A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosinephosphorylated interleukin 3 and erythropoietin receptors

Akihiko Yoshimura, T. Ohkubo, T. Kiguchi, N. A. Jenkins, D. J. Gilbert, N. G. Copeland, T. Hara, A. Miyajima

Research output: Contribution to journalArticle

580 Citations (Scopus)

Abstract

Cytokines manifest their function through alteration of gene expression. However, target genes for signals from cytokine receptors are largely unknown. We therefore searched for immediate-early cytokine-responsive genes and isolated a novel gene, CIS cytokine inducible SH2-containing protein) which is induced in hematopoietic cells by a subset of cytokines including interleukin 2 (IL2), IL3, granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO), but not by stem cell factor, granulocyte colony-stimulating factor and IL6. The CIS message encodes a polypeptide of 257 amino acids that contains an SH2 domain of 96 amino acids in the middle. To clarify the function of CIS in cytokine signal transduction, we expressed CIS in IL3-dependent hematopoietic cell lines under the control of a steroid-inducible promoter. The CIS product stably associated with the tyrosine-phosphorylated P chain of the IL3 receptor as well as the tyrosine-phosphorylated EPO receptor. Forced expression of CIS by steroid reduced the growth rate of these transformants, suggesting a negative role of CIS in signal transduction. CIS induction requires the membrane-proximal region of the cytoplasmic domain of the EPO receptor as well as that of the common β chain of the IL3, IL5 and GM-CSF receptor, whereas CIS binds to the receptor that is tyrosine phosphorylated by cytokine stimulation. Thus CIS appears to be a unique regulatory molecule for cytokine signal transduction.

Original languageEnglish
Pages (from-to)2816-2826
Number of pages11
JournalEMBO Journal
Volume14
Issue number12
Publication statusPublished - 1995
Externally publishedYes

    Fingerprint

Keywords

  • Cytokine
  • Cytokine receptor
  • Immediate-early gene
  • SH2 domain

ASJC Scopus subject areas

  • Cell Biology
  • Genetics

Cite this

Yoshimura, A., Ohkubo, T., Kiguchi, T., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Hara, T., & Miyajima, A. (1995). A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosinephosphorylated interleukin 3 and erythropoietin receptors. EMBO Journal, 14(12), 2816-2826.