CIS associates with the interleukin-2 receptor beta chain and inhibits interleukin-2-dependent signaling

J Biol Chem. 1999 Oct 15;274(42):30266-72. doi: 10.1074/jbc.274.42.30266.


CIS is a cytokine-induced SH2-containing protein that was originally cloned as an interleukin (IL)-3-inducible gene. CIS is known to associate with the IL-3 receptor beta chain and erythropoietin receptor and to inhibit signaling mediated by IL-3 and erythropoietin. We now demonstrate that CIS also interacts with the IL-2 receptor beta chain (IL-2Rbeta). This interaction requires the A region of IL-2Rbeta (residues 313-382), which also mediates the association of IL-2Rbeta with Lck and Jak3. Correspondingly, CIS inhibits functions associated with both of these kinases: Lck-mediated phosphorylation of IL-2Rbeta and IL-2-mediated activation of Stat5. Thus, we demonstrate that CIS can negatively control at least two independent IL-2 signaling pathways. Although a functional SH2 binding domain of CIS was not required for its interaction with IL-2Rbeta in vitro, its phosphotyrosine binding capability was essential for the inhibitory action of CIS. On this basis, we have generated a mutant form of CIS protein with an altered SH2 domain that acts as a dominant negative and should prove useful in further understanding CIS action.

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • DNA-Binding Proteins / metabolism
  • Humans
  • Immediate-Early Proteins / biosynthesis
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Interleukin-2 / antagonists & inhibitors*
  • Interleukin-2 / metabolism
  • Janus Kinase 1
  • Milk Proteins*
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Protein-Tyrosine Kinases / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, Interleukin-2 / metabolism*
  • STAT5 Transcription Factor
  • Signal Transduction*
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / metabolism
  • Tyrosine / metabolism
  • src Homology Domains


  • DNA-Binding Proteins
  • Immediate-Early Proteins
  • Interleukin-2
  • Milk Proteins
  • RNA, Messenger
  • Receptors, Interleukin-2
  • STAT5 Transcription Factor
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • cytokine inducible SH2-containing protein
  • Tyrosine
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • Janus Kinase 1