A family of cytokine-inducible inhibitors of signalling

Abstract

Cytokines are secreted proteins that regulate important cellular responses such as proliferation and differentiation. Key events in cytokine signal transduction are well defined: cytokines induce receptor aggregation, leading to activation of members of the JAK family of cytoplasmic tyrosine kinases. In turn, members of the STAT family of transcription factors are phosphorylated, dimerize and increase the transcription of genes with STAT recognition sites in their promoters. Less is known of how cytokine signal transduction is switched off. We have cloned a complementary DNA encoding a protein SOCS-1, containing an SH2-domain, by its ability to inhibit the macrophage differentiation of M1 cells in response to interleukin-6. Expression of SOCS-1 inhibited both interleukin-6-induced receptor phosphorylation and STAT activation. We have also cloned two relatives of SOCS-1, named SOCS-2 and SOCS-3, which together with the previously described CIS form a new family of proteins. Transcription of all four SOCS genes is increased rapidly in response to interleukin-6, in vitro and in vivo, suggesting they may act in a classic negative feedback loop to regulate cytokine signal transduction.

The biology of Stat4 and Stat6

“…A recently identi®ed family of proteins, suppressor of cytokine signaling (SOCS or SSI or JAB), is believed to regulate the JAK/STAT pathway by interfering with the function of the JAK kinases (Endo et al, 1997;Naka et al, 1997;Starr et al, 1997). Overexpression of one family member, SOCS1, in a murine B cell line resulted in decreased Jak1 phosphorylation, decreased Stat6 phosphorylation and inhibition of IL-4 induced CD23 expression (Losman et al, 1999).…”

“…Overexpression of one family member, SOCS1, in a murine B cell line resulted in decreased Jak1 phosphorylation, decreased Stat6 phosphorylation and inhibition of IL-4 induced CD23 expression (Losman et al, 1999). SOCS mRNA is induced by the cytokines themselves and SOCS1 expression in particular can be induced by IL-4 in some cell types (Naka et al, 1997;Starr et al, 1997). This leads to a model where IL-4 signaling via Stat6 initially occurs unopposed but is subsequently dampened by a negative feedback mechanism through the IL-4/Stat6 dependent induction of SOCS1 expression.…”

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).…”

Thrombin induces expression of cytokine‐induced SH2 protein (CIS) in rat brain astrocytes: Involvement of phospholipase A2, cyclooxygenase, and lipoxygenase

“…Mouse CIS intracellular expression vector was a gift from Dr. R. Starr ( Walter Eliza Hall Institute for Medical Research, Victoria, Australia) (Starr et al, 1997).…”

“…The SOCS family consists of eight proteins: cytokine-induced SH2 protein (CIS) and SOCS1-SOCS7, which contain a central SH2 domain, a conserved Cterminus referred to as the SOCS box, and a unique N-terminus (Chen et al, 2000). SOCS proteins interact directly with JAKs and inhibit their catalytic activity (Starr et al, 1997;Endo et al, 1997;Naka et al, 1997;Sakamoto et al, 1998), or interact with phosphorylated tyrosine residues in the cytoplasmic domains of cytokine receptors Verdier et al, 1998;Okabe et al, 1999).…”