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

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 beta 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 beta 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.

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

“…The CIS (cytokine-inducible SH2-containing) protein is the prototype member of the CIS/SOCS/JAB/SSI family of proteins that are rapidly induced by a number of cytokines, including IL-2 (Yoshimura et al, 1995). So far, eight members of this family of proteins have been identi®ed (Hilton et al, 1998;Kovanen and Leonard, 1999).…”

Signalling by the oncogenic receptor tyrosine kinase Xmrk leads to activation of STAT5 in Xiphophorus melanoma

“…With this approach the genes cis (cytokine inducible SH2-containing protein; Yoshimura et al, 1995), pim-1 (Selten et al, 1986) and osm (oncostatin M; Zarling et al, 1986;Yoshimura et al, 1996) could be identi®ed as STAT5 speci®c target genes. In order to study the role of STAT5 in the signalling of the Xmrk kinase, we examined by RT ± PCR analysis if the expression of cis, pim-1 and osm is induced in BaF Hm cells upon HERmrk stimulation.…”

SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling

“…SOCS proteins negatively regulate signal transduction in a classical feedback loop (Yoshimura et al, 1995;Endo et al, 1997;Naka et al, 1997;Starr et al, 1997). The members of this protein family contain a central SH2 domain, as well as a C-terminal domain called SOCS-Box, which is required for proteasomal degradation of SOCS-binding partners (De Sepulveda et al, 2000;Frantsve et al, 2001;Kamizono et al, 2001;Rui et al, 2002;Ungureanu et al, 2002).…”