The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation

The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation

^*Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, and ^†Joint Protein Structure Laboratory of The Valter and Eliza Hall Institute and Ludwig Institute for Cancer Research, P.O. Royal Melbourne Hospital, Victoria 3050, Australia; and ^‡Gryphon Sciences, 250 East Grand Avenue, South San Francisco, CA 94080

Contributed by Donald Metcalf

Abstract

The suppressors of cytokine signaling (SOCS) family of proteins act as intracellular inhibitors of several cytokine signal transduction pathways. Their expression is induced by cytokine activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and they act as a negative feedback loop by subsequently inhibiting the JAK/STAT pathway either by direct interaction with activated JAKs or with the receptors. These interactions are mediated at least in part by the SH2 domain of SOCS proteins but these proteins also contain a highly conserved C-terminal homology domain termed the SOCS box. Here we show that the SOCS box mediates interactions with elongins B and C, which in turn may couple SOCS proteins and their substrates to the proteasomal protein degradation pathway. Analogous to the family of F-box-containing proteins, it appears that the SOCS proteins may act as adaptor molecules that target activated cell signaling proteins to the protein degradation pathway.

Footnotes

↵ § To whom reprint requests should be addressed at: Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Victoria 3050, Australia. e-mail: nicola{at}wehi.edu.au.
ABBREVIATIONS:

ASB,

ankyrin-repeat-containing protein with a SOCS box;

CIS,

cytokine-inducible SH2-containing protein;

IL,

interleukin;

Jak,

Janus kinase;

LLnL,

N-acetyl-l-leucinyl-l-leucinyl-norleucinal;

PULC,

phosphoprotein-ubiquitin-ligase complex;

SOCS,

suppressors of cytokine signaling;

SSB,

SPRY domain-containing protein with a SOCS box;

UBL,

ubiquitin-like;

VHL,

von Hippel Lindau;

WSB,

WD-40-repeat-containing protein with a SOCS box;

GST,

glutathione S-transferase