Trends in Biochemical Sciences
ReviewNegative regulation of cytokine signaling: STAT-induced STAT inhibitor
Section snippets
Mechanisms of negative regulation of cytokines
The effects of cytokines are transient. Thus, regulatory mechanisms must exist to switch off signal transmission after stimulation of cytokines. However, little is known about these negative regulatory mechanisms. Some negative regulation occurs by simple competition for cytokine binding by soluble forms of cytokine receptors, generated by proteolytic cleavage or by alternative mRNA splicing. Another common mechanism used by cells to prevent continuous signaling is endocytosis of receptors.
SSI-1 (STAT-induced STAT inhibitor-1)
In 1997, a protein was isolated that becomes induced after stimulation by cytokines such as IL-6 and inhibits cytokine signal transduction by binding to JAK (Fig. 1b). The protein is variously known as SSI-1 (Ref. 12), suppressor of cytokine signaling 1 (SOCS-1; Ref. 13) or Janus kinase binding protein (JAB; Ref. 14). SSI-1 mRNA is expressed predominantly in lymphoid tissues, including the thymus gland and spleen, as well as in the lungs and testis. In M1, CT4S and NFS60 cell lines, SSI-1 mRNA
SSI family
Eight SSI-1-related proteins are now known (Fig. 2a; 19, 20, 21). All of the proteins have a central SH2 domain and a highly conserved domain (the SC motif) at the C-terminus, which is known as SOCS box or the CH domain. The other proteins in the SSI family, like SSI-1, might be involved in cytokine signaling but very little is yet known about them. Other related proteins (Fig. 2b) possess the SC motif but are not included in the SSI family because they lack the SH2 domain. Such proteins
The cytokine-inducible SH2 protein (CIS)
Cytokine-inducible SH2 protein (CIS) was first described in 1995. Its expression is induced by various cytokines (e.g. IL-2, IL-3, GM-CSF and EPO) and it possesses an SH2 domain22. The expression pattern of CIS extends over a wider range of organs than that of SSI-1. The mRNAs of both CIS and SSI-1 are induced by IL-6 stimulation of mouse liver, and expression of both SSI-1 and CIS reaches a peak after 20–40 minutes. However, SSI-1 expression returns to baseline levels 4–8 hours later, whereas
SSI-3
Although expression of SSI-3 (also known as CIS3 or SOCS-3) differs from that of SSI-1, the functions of these two inhibitors are similar in many respects. SSI-3 is most strongly expressed in the heart, placenta, skeletal muscles and peripheral lymphocytes. Various cytokines, including IL-2, IL-3, IL-4, G-CSF and EPO, induce SSI-3 expression in different cell lines. When SSI-3 is overexpressed in M1 cells, IL-6 and LIF can no longer inhibit growth or induce apoptosis, and activation of STAT3 is
Mutational analyses of SSI family proteins
Mutational analyses of the SSI-1 protein revealed that at least the SH-2 domain and the 24 amino acid residues (52–76) that precede it are essential for the inhibition of JAK activity by SSI-1. SSI-1 associates with JAK via its SH2 domain26 and has been shown to bind specifically to a phosphopeptide of JAK2 containing a phosphorylated Y1007 (Ref. 27). This tyrosine residue (Y1007) is located in the activation loop of JAK2 and is autophosphorylated by JAK itself; phosphorylation of this residue
SSI-1 knockout mouse
SSI-1 deficient mice were prepared to elucidate the physiological roles of SSI-1 (Fig. 3; 33, 34). SSI-1 (−/−) mice appear normal at birth but a body weight loss of about 40% compared with the normal animal is observed from postnatal day nine and all the animals die within three weeks. When the thymus cells of the ten-day-old mice were stimulated with α-CD3 and IL-4, phosphorylation of STAT6 persisted for as long as three hours after stimulation, whereas the phenomenon was transient in SSI-1
Future studies of the SSI family
No report has yet linked the SSI family to the pathology of any disease. However, the importance of negative feedback of hormones in the endocrine system suggests that the function of the SSI family in the regulation of cytokine functions is extremely important. Although activation of STAT by oncogenes such as v-abl and v-src (35, 36), and permanent activation of JAK and STAT in leukemic cells have been cited as examples showing the relationship between cytokine signaling and cancer37, 38, 39,
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