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

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, Humans, Immediate-Early Proteins, Interleukin-2, Janus Kinase 1, Milk Proteins, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, RNA, Messenger, Receptors, Interleukin-2, STAT5 Transcription Factor, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Trans-Activators, Tyrosine, src Homology Domains
J. Biol. Chem.
Date: Oct. 15, 1999
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