Structure and function of a new STAT-induced STAT inhibitor

Abstract

The signalling pathway that comprises JAK kinases and STAT proteins (for signal transducer and activator of transcription) is important for relaying signals from various cytokines outside the cell to the inside. The feedback mechanism responsible for switching off the cytokine signal has not been elucidated. We now report the cloning and characterization of an inhibitor of STAT activation which we name SSI-1 (for STAT-induced STAT inhibitor-1). We found that SSI-1 messenger RNA was induced by the cytokines interleukins 4 and 6 (IL-4, IL-6), leukaemia-inhibitory factor (LIF), and granulocyte colony-stimulating factor (G-CSF). Stimulation by IL-6 or LIF of murine myeloid leukaemia cells (M1 cells) induced SSI-1 mRNA expression which was blocked by transfection of a dominant-negative mutant of Stat3, indicating that the SSI-1 gene is a target of Stat3. Forced overexpression of SSI-1 complementary DNA interfered with IL-6- and LIF-mediated apoptosis and macrophage differentiation of M1 cells, as well as IL-6 induced tyrosine-phosphorylation of a receptor glycoprotein component, gp130, and of Stat3. When SSI-1 is overexpressed in COS7 cells, it can associate with the kinases Jak2 and Tyk2. These findings indicate that SSI-1 is responsible for negative-feedback regulation of the JAK-STAT pathway induced by cytokine stimulation.

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).…”

LIF-Induced STAT3 Signaling in Murine versus Human Embryonal Carcinoma (EC) Cells

“…Specifically, SOCS-1 and -3 are implicated in the downregulation of the IL-6-induced activation of STAT3 [19 -22]. Moreover, SOCS-1 and SOCS-3 can quickly be upregulated by IL-6 [17].…”