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Delineation of the regions of interleukin-2 (IL-2) receptor beta chain important for association of Jak1 and Jak3. Jak1-independent functional recruitment of Jak3 to Il-2Rbeta.

Interleukin-2 (IL-2) induces heterodimerization of the IL-2 receptor beta (IL-2Rbeta) and gammac chains of its receptor and activates the Janus family tyrosine kinases, Jak1 and Jak3. Whereas Jak1 associates with IL-2Rbeta, Jak3 associates primarily with gammac but also with IL-2Rbeta. We analyzed four IL-2Rbeta mutations that diminish IL-2-induced proliferation and found that each also decreased IL-2-induced signal transducer and activator of transcription (STAT) activation. For this reason, and because the mutations were in the IL-2Rbeta membrane-proximal region, we investigated and found that each mutation diminished IL-2Rbeta association with both Jak1 and Jak3. This suggested that these Jaks might interact with the same region of IL-2Rbeta; however, certain IL-2Rbeta internal deletions and C-terminal truncations differentially affected the association of Jak1 and Jak3. Interestingly, just as Jak1-IL-2Rbeta association is Jak3-independent and functionally important, we show that Jak3-IL-2Rbeta association is Jak1-independent and implicate this association as being important for IL-2-induced Stat5 activation. Moreover, Jak1 and Jak3 could associate only in the presence of IL-2Rbeta, suggesting that these kinases can simultaneously bind to IL-2Rbeta. Thus, our data not only demonstrate that somewhat more distal as well as membrane-proximal cytoplasmic regions of a type I cytokine receptor are important for Jak kinase association but also suggest that two IL-2Rbeta-Jak kinase interactions are important for IL-2 signaling.

Pubmed ID: 9553136

Authors

  • Zhu MH
  • Berry JA
  • Russell SM
  • Leonard WJ

Journal

The Journal of biological chemistry

Publication Data

April 24, 1998

Associated Grants

None

Mesh Terms

  • Animals
  • COS Cells
  • DNA-Binding Proteins
  • HeLa Cells
  • Humans
  • Interleukin-2
  • Janus Kinase 1
  • Janus Kinase 3
  • Mice
  • Milk Proteins
  • Mutagenesis, Site-Directed
  • Protein Binding
  • Protein-Tyrosine Kinases
  • Receptors, Interleukin-2
  • STAT5 Transcription Factor
  • Signal Transduction
  • Trans-Activators