The IL-4 Receptor — Signaling Mechanisms

  • Achsah Keegan
  • Keats Nelms
  • William E. Paul
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 365)


Interleukin-4 (IL-4) is a multifunctional cytokine that is a member of the hematopoietin family1. Its structure consists of a bundle of four left handed α helices in which the first and second and the third and fourth helices are connected by long over hand loops2,3,4,5. IL-4 is produced by CD4+ T cells1 and by basophils and mast cells6 in response to receptor-mediated stimulation. It mediates its functions by binding to high affinity receptors expressed on a wide range of hematopoeitic and non-hematopoietic cell types7. The molecule defined as the IL-4 receptor (IL-4R) possesses an extracellular domain that is a member of the hematopoeitin-receptor family8. Its cytosolic domain is ~500 amino acids in length and lacks both endogenous tyrosine kinase and nucleotide-binding motifs9. The IL-4R does possess two acid rich regions and sequences homologous to the Box 1 region defined for the gp130 component of the IL-6 receptor10.


Tyrosine Phosphorylation Cytosolic Domain Fourth Helix Receptor Gamma Chain Acid Rich Region 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    W.E. Paul, Interleukin-4: a prototypic immunoregulatory lymphokine, Blood. 77:1859 (1991).PubMedGoogle Scholar
  2. 2.
    R. Powers, D.S. Garrett, C.J. March, E.A. Frieden, A.M. Gronenborn, and G.M. Clore, The high-resolution, three-dimensional solution structure of human interleukin-4 determined by multidimensional heteronuclear magnetic resonance spectroscopy, Biochemistry. 32:6744 (1993).PubMedCrossRefGoogle Scholar
  3. 3.
    M.R. Walter, W.J. Cook, B.G. Zhao, R.J. Cameron, S.E. Ealick, et al., Crystal structure of recombinant human interleukin-4, J Biol Chem. 267:20371 (1992).PubMedGoogle Scholar
  4. 4.
    A. Wlodaver, A. Pavlovsky, and A. Gustchina, Crystal structure of human recombinant interleukin-4 at 2.25 A resolution, Febs Lett. 309:59 (1992).PubMedCrossRefGoogle Scholar
  5. 5.
    L. J. Smith, C. Redfield, J. Boyd, G.M. Lawrence, R.G. Edwards, R.A. Smith, and C.M. Dobson, Human interleukin 4. The solution structure of a four-helix bundle protein, J Mol Biol. 224:899 (1992).PubMedCrossRefGoogle Scholar
  6. 6.
    W.E. Paul, R.A. Seder, and M. Plaut, Lymphokine and cytokine production by Fc epsilon RI+ cells, Adv Immunol. 53:1 (1993).PubMedCrossRefGoogle Scholar
  7. 7.
    J. Ohara and W.E. Paul, Receptors for B-cell stimulatory factor-1 expressed on cells of haematopoietic lineage, Nature, 325:537 (1987).PubMedCrossRefGoogle Scholar
  8. 8.
    J.F. Bazan, Haemopoietic receptors and helical cytokines, Immunol Today. 11:350 (1990).PubMedCrossRefGoogle Scholar
  9. 9.
    B. Mosley, M.P. Beckmann, C.J. March, R.L. Idzerda, S.D. Gimpel, et al., The murine interleukin-4 receptor: molecular cloning and characterization of secreted and membrane bound forms, Cell. 59:335 (1989).PubMedCrossRefGoogle Scholar
  10. 10.
    M. Murakami, M. Narazaki, M. Hibi, H. Yawata, K. Yasukawa, M. Hamaguchi, T. Taga, and T. Kishimoto, Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family, Proc Natl Acad Sci USA. 88:11349 (1991).PubMedCrossRefGoogle Scholar
  11. 11.
    B.C. Cunningham, M. Ultsch, V.A. De, M.G. Mulkerrin, K.R. Clauser, and J.A. Wells, Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule, Science. 254:821 (1991).PubMedCrossRefGoogle Scholar
  12. 12.
    J.L. Boulay and W.E. Paul, The interleukin-4-related lymphokines and their binding to hematopoietin receptors, J Biol Chem. 267:20525 (1992).PubMedGoogle Scholar
  13. 13.
    S.M. Russell, A.D. Keegan, N. Harada, Y. Nakamura, M. Noguchi, et al., Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor, Science. 262:1880 (1993).PubMedCrossRefGoogle Scholar
  14. 14.
    M. Kondo, T. Takeshita, N. Ishii, M. Nakamura, S. Watanabe, K. Arai, and K. Sugamura, Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4, Science. 262:1874 (1993).PubMedCrossRefGoogle Scholar
  15. 15.
    A.O. Morla, J. Schreurs, A. Miyajima, and J.Y. Wang, Hematopoietic growth factors activate the tyrosine phosphorylation of distinct sets of proteins in interleukin-3-dependent murine cell lines, Mol Cell Biol. 8:2214 (1988).PubMedGoogle Scholar
  16. 16.
    R.J. Isfort and J.N. Ihle, Multiple hematopoietic growth factors signal through tyrosine phosphorylation, Growth Factors. 2:213 (1990).PubMedCrossRefGoogle Scholar
  17. 17.
    L.M. Wang, A.D. Keegan, W.E. Paul, M.A. Heidaran, J.S. Gutkind, and J.H. Pierce, IL-4 activates a distinct signal transduction cascade from IL-3 in factor-dependent myeloid cells, EMBO J. 11:4899 (1992).PubMedGoogle Scholar
  18. 18.
    L.M. Wang, A.D. Keegan, W. Li, G.E. Lienhard, S. Pacini, et al., Common elements in interleukin 4 and insulin signaling pathways in factor-dependent hematopoietic cells, Proc Natl Acad Sci USA. 90:4032 (1993).PubMedCrossRefGoogle Scholar
  19. 19.
    M.F. White and C.R. Kahn, The insulin signaling system, J Biol Chem 269:1 (1994).PubMedGoogle Scholar
  20. 20.
    X.J. Sun, P. Rothenberg, C.R. Kahn, J.M. Backer, E. Araki, P.A. Wilden, D.A. Cahill, B.J. Goldstein, and M.F. White, Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein, Nature, 352:73 (1991).PubMedCrossRefGoogle Scholar
  21. 21.
    L.M. Wang, M.J. Myers, X.J. Sun, S.A. Aaronson, M. White, and J.H. Pierce, IRS-1: essential for insulin-and IL-4-stimulated mitogenesis in hematopoietic cells, Science. 261:1591(1993).PubMedCrossRefGoogle Scholar
  22. 22.
    A.D. Keegan, K. Nelms, M.F. White, L.-M. Wang, J.H. Pierce, and W.E. Paul, A region of the interleukin-4 receptor containing a motif found in the insulin receptor is important for IL-4 mediated IRS-1 phosphorylation and proliferation, Cell. 76:in press (1994).Google Scholar
  23. 23.
    M.F. White, J.N. Livingston, J.M. Backer, V. Lauris, T.J. Dull, A. Ullrich, and C.R. Kahn, Mutation of the insulin receptor at tyrosine 960 inhibits signal transmission but does not affect its tyrosine kinase activity, Cell 54:641 (1988).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Achsah Keegan
    • 1
  • Keats Nelms
    • 1
  • William E. Paul
    • 1
  1. 1.Laboratory of ImmunologyNational Institute of Allergy and Infectious DiseasesBethesdaUSA

Personalised recommendations