lucas R., Massagué J. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell. 1987 Feb 13;48(3):409–415. doi: 10.1016/0092-8674(87)90192-9. [DOI] [PubMed] [Google Scholar]
  5. Chen R. H., Ebner R., Derynck R. Inactivation of the type II receptor reveals two receptor pathways for the diverse TGF-beta activities. Science. 1993 May 28;260(5112):1335–1338. doi: 10.1126/science.8388126. [DOI] [PubMed] [Google Scholar]
  6. Ebner R., Chen R. H., Shum L., Lawler S., Zioncheck T. F., Lee A., Lopez A. R., Derynck R. Cloning of a type I TGF-beta receptor and its effect on TGF-beta binding to the type II receptor. Science. 1993 May 28;260(5112):1344–1348. doi: 10.1126/science.8388127. [DOI] [PubMed] [Google Scholar]
  7. Georgi L. L., Albert P. S., Riddle D. L. daf-1, a C. elegans gene controlling dauer larva development, encodes a novel receptor protein kinase. Cell. 1990 May 18;61(4):635–645. doi: 10.1016/0092-8674(90)90475-t. [DOI] [PubMed] [Google Scholar]
  8. Hanks S. K., Quinn A. M., Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988 Jul 1;241(4861):42–52. doi: 10.1126/science.3291115. [DOI] [PubMed] [Google Scholar]
  9. Ignotz R. A., Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986 Mar 25;261(9):4337–4345. [PubMed] [Google Scholar]
  10. Laiho M., Saksela O., Keski-Oja J. Transforming growth factor-beta induction of type-1 plasminogen activator inhibitor. Pericellular deposition and sensitivity to exogenous urokinase. J Biol Chem. 1987 Dec 25;262(36):17467–17474. [PubMed] [Google Scholar]
  11. 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]
  12. Lin H. Y., Lodish H. F. Receptors for the TGF-beta superfamily: multiple polypeptides and serine/threonine kinases. Trends Cell Biol. 1993 Jan;3(1):14–19. doi: 10.1016/0962-8924(93)90195-7. [DOI] [PubMed] [Google Scholar]
  13. Lin H. Y., Wang X. F., Ng-Eaton E., Weinberg R. A., Lodish H. F. Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase. Cell. 1992 Feb 21;68(4):775–785. doi: 10.1016/0092-8674(92)90152-3. [DOI] [PubMed] [Google Scholar]
  14. Lyons R. M., Moses H. L. Transforming growth factors and the regulation of cell proliferation. Eur J Biochem. 1990 Feb 14;187(3):467–473. doi: 10.1111/j.1432-1033.1990.tb15327.x. [DOI] [PubMed] [Google Scholar]
  15. Massagué J. Identification of receptors for type-beta transforming growth factor. Methods Enzymol. 1987;146:174–195. doi: 10.1016/s0076-6879(87)46020-5. [DOI] [PubMed] [Google Scholar]
  16. Massagué J. Receptors for the TGF-beta family. Cell. 1992 Jun 26;69(7):1067–1070. doi: 10.1016/0092-8674(92)90627-o. [DOI] [PubMed] [Google Scholar]
  17. Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6:597–641. doi: 10.1146/annurev.cb.06.110190.003121. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. 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]
  20. Meloche S., Pagès G., Pouysségur J. Functional expression and growth factor activation of an epitope-tagged p44 mitogen-activated protein kinase, p44mapk. Mol Biol Cell. 1992 Jan;3(1):63–71. doi: 10.1091/mbc.3.1.63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pawson T., Gish G. D. SH2 and SH3 domains: from structure to function. Cell. 1992 Oct 30;71(3):359–362. doi: 10.1016/0092-8674(92)90504-6. [DOI] [PubMed] [Google Scholar]
  22. Taylor S. S., Knighton D. R., Zheng J., Ten Eyck L. F., Sowadski J. M. Structural framework for the protein kinase family. Annu Rev Cell Biol. 1992;8:429–462. doi: 10.1146/annurev.cb.08.110192.002241. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Williams L. T. Signal transduction by the platelet-derived growth factor receptor. Science. 1989 Mar 24;243(4898):1564–1570. doi: 10.1126/science.2538922. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. 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]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES