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.
Aman
M J
MJ
Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1674, USA.
Migone
T S
TS
Sasaki
A
A
Ascherman
D P
DP
Zhu
M h
Mh
Soldaini
E
E
Imada
K
K
Miyajima
A
A
Yoshimura
A
A
Leonard
W J
WJ
D000595:Amino Acid Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053613:Janus Kinase 1; D008894:Milk Proteins; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D007376:Interleukin-2; D053613:Janus Kinase 1; D008894:Milk Proteins; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014443:Tyrosine; C507904:JAK1 protein, human