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

M. Javad Aman, Thi Sau Migone, Atsuo Sasaki, Dana P. Ascherman, Ming Hua Zhu, Elisabetta Soldaini, Kazunori Imada, Atsushi Miyajima, Akihiko Yoshimura, Warren J. Leonard

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

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 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 β chain (IL-2Rβ). This interaction requires the A region of IL-2Rβ (residues 313-382), which also mediates the association of IL-2Rβ with Lck and Jak3. Correspondingly, CIS inhibits functions associated with both of these kinases: Lck-mediated phosphorylation of IL-2Rβ 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-2Rβ 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.

Original languageEnglish
Pages (from-to)30266-30272
Number of pages7
JournalJournal of Biological Chemistry
Volume274
Issue number42
DOIs
Publication statusPublished - 1999 Oct 15
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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