Transmembrane signaling by the interleukin-2 receptor: Progress and conundrums

Gordon B. Mills, Rosemarie Schmandt, Spencer Gibson, Bernadine Leung, Mary Hill, Chris May, Yu Fang Shi, Donald R. Branch, Laszlo Radvanyi, Kenneth E. Truitt, John Imboden

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Activation of the multicomponent interleukin-2 receptor (IL-2R) complex leads to a rapid increase in tyrosine phosphorylation of a number of cellular proteins including the IL-2Rβ and IL-2Rγ chains of the IL-2R and the RAF-1 serine threonine kinase. In addition, phosphatidylinositol 3-kinase (PI-3K) protein and activity can be immunoprecipitated with anti-phosphotyrosine and anti-IL-2Rβ antibodies from IL-2-activated but not resting T lymphocytes. We have demonstrated that the SH2 (SRC homology 2) domains of the 85 kDa subunit of PI-3K are sufficient to mediate binding of the PI-3K complex to tyrosine phosphorylated, but not non-phosphorylated IL-2Rβ, suggesting that tyrosine phosphorylation is an integral component of the activation of PI-3K by the IL-2R. Since none of the members of the IL-2R complex contains an intrinsic tyrosine kinase domain, IL-2-induced tyrosine phosphorylation must be the consequence of activation of intracellular tyrosine kinases. SRC family members including lck, lyn and fyn have been demonstrated to associate with IL-2Rβ through binding of the kinase domain to the acidic domain of IL-2Rβ. However, we have demonstrated that the serine rich (SD) region of the cytosolic domain of IL-2Rβ is also required for association of a tyrosine kinase with the IL-2R complex and that IL-2 can induce proliferation and tyrosine phosphorylation in cell lines which lack the known SRC family kinases expressed by T lymphocytes. Th us members of other kinase families besides SRC may also be involved in mediating IL-2 signal transduction. Biochemical studies and studies of cells expressing mutant IL-2 receptors indicate that IL-2-induced tyrosine kinase activation initiates a complex signaling cascade. The cascade includes SRC family kinase members such as lck, fyn, and lyn, activation of Raf-1 and PI-3K, and ras, and increased expression of the fos, fra-1, and jun protooncogenes. In addition, ligation of the IL-2R leads to rapid increases in myc expression and more delayed increases in the expression of the cdc2 and cdk2 kinases and the cyclins through a tyrosine phosphorylation independent pathway. Whether other biochemical processes initiated by IL-2R ligation, including activation of the MAP2, p70S6 and p90RSK serine threonine kinases, activation of NF-NB, and increased expression ofRaf-1, Pim-1, bcl-2, IL-2Rα and IL-2Rβ, are consequences of the IL-2-induced tyrosine kinase cascade remains to be determined. Whereas tyrosine kinase inhibitors prevent IL-2-induced proliferation in murine and human T cells, mutant IL-2Rβ chains which do not couple to the tyrosine kinase pathway retain the ability to induce proliferation in BAF pro-B cells albeit at slightly decreased levels. Thus, the role of the signaling cascade initiated by tyrosine phosphorylation in IL-2-induced proliferation remains controversial. In order to identify additional kinases which may be involved in IL-2 signal transduction, we utilized expression cloning and polymerase chain reaction to clone kinases from IL-2 responsive cells. We have identified two unique human kinases, TTK and EMT, which are induced by IL-2 in at least some T lymphocytes. It is not yet clear what role these kinases play in IL-2-induced cellular activation and proliferation.

Original languageEnglish (US)
Pages (from-to)345-364
Number of pages20
JournalSeminars in Immunology
Issue number5
StatePublished - Oct 1993
Externally publishedYes


  • Interleukin-2
  • Phosphatidylinositol-3 kinase
  • Transmembrane signaling
  • Tyrosine kinases
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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